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Sample records for cell memory responses

  1. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses.

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    Halim, Timotheus Y F; Hwang, You Yi; Scanlon, Seth T; Zaghouani, Habib; Garbi, Natalio; Fallon, Padraic G; McKenzie, Andrew N J

    2016-01-01

    Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens.

  2. Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

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    Moens, Leen; Kane, Alisa; Tangye, Stuart G

    2016-09-01

    Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these diverse responses of naïve and memory B cells is incompletely resolved. Here we investigated the nature of B-cell receptor (BCR) signaling in human splenic naïve, IgM(+) memory and isotype-switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and spleen tyrosine kinase) and propagation (B-cell linker, phospholipase Cγ2) signaling components in these different B-cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared with naïve cells. Although no differences were observed in the magnitude of Ca(2+) mobilization between subsets, IgM(+) memory B cells exhibited a more rapid Ca(2+) mobilization and a greater depletion of the Ca(2+) endoplasmic reticulum stores, while IgG(+) memory B cells had a prolonged Ca(2+) uptake. Collectively, our findings show that intrinsic signaling features of B-cell subsets contribute to the robust response of human memory B cells over naïve B cells. This has implications for our understanding of memory B-cell responses and provides a framework to modulate these responses in the setting of vaccination and immunopathologies, such as immunodeficiency and autoimmunity. PMID:27101923

  3. Regulation of germinal center responses, memory B cells and plasma cell formation-an update.

    Science.gov (United States)

    Corcoran, Lynn M; Tarlinton, David M

    2016-04-01

    Progress in understanding humoral immunity has been accelerated by the powerful experimental approaches of genetics, genomics and imaging. Excellent reviews of these advances appeared in 2015 in celebration of the 50th anniversary of the discovery of B cell and T cell lineages in the chicken. Here we provide a contemporary model of B cell differentiation, highlighting recent publications illuminating germinal center (GC), memory B cell and antibody-secreting plasma cell biology. The important contributions of CD4T cells to antibody responses have been thoroughly reviewed elsewhere.

  4. T Cell Responses: Naive to Memory and Everything in Between

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    Pennock, Nathan D.; White, Jason T.; Cross, Eric W.; Cheney, Elizabeth E.; Tamburini, Beth A.; Kedl, Ross M.

    2013-01-01

    The authors describe the actions that take place in T cells because of their amazing capacity to proliferate and adopt functional roles aimed at clearing a host of an infectious agent. There is a drastic decline in the T cell population once the primary response is over and the infection is terminated. What remains afterward is a population of T…

  5. Antigen modulation of the immune response. III. Evaluation of the hypothetical short-lived memory cell

    International Nuclear Information System (INIS)

    The putative short-lived memory cells, whose existence has been suggested by the results of secondary adoptive transfer experiments, were investigated. On the basis of the following evidences we have concluded that the short-lived memory cell is probably an artifact of the adoptive transfer technique: when immune thoracic duct lymphocytes, known to consist predominantly of long-lived memory cells, were transferred to irradiated recipients and challenged at various times after transfer, approximately 80 to 90 percent of the initial response was absent by Day 14 challenge; preirradiating adoptive recipients with increasing dose of x-irradiation tended to lengthen the observed half life of memory cells; single or multiple treatments of immune donors with 0.3 mg Vinblastin before transfer resulted in neither a depression of the initial secondary response nor an alteration in the rate of decline of the memory potential; reconstitution of irradiated hosts with normal spleen cells one day before transfer of memory cells and challenge resulted in inhibition of the adoptive secondary response; and the transfer of memory cells to antigen free intermediate hosts, in which they were allowed to reside for one day or fourteen days before transfer to irradiated recipients, resulted in only a slight decline in their capacity to respond. We propose that the rapid decline of memory potential in adoptive recipients challenged at various times after transfer is due to modulating effects by the hosts as it recovers from irradiation. These effects may be the result of cell crowding or the loss of irradiation-produced stimulatory factors. The relevance of these findings to adoptive transfer systems in general and the secondary response of intact animals is discussed

  6. ZBTB32 Restricts the Duration of Memory B Cell Recall Responses.

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    Jash, Arijita; Wang, Yinan; Weisel, Florian J; Scharer, Christopher D; Boss, Jeremy M; Shlomchik, Mark J; Bhattacharya, Deepta

    2016-08-15

    Memory B cell responses are more rapid and of greater magnitude than are primary Ab responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of Ab recall responses. ZBTB32 is highly expressed by mouse and human memory B cells but not by their naive counterparts. Zbtb32(-/-) mice mount normal primary Ab responses to T-dependent Ags. However, Zbtb32(-/-) memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32(-/-) secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32(-/-) secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of Ab recall responses. PMID:27357154

  7. NK Cell-Mediated Regulation of Protective Memory Responses against Intracellular Ehrlichial Pathogens.

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    Samar Habib

    Full Text Available Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis. We previously showed that natural killer (NK cells play a critical role in host defense against Ehrlichia during primary infection. However, the contribution of NK cells to the memory response against Ehrlichia remains elusive. Primary infection of C57BL/6 mice with Ehrlichia muris provides long-term protection against a second challenge with the highly virulent Ixodes ovatus Ehrlichia (IOE, which ordinarily causes fatal disease in naïve mice. Here, we show that the depletion of NK cells in E. muris-primed mice abrogates the protective memory response against IOE. Approximately, 80% of NK cell-depleted E. muris-primed mice succumbed to lethal IOE infection on days 8-10 after IOE infection, similar to naïve mice infected with the same dose of IOE. The lack of a recall response in NK cell-depleted mice correlated with an increased bacterial burden, extensive liver injury, decreased frequency of Ehrlichia-specific IFN-γ-producing memory CD4+ and CD8+ T-cells, and a low titer of Ehrlichia-specific antibodies. Intraperitoneal infection of mice with E. muris resulted in the production of IL-15, IL-12, and IFN-γ as well as an expansion of activated NKG2D+ NK cells. The adoptive transfer of purified E. muris-primed hepatic and splenic NK cells into Rag2-/-Il2rg-/- recipient mice provided protective immunity against challenge with E. muris. Together, these data suggest that E. muris-induced memory-like NK cells, which contribute to the protective, recall response against Ehrlichia.

  8. HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation

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    Wheatley, Adam K.; Kristensen, Anne B.; Lay, William N.; Kent, Stephen J.

    2016-01-01

    Infection with HIV drives significant alterations in B cell phenotype and function that can markedly influence antibody responses to immunisation. Anti-retroviral therapy (ART) can partially reverse many aspects of B cell dysregulation, however complete normalisation of vaccine responsiveness is not always observed. Here we examine the effects of underlying HIV infection upon humoral immunity to seasonal influenza vaccines. Serological and memory B cell responses were assessed in 26 HIV+ subjects receiving ART and 30 healthy controls immunised with the 2015 Southern Hemisphere trivalent inactivated influenza vaccine (IIV3). Frequencies and phenotypes of influenza hemagglutinin (HA)-specific B cells were assessed by flow cytometry using recombinant HA probes. Serum antibody was measured using hemagglutination inhibition assays. Serological responses to IIV3 were comparable between HIV+ and HIV− subjects. Likewise, the activation and expansion of memory B cell populations specific for vaccine-component influenza strains was observed in both cohorts, however peak frequencies were diminished in HIV+ subjects compared to uninfected controls. Lower circulating frequencies of memory B cells recognising vaccine-component and historical influenza strains were observed in HIV+ subjects at baseline, that were generally restored to levels comparable with HIV− controls post-vaccination. HIV infection is therefore associated with depletion of selected HA-specific memory B cell pools. PMID:27220898

  9. Acellular pertussis booster in adolescents induces Th1 and memory CD8+ T cell immune response.

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    Nikolaus Rieber

    Full Text Available In a number of countries, whole cell pertussis vaccines (wcP were replaced by acellular vaccines (aP due to an improved reactogenicity profile. Pertussis immunization leads to specific antibody production with the help of CD4(+ T cells. In earlier studies in infants and young children, wcP vaccines selectively induced a Th1 dominated immune response, whereas aP vaccines led to a Th2 biased response. To obtain data on Th1 or Th2 dominance of the immune response in adolescents receiving an aP booster immunization after a wcP or aP primary immunization, we analyzed the concentration of Th1 (IL-2, TNF-α, INF-γ and Th2 (IL-4, IL-5, IL-10 cytokines in supernatants of lymphocyte cultures specifically stimulated with pertussis antigens. We also investigated the presence of cytotoxic T cell responses against the facultative intracellular bacterium Bordetella pertussis by quantifying pertussis-specific CD8(+ T cell activation following the aP booster immunization. Here we show that the adolescent aP booster vaccination predominantly leads to a Th1 immune response based on IFNgamma secretion upon stimulation with pertussis antigen, irrespective of a prior whole cell or acellular primary vaccination. The vaccination also induces an increase in peripheral CD8(+CD69(+ activated pertussis-specific memory T cells four weeks after vaccination. The Th1 bias of this immune response could play a role for the decreased local reactogenicity of this adolescent aP booster immunization when compared to the preceding childhood acellular pertussis booster. Pertussis-specific CD8(+ memory T cells may contribute to protection against clinical pertussis.

  10. Human Memory CD4+ T Cell Immune Responses against Giardia lamblia.

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    Saghaug, Christina Skår; Sørnes, Steinar; Peirasmaki, Dimitra; Svärd, Staffan; Langeland, Nina; Hanevik, Kurt

    2016-01-01

    The intestinal protozoan parasite Giardia lamblia may cause severe prolonged diarrheal disease or pass unnoticed as an asymptomatic infection. T cells seem to play an important role in the immune response to Giardia infection, and memory responses may last years. Recently, TH17 responses have been found in three animal studies of Giardia infection. The aim of this study was to characterize the human CD4(+) T cell responses to Giardia. Peripheral blood mononuclear cells (PBMCs) were obtained from 21 returning travelers with recent or ongoing giardiasis and 12 low-risk healthy controls and stimulated in vitro with Giardia lamblia proteins. Production of tumor necrosis factor alpha (TNF-α), gamma interferon, interleukin-17A (IL-17A), IL-10, and IL-4 was measured in CD4(+) effector memory (EM) T cells after 24 h by flow cytometry. After 6 days of culture, activation and proliferation were measured by flow cytometry, while an array of inflammatory cytokine levels in supernatants were measured with multiplex assays. We found the number of IL-17A-producing CD4(+) EM T cells, as well as that of cells simultaneously producing both IL-17A and TNF-α, to be significantly elevated in the Giardia-exposed individuals after 24 h of antigen stimulation. In supernatants of PBMCs stimulated with Giardia antigens for 6 days, we found inflammation-associated cytokines, including 1L-17A, as well as CD4(+) T cell activation and proliferation, to be significantly elevated in the Giardia-exposed individuals. We conclude that symptomatic Giardia infection in humans induces a CD4(+) EM T cell response of which IL-17A production seems to be an important component. PMID:26376930

  11. Indoleamine 2,3-dioxygenase (IDO) activity during the primary immune response to influenza infection modifies the memory T cell response to influenza challenge.

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    Sage, Leo K; Fox, Julie M; Mellor, Andrew L; Tompkins, Stephen M; Tripp, Ralph A

    2014-04-01

    The generation of a heterosubtypic memory T cell response is important for cross-protective immunity against unrelated strains of influenza virus. One way to facilitate the generation of the memory T cell population is to control the activity of immune modulatory agents. The enzyme, indoleamine 2,3-dioxygenase (IDO), is upregulated during influenza infection by the interferon response where IDO activity depletes tryptophan required in T cell response. In this study, IDO activity was pharmacologically inhibited with 1-methyl-tryptophan (1MT) during the primary response to influenza virus infection and the effect on the memory T cell response was evaluated. 1MT treatment improved the memory T cell response to influenza virus challenge by increasing interferon gamma expression by CD4 and CD8 T cells, and numbers of lung virus-specific CD8+ T cells, and increased the Th1 response as well as modifying the immunodominance hierarchy to increase the number of subdominant epitope specific CD8+ T cells, a feature which may be linked to decreased regulatory T cell function. These changes also accompanied evidence of accelerated lung tissue repair upon virus challenge. These findings suggest that modulation of IDO activity could be exploited in influenza vaccine development to enhance memory T cell responses and reduce disease burden. PMID:24702331

  12. Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection.

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    Ng, Oi-Wing; Chia, Adeline; Tan, Anthony T; Jadi, Ramesh S; Leong, Hoe Nam; Bertoletti, Antonio; Tan, Yee-Joo

    2016-04-12

    Severe acute respiratory syndrome (SARS) is a highly contagious infectious disease which first emerged in late 2002, caused by a then novel human coronavirus, SARS coronavirus (SARS-CoV). The virus is believed to have originated from bats and transmitted to human through intermediate animals such as civet cats. The re-emergence of SARS-CoV remains a valid concern due to the continual persistence of zoonotic SARS-CoVs and SARS-like CoVs (SL-CoVs) in bat reservoirs. In this study, the screening for the presence of SARS-specific T cells in a cohort of three SARS-recovered individuals at 9 and 11 years post-infection was carried out, and all memory T cell responses detected target the SARS-CoV structural proteins. Two CD8(+) T cell responses targeting the SARS-CoV membrane (M) and nucleocapsid (N) proteins were characterized by determining their HLA restriction and minimal T cell epitope regions. Furthermore, these responses were found to persist up to 11 years post-infection. An absence of cross-reactivity of these CD8(+) T cell responses against the newly-emerged Middle East respiratory syndrome coronavirus (MERS-CoV) was also demonstrated. The knowledge of the persistence of SARS-specific celullar immunity targeting the viral structural proteins in SARS-recovered individuals is important in the design and development of SARS vaccines, which are currently unavailable. PMID:26954467

  13. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation

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    Weng, Nan-ping; Araki, Yasuto; Subedi, Kalpana

    2015-01-01

    How the immune system remembers a previous encounter with a pathogen and responds more efficiently to a subsequent encounter has been one of the central enigmas for immunologists for over a century. The identification of pathogen-specific memory lymphocytes that arise after an infection provided a cellular basis for immunological memory. But the molecular mechanisms of immunological memory remain only partially understood. The emerging evidence suggests that epigenetic changes have a key role in controlling the distinct transcriptional profiles of memory lymphocytes and thus in shaping their function. In this Review, we summarize the recent progress that has been made in assessing the differential gene expression and chromatin modifications in memory CD4+ and CD8+ T cells, and we present our current understanding of the molecular basis of memory T cell function. PMID:22421787

  14. Phenotypic and functional characterization of human memory T cell responses to Burkholderia pseudomallei.

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    Patcharaporn Tippayawat

    Full Text Available BACKGROUND: Infection with the Gram-negative bacterium Burkholderia pseudomallei is an important cause of community-acquired lethal sepsis in endemic regions in southeast Asia and northern Australia and is increasingly reported in other tropical areas. In animal models, production of interferon-gamma (IFN-gamma is critical for resistance, but in humans the characteristics of IFN-gamma production and the bacterial antigens that are recognized by the cell-mediated immune response have not been defined. METHODS: Peripheral blood from 133 healthy individuals who lived in the endemic area and had no history of melioidosis, 60 patients who had recovered from melioidosis, and 31 other patient control subjects were stimulated by whole bacteria or purified bacterial proteins in vitro, and IFN-gamma responses were analyzed by ELISPOT and flow cytometry. FINDINGS: B. pseudomallei was a potent activator of human peripheral blood NK cells for innate production of IFN-gamma. In addition, healthy individuals with serological evidence of exposure to B. pseudomallei and patients recovered from active melioidosis developed CD4(+ (and CD8(+ T cells that recognized whole bacteria and purified proteins LolC, OppA, and PotF, members of the B. pseudomallei ABC transporter family. This response was primarily mediated by terminally differentiated T cells of the effector-memory (T(EMRA phenotype and correlated with the titer of anti-B. pseudomallei antibodies in the serum. CONCLUSIONS: Individuals living in a melioidosis-endemic region show clear evidence of T cell priming for the ability to make IFN-gamma that correlates with their serological status. The ability to detect T cell responses to defined B. pseudomallei proteins in large numbers of individuals now provides the opportunity to screen candidate antigens for inclusion in protein or polysaccharide-conjugate subunit vaccines against this important but neglected disease.

  15. Memory-Like CD8+ T Cells Generated during Homeostatic Proliferation Defer to Antigen-Experienced Memory Cells1

    OpenAIRE

    Cheung, Kitty P.; Yang, Edward; Goldrath, Ananda W

    2009-01-01

    Naive T cells proliferate in response to lymphopenia and acquire the phenotypic and functional qualities of memory T cells, providing enhanced protection against infection. How well memory-like T cells generated during lymphopenia-induced homeostatic proliferation (HP)-memory differentiate into secondary memory cells and compete with Ag-experienced true-memory cells is unknown. We found that CD8+ HP-memory T cells generated robust responses upon infection and produced a secondary memory popul...

  16. Stiffness memory of EA.hy926 endothelial cells in response to chronic hyperglycemia

    OpenAIRE

    Targosz-Korecka, Marta; Brzezinka, Grzegorz D; Malek, Katarzyna E; Stȩpień, Ewa; Szymonski, Marek

    2013-01-01

    Background Glycemic memory of endothelial cells is an effect of long-lasting hyperglycemia and is a cause of various diabetics complications, that arises despite of the treatment targeted towards returning low glucose level in blood system. On the other hand, endothelial dysfunction, which is believed to be a main cause of cardiovascular complications, is exhibited in the changes of mechanical properties of cells. Although formation of the glycemic memory was widely investigated, its impact o...

  17. Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection.

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    Harari, Alexandre; Rizzardi, G Paolo; Ellefsen, Kim; Ciuffreda, Donatella; Champagne, Patrick; Bart, Pierre-Alexandre; Kaufmann, Daniel; Telenti, Amalio; Sahli, Roland; Tambussi, Giuseppe; Kaiser, Laurent; Lazzarin, Adriano; Perrin, Luc; Pantaleo, Giuseppe

    2002-08-15

    CD4 T-cell-specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1- and CMV-specific interferon-gamma-secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1-specific CD4 T-cell responses. A substantial proportion of CD4(+)CCR7(-) T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

  18. CCR5 plays a key role in the early memory CD8+ T cell response to respiratory virus infections

    OpenAIRE

    Kohlmeier, Jacob E.; Miller, Shannon C.; Smith, Joanna; Lu, Bao; Gerard, Craig; Cookenham, Tres; Roberts, Alan D.; Woodland, David L

    2008-01-01

    Innate recognition of invading pathogens in peripheral tissues results in the recruitment of circulating memory CD8+ T cells to sites of localized inflammation during the early phase of a recall response. However, the mechanisms that control the rapid recruitment of these cells to peripheral sites are poorly understood, particularly in relation to influenza and parainfluenza infections of the respiratory tract. In this study, we demonstrate a crucial role for CCR5 in the accelerated recruitme...

  19. Oral vaccination with lipid-formulated BCG induces a long-lived, multifunctional CD4(+ T cell memory immune response.

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    Lindsay R Ancelet

    Full Text Available Oral delivery of BCG in a lipid formulation (Liporale™-BCG targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4(+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4(+ T cell response, evident by the detection of effector CD4(+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4(+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4(+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4(+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines.

  20. Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans.

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    Stephen M Todryk

    Full Text Available BACKGROUND: Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against diverse pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria. Memory T cells reactive against thrombospondin-related adhesive protein (TRAP and circumsporozoite (CS protein, major vaccine candidate antigens, were measured, as were frequencies of CD4(+ CD25(high T cells, which may suppress immunity, and CD56(+ NK cells and gammadelta T cells, which may be effectors or may modulate immunity. METHODOLOGY AND PRINCIPAL FINDINGS: 112 healthy volunteers living in rural Kenya were entered in the study. Memory T cells reactive against TRAP and CS were measured using a cultured IFNgamma ELISPOT approach, whilst CD4(+ CD25(high T cells, CD56(+ NK cells, and gammadelta T cells were measured by flow cytometry. We found that T cell responses against TRAP were established early in life (<5 years in contrast to CS, and cultured ELISPOT memory T cell responses did not correlate with ex-vivo IFNgamma ELISPOT effector responses. Data was examined for associations with risk of clinical malaria for a period of 300 days. Multivariate logistic analysis incorporating age and CS response showed that cultured memory T cell responses against TRAP were associated with a significantly reduced incidence of malaria (p = 0.028. This was not seen for CS responses. Higher numbers of CD4(+ CD25(high T cells, potentially regulatory T cells, were associated with a significantly increased risk of clinical malaria (p = 0.039. CONCLUSIONS: These data demonstrate a role for central memory T cells in natural malarial immunity and support current vaccination strategies aimed at inducing durable protective T cell responses against the TRAP antigen. They also

  1. Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation.

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    Li, Jasmine; Hardy, Kristine; Phetsouphanh, Chan; Tu, Wen Juan; Sutcliffe, Elissa L; McCuaig, Robert; Sutton, Christopher R; Zafar, Anjum; Munier, C Mee Ling; Zaunders, John J; Xu, Yin; Theodoratos, Angelo; Tan, Abel; Lim, Pek Siew; Knaute, Tobias; Masch, Antonia; Zerweck, Johannes; Brezar, Vedran; Milburn, Peter J; Dunn, Jenny; Casarotto, Marco G; Turner, Stephen J; Seddiki, Nabila; Kelleher, Anthony D; Rao, Sudha

    2016-06-15

    Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4(+) T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4(+) T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells. PMID:27149922

  2. Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation

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    Li, Jasmine; Hardy, Kristine; Phetsouphanh, Chan; Tu, Wen Juan; Sutcliffe, Elissa L.; McCuaig, Robert; Sutton, Christopher R.; Zafar, Anjum; Munier, C. Mee Ling; Zaunders, John J.; Xu, Yin; Theodoratos, Angelo; Tan, Abel; Lim, Pek Siew; Knaute, Tobias; Masch, Antonia; Zerweck, Johannes; Brezar, Vedran; Milburn, Peter J.; Dunn, Jenny; Casarotto, Marco G.; Turner, Stephen J.; Seddiki, Nabila; Kelleher, Anthony D.

    2016-01-01

    ABSTRACT Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4+ T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4+ T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells. PMID:27149922

  3. Age and CD161 expression contribute to inter-individual variation in interleukin-23 response in CD8+ memory human T cells.

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    Hui Shen

    Full Text Available The interleukin-23 (IL-23 pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson's correlation coefficient, r = -0.37, p = 0.001 source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R, RORC (RORγt and CD161 (KLRB1, whereas RORA (RORα and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001. Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = -0.34, p = 0.05. Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes.

  4. O-Specific Polysaccharide-Specific Memory B Cell Responses in Young Children, Older Children, and Adults Infected with Vibrio cholerae O1 Ogawa in Bangladesh.

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    Aktar, Amena; Rahman, M Arifur; Afrin, Sadia; Faruk, M Omar; Uddin, Taher; Akter, Aklima; Sami, M Israk Nur; Yasmin, Tahirah; Chowdhury, Fahima; Khan, Ashraful I; Leung, Daniel T; LaRocque, Regina C; Charles, Richelle C; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B; Harris, Jason B; Qadri, Firdausi; Ryan, Edward T

    2016-05-01

    Cholera caused by Vibrio cholerae O1 confers at least 3 to 10 years of protection against subsequent disease regardless of age, despite a relatively rapid fall in antibody levels in peripheral blood, suggesting that memory B cell responses may play an important role in protection. The V. cholerae O1-specific polysaccharide (OSP) component of lipopolysaccharide (LPS) is responsible for serogroup specificity, and it is unclear if young children are capable of developing memory B cell responses against OSP, a T cell-independent antigen, following cholera. To address this, we assessed OSP-specific memory B cell responses in young children (2 to 5 years, n = 11), older children (6 to 17 years, n = 21), and adults (18 to 55 years, n = 28) with cholera caused by V. cholerae O1 in Dhaka, Bangladesh. We also assessed memory B cell responses against LPS and vibriocidal responses, and plasma antibody responses against OSP, LPS, and cholera toxin B subunit (CtxB; a T cell-dependent antigen) on days 2 and 7, as well as days 30, 90, and 180 after convalescence. In all age cohorts, vibriocidal responses and plasma OSP, LPS, and CtxB-specific responses peaked on day 7 and fell toward baseline over the follow-up period. In comparison, we were able to detect OSP memory B cell responses in all age cohorts of patients with detectable responses over baseline for 90 to 180 days. Our results suggest that OSP-specific memory B cell responses can occur following cholera, even in the youngest children, and may explain in part the age-independent induction of long-term immunity following naturally acquired disease. PMID:27009211

  5. Trypanosomiasis-induced B cell apoptosis results in loss of protective anti-parasite antibody responses and abolishment of vaccine-induced memory responses.

    Directory of Open Access Journals (Sweden)

    Magdalena Radwanska

    2008-05-01

    independent IgM(+MZ B cells that are normally functioning as the primary immune barrier against blood-borne pathogens. In addition, ongoing trypanosome infections results in the rapid loss of B cell responsiveness and prevent the induction of protective memory responses. Finally, trypanosome infections disable the host's capacity to recall vaccine-induced memory responses against non-related pathogens. In particular, these last results call for detailed studies of the effect of HAT on memory recall responses in humans, prior to the planning of any mass vaccination campaign in HAT endemic areas.

  6. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation

    OpenAIRE

    Weng, Nan-ping; Araki, Yasuto; Subedi, Kalpana

    2012-01-01

    How the immune system remembers a previous encounter with a pathogen and responds more efficiently to a subsequent encounter has been one of the central enigmas for immunologists for over a century. The identification of pathogen-specific memory lymphocytes that arise after an infection provided a cellular basis for immunological memory. But the molecular mechanisms of immunological memory remain only partially understood. The emerging evidence suggests that epigenetic changes have a key role...

  7. Transcriptome Signatures Reveal Rapid Induction of Immune-Responsive Genes in Human Memory CD8(+) T Cells.

    Science.gov (United States)

    Yang, Cheng; Khanniche, Asma; DiSpirito, Joanna R; Ji, Ping; Wang, Shujun; Wang, Ying; Shen, Hao

    2016-01-01

    Memory T cells (TM) play a prominent role in protection and auto-immunity due to their ability to mount a more effective response than naïve T cells (TN). However, the molecular mechanisms underlying enhanced functionality of TM are not well defined, particularly in human TM. We examined the global gene expression profiles of human CD8(+) TN and TM before and after stimulation. There were 1,284, 1,373 and 1,629 differentially expressed genes between TN and TM at 0 hr, 4 hr and 24 hr after stimulation, respectively, with more genes expressed to higher levels in TM. Genes rapidly up-regulated in TN cells were largely involved in nitrogen, nucleoside and amino acid metabolisms. In contrast, those in CD8(+) TM were significantly enriched for immune-response-associated processes, including cytokine production, lymphocyte activation and chemotaxis. Multiple cytokines were rapidly up-regulated in TM cells, including effector cytokines known to be produced by CD8(+) T cells and important for their functions, as well as regulatory cytokines, both pro- and anti-inflammatory, that are not typically produced by CD8(+) T cells. These results provide new insights into molecular mechanisms that contribute to the enhanced functionality of human CD8(+) TM and their prominent role in protection and auto-immunity. PMID:27243788

  8. Loss of multi-epitope specificity in memory CD4(+ T cell responses to B. pertussis with age.

    Directory of Open Access Journals (Sweden)

    Wanda G H Han

    Full Text Available Pertussis is still occurring in highly vaccinated populations, affecting individuals of all ages. Long-lived Th1 CD4(+ T cells are essential for protective immunity against pertussis. For better understanding of the limited immunological memory to Bordetella pertussis, we used a panel of Pertactin and Pertussis toxin specific peptides to interrogate CD4(+ T cell responses at the epitope level in a unique cohort of symptomatic pertussis patients of different ages, at various time intervals after infection. Our study showed that pertussis epitope-specific T cell responses contained Th1 and Th2 components irrespective of the epitope studied, time after infection, or age. In contrast, the breadth of the pertussis-directed CD4(+ T cell response seemed dependent on age and closeness to infection. Multi-epitope specificity long-term after infection was lost in older age groups. Detailed knowledge on pertussis specific immune mechanisms and their insufficiencies is important for understanding resurgence of pertussis in highly vaccinated populations.

  9. Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

    DEFF Research Database (Denmark)

    Coleman, Miranda; Jessup, Claire F.; Bridge, Jennifer A.;

    2016-01-01

    graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell–mediated gene therapy effectively terminates antigen-specific memory T...... in islet transplantation, and this will extend to application of personalized approaches using stem cell–derived replacement β-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β-cells. Here, we show that transfer of bone marrow encoding cognate......-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells....

  10. Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients.

    Science.gov (United States)

    Ezzelarab, M B; Zhang, H; Guo, H; Lu, L; Zahorchak, A F; Wiseman, R W; Nalesnik, M A; Bhama, J K; Cooper, D K C; Thomson, A W

    2016-07-01

    The ability of regulatory T cells (Treg) to prolong allograft survival and promote transplant tolerance in lymphodepleted rodents is well established. Few studies, however, have addressed the therapeutic potential of adoptively transferred, CD4(+) CD25(+) CD127(-) Foxp3(+) (Treg) in clinically relevant large animal models. We infused ex vivo-expanded, functionally stable, nonselected Treg (up to a maximum cumulative dose of 1.87 billion cells) into antithymocyte globulin-lymphodepleted, MHC-mismatched cynomolgus monkey heart graft recipients before homeostatic recovery of effector T cells. The monkeys also received tacrolimus, anti-interleukin-6 receptor monoclonal antibodies and tapered rapamycin maintenance therapy. Treg administration in single or multiple doses during the early postsurgical period (up to 1 month posttransplantation), when host T cells were profoundly depleted, resulted in inferior graft function compared with controls. This was accompanied by increased incidences of effector memory T cells, enhanced interferon-γ production by host CD8(+) T cells, elevated levels of proinflammatory cytokines, and antidonor alloantibodies. The findings caution against infusion of Treg during the early posttransplantation period after lymphodepletion. Despite marked but transient increases in Treg relative to endogenous effector T cells and use of reputed "Treg-friendly" agents, the host environment/immune effector mechanisms instigated under these conditions can perturb rather than favor the potential therapeutic efficacy of adoptively transferred Treg. PMID:26700196

  11. Association of Neisseria gonorrhoeae Opa(CEA with dendritic cells suppresses their ability to elicit an HIV-1-specific T cell memory response.

    Directory of Open Access Journals (Sweden)

    Qigui Yu

    Full Text Available Infection with Neisseria gonorrhoeae (N. gonorrhoeae can trigger an intense local inflammatory response at the site of infection, yet there is little specific immune response or development of immune memory. Gonococcal surface epitopes are known to undergo antigenic variation; however, this is unlikely to explain the weak immune response to infection since individuals can be re-infected by the same serotype. Previous studies have demonstrated that the colony opacity-associated (Opa proteins on the N. gonorrhoeae surface can bind human carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1 on CD4⁺ T cells to suppress T cell activation and proliferation. Interesting in this regard, N. gonorrhoeae infection is associated with impaired HIV-1 (human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte (CTL responses and with transient increases in plasma viremia in HIV-1-infected patients, suggesting that N. gonorrhoeae may also subvert immune responses to co-pathogens. Since dendritic cells (DCs are professional antigen presenting cells (APCs that play a key role in the induction of an adaptive immune response, we investigated the effects of N. gonorrhoeae Opa proteins on human DC activation and function. While morphological changes reminiscent of DC maturation were evident upon N. gonorrhoeae infection, we observed a marked downregulation of DC maturation marker CD83 when the gonococci expressing CEACAM1-specific Opa(CEA, but not other Opa variants. Consistent with a gonococcal-induced defect in maturation, Opa(CEA binding to CEACAM1 reduced the DCs' capacity to stimulate an allogeneic T cell proliferative response. Moreover, Opa(CEA-expressing N. gonorrhoeae showed the potential to impair DC-dependent development of specific adaptive immunity, since infection with Opa(CEA-positive gonococci suppressed the ability of DCs to stimulate HIV-1-specific memory CTL responses. These results reveal a novel mechanism to explain

  12. Association of Neisseria gonorrhoeae Opa(CEA) with dendritic cells suppresses their ability to elicit an HIV-1-specific T cell memory response.

    Science.gov (United States)

    Yu, Qigui; Chow, Edith M C; McCaw, Shannon E; Hu, Ningjie; Byrd, Daniel; Amet, Tohti; Hu, Sishun; Ostrowski, Mario A; Gray-Owen, Scott D

    2013-01-01

    Infection with Neisseria gonorrhoeae (N. gonorrhoeae) can trigger an intense local inflammatory response at the site of infection, yet there is little specific immune response or development of immune memory. Gonococcal surface epitopes are known to undergo antigenic variation; however, this is unlikely to explain the weak immune response to infection since individuals can be re-infected by the same serotype. Previous studies have demonstrated that the colony opacity-associated (Opa) proteins on the N. gonorrhoeae surface can bind human carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) on CD4⁺ T cells to suppress T cell activation and proliferation. Interesting in this regard, N. gonorrhoeae infection is associated with impaired HIV-1 (human immunodeficiency virus type 1)-specific cytotoxic T-lymphocyte (CTL) responses and with transient increases in plasma viremia in HIV-1-infected patients, suggesting that N. gonorrhoeae may also subvert immune responses to co-pathogens. Since dendritic cells (DCs) are professional antigen presenting cells (APCs) that play a key role in the induction of an adaptive immune response, we investigated the effects of N. gonorrhoeae Opa proteins on human DC activation and function. While morphological changes reminiscent of DC maturation were evident upon N. gonorrhoeae infection, we observed a marked downregulation of DC maturation marker CD83 when the gonococci expressing CEACAM1-specific Opa(CEA), but not other Opa variants. Consistent with a gonococcal-induced defect in maturation, Opa(CEA) binding to CEACAM1 reduced the DCs' capacity to stimulate an allogeneic T cell proliferative response. Moreover, Opa(CEA)-expressing N. gonorrhoeae showed the potential to impair DC-dependent development of specific adaptive immunity, since infection with Opa(CEA)-positive gonococci suppressed the ability of DCs to stimulate HIV-1-specific memory CTL responses. These results reveal a novel mechanism to explain why

  13. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.

    Directory of Open Access Journals (Sweden)

    Davide Corti

    Full Text Available BACKGROUND: The isolation of human monoclonal antibodies (mAbs that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. METHODS AND FINDINGS: We immortalized IgG(+ memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16 specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194 bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20 with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. CONCLUSIONS: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

  14. Coordinated expansion of both memory T cells and NK cells in response to CMV infection in humans.

    Science.gov (United States)

    Bayard, Charles; Lepetitcorps, Hélène; Roux, Antoine; Larsen, Martin; Fastenackels, Solène; Salle, Virginie; Vieillard, Vincent; Marchant, Arnaud; Stern, Marc; Boddaert, Jacques; Bajolle, Fanny; Appay, Victor; Sauce, Delphine

    2016-05-01

    NK cells are key players in the fight against persistent viruses. Human cytomegalovirus (HCMV) infection is associated with the presence of a population of CD16(+) CD56(dim) NKG2C(+) NK cells in both acutely and latently infected individuals. Here, we studied the nature of these terminally differentiated NK cells in different human populations infected with HCMV: healthy donors stratified by age, thymectomized individuals, pregnant women suffering from primary CMV infection, and lung transplant patients. Both CD16(+) CD56(dim) NK- and CD8 T-cell phenotypes as well as functional capacities were determined and stratified according to age and/or CMV event. Similarly to T-cell responsiveness, we observe an accumulation over time of NKG2C(+) NK cells, which preferentially expressed CD57. This accumulation is particularly prominent in elderly and amplified further by CMV infection. Latent HCMV infection (without replication) is sufficient for NKG2C(+) CD57(+) NK cells to persist in healthy individuals but is not necessarily required in old age. Collectively, the present work supports the emerging concept that CMV shapes both innate and adaptive immunity in humans. PMID:26910859

  15. Coordinated expansion of both memory T cells and NK cells in response to CMV infection in humans.

    Science.gov (United States)

    Bayard, Charles; Lepetitcorps, Hélène; Roux, Antoine; Larsen, Martin; Fastenackels, Solène; Salle, Virginie; Vieillard, Vincent; Marchant, Arnaud; Stern, Marc; Boddaert, Jacques; Bajolle, Fanny; Appay, Victor; Sauce, Delphine

    2016-05-01

    NK cells are key players in the fight against persistent viruses. Human cytomegalovirus (HCMV) infection is associated with the presence of a population of CD16(+) CD56(dim) NKG2C(+) NK cells in both acutely and latently infected individuals. Here, we studied the nature of these terminally differentiated NK cells in different human populations infected with HCMV: healthy donors stratified by age, thymectomized individuals, pregnant women suffering from primary CMV infection, and lung transplant patients. Both CD16(+) CD56(dim) NK- and CD8 T-cell phenotypes as well as functional capacities were determined and stratified according to age and/or CMV event. Similarly to T-cell responsiveness, we observe an accumulation over time of NKG2C(+) NK cells, which preferentially expressed CD57. This accumulation is particularly prominent in elderly and amplified further by CMV infection. Latent HCMV infection (without replication) is sufficient for NKG2C(+) CD57(+) NK cells to persist in healthy individuals but is not necessarily required in old age. Collectively, the present work supports the emerging concept that CMV shapes both innate and adaptive immunity in humans.

  16. Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory.

    Directory of Open Access Journals (Sweden)

    Maria del Rosario Espinoza Mora

    Full Text Available Regulatory T cells (T(reg have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4(+CD25(+ T(reg were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3(+CD25(- T(reg. To obtain more insights in the specific function of T(reg during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG. As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP of Plasmodium berghei (Pb was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC. Using this system we demonstrate here that the number of CSP-specific T cells increases when T(reg are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.

  17. HIV-Exposed Uninfected Infants Show Robust Memory B-Cell Responses in Spite of a Delayed Accumulation of Memory B Cells: an Observational Study in the First 2 Years of Life.

    Science.gov (United States)

    Nduati, Eunice W; Nkumama, Irene N; Gambo, Faith K; Muema, Daniel M; Knight, Miguel G; Hassan, Amin S; Jahangir, Margaret N; Etyang, Timothy J; Berkley, James A; Urban, Britta C

    2016-07-01

    Improved HIV care has led to an increase in the number of HIV-exposed uninfected (HEU) infants born to HIV-infected women. Although they are uninfected, these infants experience increased morbidity and mortality. One explanation may be that their developing immune system is altered by HIV exposure, predisposing them to increased postnatal infections. We explored the impact of HIV exposure on the B-cell compartment by determining the B-cell subset distribution, the frequency of common vaccine antigen-specific memory B cells (MBCs), and the levels of antibodies to the respective antigens in HEU and HIV-unexposed uninfected (HUU) infants born to uninfected mothers, using flow cytometry, a B-cell enzyme-linked immunosorbent spot assay, and an enzyme-linked immunosorbent assay, respectively, during the first 2 years of life. For the majority of the B-cell subsets, there were no differences between HEU and HUU infants. However, HIV exposure was associated with a lower proportion of B cells in general and MBCs in particular, largely due to a lower proportion of unswitched memory B cells. This reduction was maintained even after correcting for age. These phenotypic differences in the MBC compartment did not affect the ability of HEU infants to generate recall responses to previously encountered antigens or reduce the antigen-specific antibody levels at 18 months of life. Although HIV exposure was associated with a transient reduction in the proportion of MBCs, we found that the ability of HEU infants to mount robust MBC and serological responses was unaffected. PMID:27170641

  18. Differential expression of alpha 4 integrins on effector memory T helper cells during Bordetella infections. Delayed responses in Bordetella pertussis.

    Directory of Open Access Journals (Sweden)

    Tuan M Nguyen

    Full Text Available Bordetella pertussis (B. pertussis is the causative agent of whooping cough, a respiratory disease that is reemerging worldwide. Mechanisms of selective lymphocyte trafficking to the airways are likely to be critical in the immune response to this pathogen. We compared murine infection by B. pertussis, B. parapertussis, and a pertussis toxin-deleted B. pertussis mutant (BpΔPTX to test the hypothesis that effector memory T-helper cells (emTh display an altered pattern of trafficking receptor expression in B. pertussis infection due to a defect in imprinting. Increased cell recruitment to the lungs at 5 days post infection (p.i. with B. parapertussis, and to a lesser extent with BpΔPTX, coincided with an increased frequency of circulating emTh cells expressing the mucosal-associated trafficking receptors α4β7 and α4β1 while a reduced population of these cells was observed in B. pertussis infection. These cells were highly evident in the blood and lungs in B. pertussis infection only at 25 days p.i. when B. parapertussis and BpΔPTX infections were resolved. Although at 5 days p.i., an equally high percentage of lung dendritic cells (DCs from all infections expressed maturation markers, this expression persisted only in B. pertussis infection at 25 days p.i. Furthermore, at 5 days p.i with B. pertussis, lung DCs migration to draining lymph nodes may be compromised as evidenced by decreased frequency of CCR7(+ DCs, inhibited CCR7-mediated in vitro migration, and fewer DCs in lung draining lymph nodes. Lastly, a reduced frequency of allogeneic CD4(+ cells expressing α4β1 was detected following co-culture with lung DCs from B. pertussis-infected mice, suggesting a defect in DC imprinting in comparison to the other infection groups. The findings in this study suggest that B. pertussis may interfere with imprinting of lung-associated trafficking receptors on T lymphocytes leading to extended survival in the host and a prolonged course of disease.

  19. Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells

    Science.gov (United States)

    Bernasconi, Nadia L.; Traggiai, Elisabetta; Lanzavecchia, Antonio

    2002-12-01

    Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.

  20. Lipoxin A₄ modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism.

    Science.gov (United States)

    Ramon, Sesquile; Bancos, Simona; Serhan, Charles N; Phipps, Richard P

    2014-02-01

    Specialized proresolving mediators are endogenous bioactive lipid molecules that play a fundamental role in the regulation of inflammation and its resolution. Lipoxins and other specialized proresolving mediators have been identified in important immunological tissues including bone marrow, spleen, and blood. Lipoxins regulate functions of the innate immune system including the promotion of monocyte recruitment and increase macrophage phagocytosis of apoptotic neutrophils. A major knowledge gap is whether lipoxins influence adaptive immune cells. Here, we analyzed the actions of lipoxin A₄ (LXA₄) and its receptor ALX/FPR2 on human and mouse B cells. LXA₄ decreased IgM and IgG production on activated human B cells through ALX/FPR2-dependent signaling, which downregulated NF-κB p65 nuclear translocation. LXA₄ also inhibited human memory B-cell antibody production and proliferation, but not naïve B-cell function. Lastly, LXA₄ decreased antigen-specific antibody production in an OVA immunization mouse model. To our knowledge, this is the first description of the actions of lipoxins on human B cells, demonstrating a link between resolution signals and adaptive immunity. Regulating antibody production is crucial to prevent unwanted inflammation. Harnessing the ability of lipoxins to decrease memory B-cell antibody production can be beneficial to threat inflammatory and autoimmune disorders.

  1. Age and CD161 Expression Contribute to Inter-Individual Variation in Interleukin-23 Response in CD8+ Memory Human T Cells

    OpenAIRE

    Hui Shen; Wei Zhang; Clara Abraham; Judy H Cho

    2013-01-01

    The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant...

  2. Functionality of dengue virus specific memory T cell responses in individuals who were hospitalized or who had mild or subclinical dengue infection.

    Directory of Open Access Journals (Sweden)

    Chandima Jeewandara

    2015-04-01

    Full Text Available Although antibody responses to dengue virus (DENV in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell responses in relation to clinical disease severity is incompletely understood.Using ex vivo IFNγ ELISpot assays, and by determining cytokines produced in ELISpot supernatants, we investigated the functionality of DENV-specific memory T cell responses in a large cohort of individuals from Sri Lanka (n=338, who were naturally infected and were either hospitalized due to dengue or had mild or sub clinical dengue infection. We found that T cells of individuals with both past mild or sub clinical dengue infection and who were hospitalized produced multiple cytokines when stimulated with DENV-NS3 peptides. However, while DENV-NS3 specific T cells of those with mild/sub clinical dengue infection were more likely to produce only granzyme B (p=0.02, those who were hospitalized were more likely to produce both TNFα and IFNγ (p=0.03 or TNFα alone. We have also investigated the usefulness of a novel T cell based assay, which can be used to determine the past infecting DENV serotype. 92.4% of DENV seropositive individuals responded to at least one DENV serotype of this assay and none of the seronegatives responded. Individuals who were seronegative, but had received the Japanese encephalitis vaccine too made no responses, suggesting that the peptides used in this assay did not cross react with the Japanese encephalitis virus.The types of cytokines produced by DENV-specific memory T cells appear to influence the outcome of clinical disease severity. The novel T cell based assay, is likely to be useful in determining the past infecting DENV serotype in immune-epidemiological studies and also in dengue vaccine trials.

  3. Non-malignant clonal expansions of memory CD8+ T cells that arise with age vary in their capacity to mount recall responses to infection1

    OpenAIRE

    Kohlmeier, Jacob E.; Connor, Lisa M.; Roberts, Alan D.; Cookenham, Tres; Martin, Kyle; Woodland, David L

    2010-01-01

    Immune responsiveness declines with age in part due to the development of CD8+ T cell expansions (TCE) that can dominate the peripheral T cell pool. Although some TCE arise due to persistent antigen stimulation from chronic infections, others arise in the apparent absence of chronic infection. We have recently shown that this latter class of TCE can arise over time from the memory CD8+ T cell pool established by an acute viral infection. Unlike TCE driven by chronic infections, these age-rela...

  4. Subsets of memory CD4+ T cell and bactericidal antibody response to Neisseria meningitidis serogroup C after immunization of HIV-infected children and adolescents.

    Directory of Open Access Journals (Sweden)

    Lucimar G Milagres

    Full Text Available Meningococcal disease is endemic in Brazil, with periodic outbreaks and case fatality rates reach as high as 18 to 20% of cases. Conjugate vaccines against meningococci are immunogenic in healthy children. However, we have previously shown a poor bactericidal antibody response to a Men C conjugate vaccine in Brazilian HIV-infected children and adolescents after a single vaccine administration. The goal of the present work was to investigate associations between bactericidal antibody response induced by MenC vaccine and the frequency and activation profile (expression of CD38, HLA-DR and CCR5 molecules of total CD4+ memory T cell sub-populations in HIV-1-infected children and adolescents. Responders to vaccination against MenC had a predominance (about 44% of CD4+ TINTERMEDIATE subset followed by TTRANSITIONAL memory subset (23 to 26%. Importantly, CD4+ TINT frequency was positively associated with bactericidal antibody response induced by vaccination. The positive correlation persisted despite the observation that the frequency TINT CD38+HLA-DR+ was higher in responders. In contrast, CD4+ TCENTRAL MEMORY (TCM subset negatively correlated with bactericidal antibodies. In conclusion, these data indicate that less differentiated CD+ T cells, like TCM may be constantly differentiating into intermediate and later differentiated CD4+ T cell subsets. These include CD4 TINT subset which showed a positive association with bactericidal antibodies.

  5. Pre-existing vector immunity does not prevent replication deficient adenovirus from inducing efficient CD8 T-cell memory and recall responses

    DEFF Research Database (Denmark)

    Steffensen, Maria Abildgaard; Jensen, Benjamin Anderschou Holbech; Holst, Peter Johannes;

    2012-01-01

    directed against epitopes in the adenoviral vector seemed to correlate with repression of the induced response in re-vaccinated B-cell deficient mice. More importantly, despite a repressed primary effector CD8 T-cell response in Ad5-immune animals subjected to vaccination, memory T cells were generated......Adenoviral vectors have shown a great potential for vaccine development due to their inherent ability to induce potent and protective CD8 T-cell responses. However, a critical issue regarding the use of these vectors is the existence of inhibitory immunity against the most commonly used Ad5 vector...... in a large part of the human population. We have recently developed an improved adenoviral vaccine vector system in which the vector expresses the transgene tethered to the MHC class II associated invariant chain (Ii). To further evaluate the potential of this system, the concept of pre-existing inhibitory...

  6. Memory-like CD8⁺ T cells generated during homeostatic proliferation defer to antigen-experienced memory cells

    OpenAIRE

    Cheung, Kitty Pui Hang

    2009-01-01

    Naïve T cells proliferate in response to lymphopenia and acquire the phenotypic and functional qualities of memory T cells, providing enhanced protection against infection. How well 'memory-like' T cells generated during lymphopenia-induced homeostatic proliferation (HP-memory) differentiate into secondary memory cells and compete with antigen-experienced 'true-memory' cells is previously unknown. We found that CD8⁺ HP-memory T cells generated robust responses upon infection and produced a se...

  7. Memory T cells in organ transplantation: progress and challenges.

    Science.gov (United States)

    Espinosa, Jaclyn R; Samy, Kannan P; Kirk, Allan D

    2016-06-01

    Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses. PMID:26923209

  8. Application of long-term cultured interferon-gamma enzyme-linked immunospot assay for assessing effector and memory T cell responses in cattle

    Science.gov (United States)

    Effector and memory T cells are generated through developmental programing of naïve cells following antigen recognition. If the infection is controlled, up to 95% of the T cells generated during the expansion phase are eliminated (i.e., contraction phase) and memory T cells remain, sometimes for a l...

  9. Pre-existing vector immunity does not prevent replication deficient adenovirus from inducing efficient CD8 T-cell memory and recall responses.

    Directory of Open Access Journals (Sweden)

    Maria Abildgaard Steffensen

    Full Text Available Adenoviral vectors have shown a great potential for vaccine development due to their inherent ability to induce potent and protective CD8 T-cell responses. However, a critical issue regarding the use of these vectors is the existence of inhibitory immunity against the most commonly used Ad5 vector in a large part of the human population. We have recently developed an improved adenoviral vaccine vector system in which the vector expresses the transgene tethered to the MHC class II associated invariant chain (Ii. To further evaluate the potential of this system, the concept of pre-existing inhibitory immunity to adenoviral vectors was revisited to investigate whether the inhibition previously seen with the Ad5 vector also applied to the optimized vector system. We found this to be the case, and antibodies dominated as the mechanism underlying inhibitory vector immunity. However, presence of CD8 T cells directed against epitopes in the adenoviral vector seemed to correlate with repression of the induced response in re-vaccinated B-cell deficient mice. More importantly, despite a repressed primary effector CD8 T-cell response in Ad5-immune animals subjected to vaccination, memory T cells were generated that provided the foundation for an efficient recall response and protection upon subsequent viral challenge. Furthermore, the transgene specific response could be efficiently boosted by homologous re-immunization. Taken together, these studies indicate that adenoviral vectors can be used to induce efficient CD8 T-cell memory even in individuals with pre-existing vector immunity.

  10. Association of Neisseria gonorrhoeae OpaCEA with Dendritic Cells Suppresses Their Ability to Elicit an HIV-1-Specific T Cell Memory Response

    OpenAIRE

    Qigui Yu; Chow, Edith M.C.; McCaw, Shannon E.; Ningjie Hu; Daniel Byrd; Tohti Amet; Sishun Hu; Ostrowski, Mario A.; Gray-Owen, Scott D.

    2013-01-01

    Infection with Neisseria gonorrhoeae (N. gonorrhoeae) can trigger an intense local inflammatory response at the site of infection, yet there is little specific immune response or development of immune memory. Gonococcal surface epitopes are known to undergo antigenic variation; however, this is unlikely to explain the weak immune response to infection since individuals can be re-infected by the same serotype. Previous studies have demonstrated that the colony opacity-associated (Opa) proteins...

  11. Vaccination for 2009 pandemic H1N1 influenza A did not induce conserved epitope-specific memory CD8 T cell responses in HIV+ northern Thai children.

    Science.gov (United States)

    Chawansuntati, Kriangkrai; Aurpibul, Linda; Wipasa, Jiraprapa

    2015-09-11

    The influenza virus causes severe illness in susceptible populations, including children and people living with human immunodeficiency virus (HIV). Here, we investigated cell-mediated immune responses (CMI) against influenza CD8 T cell conserved epitopes in HIV-infected (HIV+) northern Thai children following the 2009 pandemic H1N1 influenza A vaccination. Sixty HIV+ children were vaccinated with two doses of the 2009 pandemic influenza vaccine and their CD8T cell responses were assessed. We found no significant differences in the increase of cytokines-producing and CD107a-expressing CD8+ T cells or CD8+ memory T cells in response to pooled conserved epitopes stimulation in vitro between children with different serologic responses to the vaccine at all time points of the study. Our results suggest that the 2009 pandemic H1N1 vaccine did not induce the conserved epitope-specific immune responses in HIV+ children. Vaccine design and vaccination strategy against influenza in these populations warrant further studies.

  12. B cells help alloreactive T cells differentiate into memory T cells1

    OpenAIRE

    Ng, Yue-Harn; Oberbarnscheidt, Martin H.; Chandramoorthy, Harish Chinna Konda; Hoffman, Rosemary; Chalasani, Geetha

    2010-01-01

    B cells are recognized as effector cells in allograft rejection that are dependent upon T cell help to produce alloantibodies causing graft injury. It is not known if B cells can also help T cells differentiate into memory cells in the alloimmune response. We found that in B cell-deficient hosts, differentiation of alloreactive T cells into effectors was intact whereas their development into memory T cells was impaired. To test if B cell help for T cells was required for their continued diffe...

  13. A candidate HIV/AIDS vaccine (MVA-B lacking vaccinia virus gene C6L enhances memory HIV-1-specific T-cell responses.

    Directory of Open Access Journals (Sweden)

    Juan García-Arriaza

    Full Text Available The vaccinia virus (VACV C6 protein has sequence similarities with the poxvirus family Pox_A46, involved in regulation of host immune responses, but its role is unknown. Here, we have characterized the C6 protein and its effects in virus replication, innate immune sensing and immunogenicity in vivo. C6 is a 18.2 kDa protein, which is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of the C6L gene from the poxvirus vector MVA-B expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B ΔC6L had no effect on virus growth kinetics; therefore C6 protein is not essential for virus replication. The innate immune signals elicited by MVA-B ΔC6L in human macrophages and monocyte-derived dendritic cells (moDCs are characterized by the up-regulation of the expression of IFN-β and IFN-α/β-inducible genes. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that MVA-B ΔC6L enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4+ and CD8+ T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8+ T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8+ T-cell responses, MVA-B ΔC6L induced more Gag-Pol-Nef-specific CD8+ T-cell responses. Furthermore, MVA-B ΔC6L enhanced the levels of antibodies against Env in comparison with MVA-B. These findings revealed that C6 can be considered as an immunomodulator and that deleting C6L gene in MVA-B confers an immunological benefit by enhancing IFN-β-dependent responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.

  14. T-cell memory responses elicited by yellow fever vaccine are targeted to overlapping epitopes containing multiple HLA-I and -II binding motifs.

    Directory of Open Access Journals (Sweden)

    Andréa Barbosa de Melo

    Full Text Available The yellow fever vaccines (YF-17D-204 and 17DD are considered to be among the safest vaccines and the presence of neutralizing antibodies is correlated with protection, although other immune effector mechanisms are known to be involved. T-cell responses are known to play an important role modulating antibody production and the killing of infected cells. However, little is known about the repertoire of T-cell responses elicited by the YF-17DD vaccine in humans. In this report, a library of 653 partially overlapping 15-mer peptides covering the envelope (Env and nonstructural (NS proteins 1 to 5 of the vaccine was utilized to perform a comprehensive analysis of the virus-specific CD4(+ and CD8(+ T-cell responses. The T-cell responses were screened ex-vivo by IFN-γ ELISPOT assays using blood samples from 220 YF-17DD vaccinees collected two months to four years after immunization. Each peptide was tested in 75 to 208 separate individuals of the cohort. The screening identified sixteen immunodominant antigens that elicited activation of circulating memory T-cells in 10% to 33% of the individuals. Biochemical in-vitro binding assays and immunogenetic and immunogenicity studies indicated that each of the sixteen immunogenic 15-mer peptides contained two or more partially overlapping epitopes that could bind with high affinity to molecules of different HLAs. The prevalence of the immunogenicity of a peptide in the cohort was correlated with the diversity of HLA-II alleles that they could bind. These findings suggest that overlapping of HLA binding motifs within a peptide enhances its T-cell immunogenicity and the prevalence of the response in the population. In summary, the results suggests that in addition to factors of the innate immunity, "promiscuous" T-cell antigens might contribute to the high efficacy of the yellow fever vaccines.

  15. Antigen-specific memory Treg control memory responses to influenza virus infection

    OpenAIRE

    Brincks, Erik L.; Roberts, Alan D.; Cookenham, Tres; Sell, Stewart; Kohlmeier, Jacob E.; Blackman, Marcia A.; Woodland, David L

    2013-01-01

    Regulatory CD4+FoxP3+ T cells (Treg) are key regulators of inflammatory responses and control the magnitude of cellular immune responses to viral infections. However, little is known about how Treg contribute to immune regulation during memory responses to previously-encountered pathogens. Here we utilized influenza NP311-325/IAb Class II tetramers to track the antigen-specific Treg response to primary and secondary influenza virus infections. During secondary infections, antigen-specific mem...

  16. Memory T follicular helper CD4 T cells

    Directory of Open Access Journals (Sweden)

    J. Scott eHale

    2015-02-01

    Full Text Available T follicular helper (Tfh cells are the subset of CD4 T helper cells that are required for generation and maintenance of germinal center reactions and the generation of long-lived humoral immunity. This specialized T helper subset provides help to cognate B cells via their expression of CD40 ligand, IL-21, IL-4, and other molecules. Tfh cells are characterized by their expression of the chemokine receptor CXCR5, expression of the transcriptional repressor Bcl6, and their capacity to migrate to the follicle and promote germinal center B cell responses. Until recently, it remained unclear whether Tfh cells differentiated into memory cells and whether they maintain their Tfh commitment at the memory phase. This review will highlight several recent studies that support the idea of Tfh-committed CD4 T cells at the memory stage of the immune response. The implication of these findings is that memory Tfh cells retain their capacity to recall their Tfh-specific effector functions upon reactivation to provide help for B cell responses and play an important role in prime and boost vaccination or during recall responses to infection. The markers that are useful for distinguishing Tfh effector and memory cells, as well as the limitations of using these markers will be discussed. Tfh effector and memory generation, lineage maintenance, and plasticity relative to other T helper lineages (Th1, Th2, Th17, etc will also be discussed. Ongoing discoveries regarding the maintenance and lineage stability versus plasticity of memory Tfh cells will improve strategies that utilize CD4 T cell memory to modulate antibody responses during prime and boost vaccination.

  17. BTLA interaction with HVEM expressed on CD8(+ T cells promotes survival and memory generation in response to a bacterial infection.

    Directory of Open Access Journals (Sweden)

    Marcos W Steinberg

    Full Text Available The B and T lymphocyte attenuator (BTLA is an Ig super family member that binds to the herpes virus entry mediator (HVEM, a TNF receptor super family (TNFRSF member. Engagement of BTLA by HVEM triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8(+ T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8(+ T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8(+ T cells. HVEM expression on the CD8(+ T cells as well as BTLA expression on a cell type other than CD8(+ T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8(+ T cell during bacterial infection.

  18. T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells.

    Directory of Open Access Journals (Sweden)

    Gang Li

    Full Text Available Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62L(highCD44(low Sca-1(+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells.

  19. A human memory T-cell subset with stem cell-like properties

    OpenAIRE

    Gattinoni, Luca; Lugli, Enrico; Ji, Yun; Pos, Zoltan; Paulos, Chrystal M.; Quigley, Máire F.; Almeida, Jorge R.; Gostick, Emma; Yu, Zhiya; Carpenito, Carmine; Wang, Ena; Douek, Daniel C.; Price, David A.; June, Carl H.; Marincola, Francesco M.

    2011-01-01

    Immunological memory is thought to depend upon a stem cell-like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T-cell population that displays enhanced self-renewal and multipotent capacity to derive central memory, effector memory and effector T cells. These cells, specific for multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27...

  20. Dissociating response systems: erasing fear from memory

    NARCIS (Netherlands)

    A.C. Soeter; M. Kindt

    2010-01-01

    In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid

  1. A human memory T-cell subset with stem cell-like properties

    Science.gov (United States)

    Gattinoni, Luca; Lugli, Enrico; Ji, Yun; Pos, Zoltan; Paulos, Chrystal M.; Quigley, Máire F.; Almeida, Jorge R.; Gostick, Emma; Yu, Zhiya; Carpenito, Carmine; Wang, Ena; Douek, Daniel C.; Price, David A.; June, Carl H.; Marincola, Francesco M.; Roederer, Mario; Restifo, Nicholas P.

    2011-01-01

    Immunological memory is thought to depend upon a stem cell-like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T-cell population that displays enhanced self-renewal and multipotent capacity to derive central memory, effector memory and effector T cells. These cells, specific for multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+ T-cell compartment characteristic of naïve T cells. However, they expressed increased levels of CD95, IL-2Rβ, CXCR3, and LFA-1, and exhibited numerous functional attributes distinctive of memory cells. Compared to known memory populations, these lymphocytes displayed increased proliferative capacity, more efficiently reconstituted immunodeficient hosts and mediated superior anti-tumor responses in a humanized mouse model. The identification of a human stem cell-like memory T-cell population is of direct relevance to the design of vaccines and T-cell therapies. PMID:21926977

  2. Affinity enhancement of antibodies: how low-affinity antibodies produced early in immune responses are followed by high-affinity antibodies later and in memory B-cell responses.

    Science.gov (United States)

    Eisen, Herman N

    2014-05-01

    The antibodies produced initially in response to most antigens are high molecular weight (MW) immunoglobulins (IgM) with low affinity for the antigen, while the antibodies produced later are lower MW classes (e.g., IgG and IgA) with, on average, orders of magnitude higher affinity for that antigen. These changes, often termed affinity maturation, take place largely in small B-cell clusters (germinal center; GC) in lymphoid tissues in which proliferating antigen-stimulated B cells express the highly mutagenic cytidine deaminase that mediates immunoglobulin class-switching and sequence diversification of the immunoglobulin variable domains of antigen-binding receptors on B cells (BCR). Of the large library of BCR-mutated B cells thus rapidly generated, a small minority with affinity-enhancing mutations are selected to survive and differentiate into long-lived antibody-secreting plasma cells and memory B cells. BCRs are also endocytic receptors; they internalize and cleave BCR-bound antigen, yielding peptide-MHC complexes that are recognized by follicular helper T cells. Imperfect correlation between BCR affinity for antigen and cognate T-cell engagement may account for the increasing affinity heterogeneity that accompanies the increasing average affinity of antibodies. Conservation of mechanisms underlying mutation and selection of high-affinity antibodies over the ≈200 million years of evolution separating bird and mammal lineages points to the crucial role of antibody affinity enhancement in adaptive immunity.

  3. Superior T memory stem cell persistence supports long-lived T cell memory

    Science.gov (United States)

    Lugli, Enrico; Dominguez, Maria H.; Gattinoni, Luca; Chattopadhyay, Pratip K.; Bolton, Diane L.; Song, Kaimei; Klatt, Nichole R.; Brenchley, Jason M.; Vaccari, Monica; Gostick, Emma; Price, David A.; Waldmann, Thomas A.; Restifo, Nicholas P.; Franchini, Genoveffa; Roederer, Mario

    2013-01-01

    Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell–like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells. PMID:23281401

  4. Transient Surface CCR5 Expression by Naive CD8+ T Cells within Inflamed Lymph Nodes Is Dependent on High Endothelial Venule Interaction and Augments Th Cell-Dependent Memory Response.

    Science.gov (United States)

    Askew, David; Su, Charles A; Barkauskas, Deborah S; Dorand, R Dixon; Myers, Jay; Liou, Rachel; Nthale, Joseph; Huang, Alex Y

    2016-05-01

    In inflamed lymph nodes, Ag-specific CD4(+) and CD8(+) T cells encounter Ag-bearing dendritic cells and, together, this complex enhances the release of CCL3 and CCL4, which facilitate additional interaction with naive CD8(+) T cells. Although blocking CCL3 and CCL4 has no effect on primary CD8(+) T cell responses, it dramatically impairs the development of memory CD8(+) T cells upon Ag rechallenge. Despite the absence of detectable surface CCR5 expression on circulating native CD8(+) T cells, these data imply that naive CD8(+) T cells are capable of expressing surface CCR5 prior to cognate Ag-induced TCR signaling in inflamed lymph nodes; however, the molecular mechanisms have not been characterized to date. In this study, we show that CCR5, the receptor for CCL3 and CCL4, can be transiently upregulated on a subset of naive CD8(+) T cells and that this upregulation is dependent on direct contact with the high endothelial venule in inflamed lymph node. Binding of CD62L and CD11a on T cells to their ligands CD34 and CD54 on the high endothelial venule can be enhanced during inflammation. This enhanced binding and subsequent signaling promote the translocation of CCR5 molecules from intracellular vesicles to the surface of the CD8(+) T cell. The upregulation of CCR5 on the surface of the CD8(+) T cells increases the number of contacts with Ag-bearing dendritic cells, which ultimately results in increased CD8(+) T cell response to Ag rechallenge.

  5. Th17 memory cells: live long and proliferate.

    Science.gov (United States)

    McGeachy, Mandy J

    2013-11-01

    The development of immune memory is a double-edged sword, helping to maintain health by preventing repeated infections but also driving chronic inflammation when dysregulated. Th17 cells are now well-known as major drivers of autoimmune disease but also play roles in protective immune responses against pathogens. This mini-review will focus on the recent evidence for long-lived, robust Th17 memory cell populations in mouse models and humans, and their functional roles in mediating host protection and chronic disease states. PMID:24006508

  6. Pathogenic memory type Th2 cells in allergic inflammation.

    Science.gov (United States)

    Endo, Yusuke; Hirahara, Kiyoshi; Yagi, Ryoji; Tumes, Damon J; Nakayama, Toshinori

    2014-02-01

    Immunological memory is a hallmark of adaptive immunity. Memory CD4 T helper (Th) cells are central to acquired immunity, and vaccines for infectious diseases are developed based on this concept. However, memory Th cells also play a critical role in the pathogenesis of various chronic inflammatory diseases, including asthma. We refer to these populations as 'pathogenic memory Th cells.' Here, we review recent developments highlighting the functions and characteristics of several pathogenic memory type Th2 cell subsets in allergic inflammation. Also discussed are the similarities and differences between pathogenic memory Th2 cells and recently identified type 2 innate lymphoid cells (ILC2), focusing on cytokine production and phenotypic profiles.

  7. ERAP1 functions override the intrinsic selection of specific antigens as immunodominant peptides, thereby altering the potency of antigen-specific cytolytic and effector memory T-cell responses.

    Science.gov (United States)

    Rastall, David P W; Aldhamen, Yasser A; Seregin, Sergey S; Godbehere, Sarah; Amalfitano, Andrea

    2014-12-01

    Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a critical component of the adaptive immune system that has been shown to increase or decrease the presentation of specific peptides on MHC class I molecules. Here, we have demonstrated that ERAP1 functions are not only important during the presentation of antigen-derived peptides, but these functions can also completely change which antigen-derived peptides ultimately become selected as immunodominant T-cell epitopes. Our results suggest that ERAP1 may do this by destroying epitopes that would otherwise become immunodominant in the absence of adequate ERAP1 functionality. We further establish that ERAP1-mediated influences on T-cell functions are both qualitative and quantitative, by demonstrating that loss of ERAP1 function redirects CTL killing toward a different set of antigen-derived epitopes and increases the percent of antigen-specific memory T cells elicited by antigen exposure. As a result, our studies suggest that normal ERAP1 activity can act to suppress the numbers of T effector memory cells that respond to a given antigen. This unique finding may shed light on why certain ERAP1 single nucleotide polymorphisms are associated with several autoimmune diseases, for example, by significantly altering the robustness and quality of CD8+ T-cell memory responses to antigen-derived peptides. PMID:25087231

  8. An HIV-1 envelope immunogen with W427S mutation in CD4 binding site induced more T follicular helper memory cells and reduced non-specific antibody responses.

    Directory of Open Access Journals (Sweden)

    Hao-Tong Yu

    Full Text Available The CD4 binding site (CD4BS of the HIV-1 envelope glycoprotein (Env contains epitopes for broadly neutralizing antibody (nAb and is the target for the vaccine development. However, the CD4BS core including residues 425-430 overlaps the B cell superantigen site and may be related to B cell exhaustion in HIV-1 infection. Furthermore, production of nAb and high-affinity plasma cells needs germinal center reaction and the help of T follicular helper (Tfh cells. We believe that strengthening the ability of Env CD4BS in inducing Tfh response and decreasing the effects of the superantigen are the strategies for eliciting nAb and development of HIV-1 vaccine. We constructed a gp120 mutant W427S of an HIV-1 primary R5 strain and examined its ability in the elicitation of Ab and the production of Tfh by immunization of BALB/c mice. We found that the trimeric wild-type gp120 can induce more non-specific antibody-secreting plasma cells, higher serum IgG secretion, and more Tfh cells by splenocyte. The modified W427S gp120 elicits higher levels of specific binding antibodies as well as nAbs though it produces less Tfh cells. Furthermore, higher Tfh cell frequency does not correlate to the specific binding Abs or nAbs indicating that the wild-type gp120 induced some non-specific Tfh that did not contribute to the production of specific Abs. This gp120 mutant led to more memory Tfh production, especially, the effector memory Tfh cells. Taken together, W427S gp120 could induce higher level of specific binding and neutralizing Ab production that may be associated with the reduction of non-specific Tfh but strengthening of the memory Tfh.

  9. Development and function of protective and pathologic memory CD4 T cells

    Directory of Open Access Journals (Sweden)

    Megan KL Macleod

    2015-09-01

    Full Text Available IImmunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naïve and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy.

  10. Comparison of human memory CD8 T cell responses to adenoviral early and late proteins in peripheral blood and lymphoid tissue.

    Directory of Open Access Journals (Sweden)

    Amita Joshi

    Full Text Available Treatment of invasive adenovirus (Ad disease in hematopoietic stem cell transplant (SCT recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977 and late protein hexon (H-892 were compared in peripheral blood (PB and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly higher frequency of P-977+CD8+ T cells compared to H-892+CD8+ T cells; this trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and exhibited lower levels of the activation marker CD25 but higher proliferative potential than PB T cells. Finally, in parallel with the kinetics of mRNA expression, P-977-specific CTLs lysed targets as early as 8 hrs post infection. In contrast, H-892-specific CTLs did not kill unless infected fibroblasts were pretreated with IFN-γ to up regulate HLA class I antigens, and cytotoxicity was delayed until 16-24 hours. These data show that, in contrast to hexon CTLs, central memory type DNA polymerase CTLs dominate the lymphoid compartment and kill fibroblasts earlier after infection without requiring exogenous IFN-γ. Thus, use of CTLs targeted to both early and late Ad proteins may improve the efficacy of immunotherapy for life-threatening Ad disease in SCT recipients.

  11. Incomplete effector/memory differentiation of antigen-primed CD8+ T cells in gene gun DNA-vaccinated mice

    DEFF Research Database (Denmark)

    Bartholdy, Christina; Stryhn, Anette; Hansen, Nils Jacob Vest;

    2003-01-01

    DNA vaccination is an efficient way to induce CD8+ T cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. To study this, we induced CD8+ memory responses directed towards defined viral epitopes, using DNA vaccines encoding immunodominant MHC class I...

  12. CD21(-/low) B cells in human blood are memory cells.

    Science.gov (United States)

    Thorarinsdottir, K; Camponeschi, A; Cavallini, N; Grimsholm, O; Jacobsson, L; Gjertsson, I; Mårtensson, I-L

    2016-08-01

    The complement receptor 2 (CR2, CD21) is part of a complex (CD21/CD19/CD81) acting as a co-receptor to the B cell receptor (BCR). Simultaneous triggering of the BCR and CD21 lowers the threshold for B cell activation. Although CD21 is important, B cells that express low amounts or lack surface CD21 (CD21(-/low) ) are increased in conditions with chronic inflammation, e.g. autoimmune diseases. However, little is known about the CD21(-/low) B cell subset in peripheral blood from healthy donors. Here, we show that CD21(-/low) cells represent approximately 5% of B cells in peripheral blood from adults but are barely detectable in cord blood, after excluding transitional B cells. The CD21(-/low) subset can be divided into CD38(-) 24(+) and CD38(-) 24(low) cells, where most of the CD38(-) 24(+) are CD27(+) immunoglobulin (Ig)M(+) IgD(+) and the CD38(-) 24(low) are switched CD27(-) . Expression levels of additional markers, e.g. CD95 and CD62L, are similar to those on classical memory B cells. In contrast to naive cells, the majority of CD21(-/low) cells lack expression of the ABCB1 transporter. Stimulation with a combination of BCR, Toll-like receptor (TLR)-7/8 and interleukin (IL)-2 induces proliferation and differentiation of the CD21(-/low) B cells comparable to CD21(+) CD27(+) memory B cells. The response excluding BCR agonist is not on par with that of classical memory B cells, although clearly above that of naive B cells. This is ascribed to a weaker response by the CD38(-) 24(low) subset, implying that some memorycells require not only TLR but also BCR triggering. We conclude that the CD21(-/low) cells in healthy donors are memory B cells. PMID:27010233

  13. Bone marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells

    Directory of Open Access Journals (Sweden)

    Francesca eDi Rosa

    2016-02-01

    Full Text Available Changes in T cell trafficking accompany the naïve to memory T cell antigen-driven differentiation, which remains an incompletely defined developmental step. Upon priming, each naïve T cell encounters essential signals–i.e. antigen, co-stimuli and cytokines– in a secondary lymphoid organ; nevertheless its daughter effector and memory T cells recirculate and receive further signals during their migration through various lymphoid and non-lymphoid organs. These additional signals from tissue microenvironments have an impact on immune response features, including T cell effector function, expansion and contraction, memory differentiation, long-term maintenance and recruitment upon antigenic re-challenge into local and/or systemic responses. The critical role of T cell trafficking in providing efficient T cell memory has long been a focus of interest. It is now well recognized that naïve and memory T cells have different migratory pathways, and that memory T cells are heterogeneous with respect to their trafficking. We and others have observed that, long time after priming, memory T cells are preferentially found in certain niches such as the bone marrow or at the skin/mucosal site of pathogen entry, even in the absence of residual antigen. The different underlying mechanisms and peculiarities of resulting immunity are currently under study. In this review, we summarize key findings on bone marrow and tissue-resident memory T cells and revisit some issues in memory T cell maintenance within such niches. Moreover, we discuss bone marrow seeding by memory T cells in the context of migration patterns and protective functions of either recirculating or tissue-resident memory T cells.

  14. Doped SbTe phase change material in memory cells

    NARCIS (Netherlands)

    Zandt, in ‘t M.A.A.; Jedema, F.J.; Gravesteijn, D.J.; Attenborough, K.; Wolters, R.A.M.

    2009-01-01

    Phase Change Random Access Memory (PCRAM) is investigated as replacement for Flash. The memory concept is based on switching a chalcogenide from the crystalline (low ohmic) to the amorphous (high ohmic) state and vice versa. Basically two memory cell concepts exist: the Ovonic Unified Memory (OUM) a

  15. Glucocorticoids boost stimulus-response memory formation in humans.

    Science.gov (United States)

    Guenzel, Friederike M; Wolf, Oliver T; Schwabe, Lars

    2014-07-01

    Stress affects memory beyond hippocampus-dependent spatial or episodic memory processes. In particular, stress may influence also striatum-dependent stimulus-response (S-R) memory processes. Rodent studies point to an important role of glucocorticoids in the modulation of S-R memory. However, whether glucocorticoids influence S-R memory processes in humans is still unknown. Therefore, we examined in the current experiment the impact of glucocorticoids on the formation of S-R memories in humans. For this purpose, healthy men and women received either hydrocortisone or a placebo 45 min before completing an S-R association learning task and an S-R navigation task. In addition, participants performed also a virtual spatial navigation task and a spatial navigation task in a real environment. Memory of all four learning tasks was tested one week later. Our data showed that hydrocortisone before learning enhanced memory of the S-R association learning task. Moreover, hydrocortisone enhanced the memory of the virtual spatial navigation task, mainly in women. Memory performance in the other tasks remained unaffected by hydrocortisone. These findings provide first evidence that glucocorticoids may facilitate S-R memory formation processes in humans.

  16. Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis.

    Science.gov (United States)

    Mahanonda, Rangsini; Champaiboon, Chantrakorn; Subbalekha, Keskanya; Sa-Ard-Iam, Noppadol; Rattanathammatada, Warattaya; Thawanaphong, Saranya; Rerkyen, Pimprapa; Yoshimura, Fuminobu; Nagano, Keiji; Lang, Niklaus P; Pichyangkul, Sathit

    2016-08-01

    The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19(+)CD27(+)CD38(-) memory B cells, the major B cell component in periodontitis was CD19(+)CD27(+)CD38(+)CD138(+)HLA-DR(low) plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell-activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis. PMID:27335500

  17. Bone Marrow T Cells and the Integrated Functions of Recirculating and Tissue-Resident Memory T Cells.

    Science.gov (United States)

    Di Rosa, Francesca; Gebhardt, Thomas

    2016-01-01

    Changes in T cell trafficking accompany the naive to memory T cell antigen-driven differentiation, which remains an incompletely defined developmental step. Upon priming, each naive T cell encounters essential signals - i.e., antigen, co-stimuli and cytokines - in a secondary lymphoid organ; nevertheless, its daughter effector and memory T cells recirculate and receive further signals during their migration through various lymphoid and non-lymphoid organs. These additional signals from tissue microenvironments have an impact on immune response features, including T cell effector function, expansion and contraction, memory differentiation, long-term maintenance, and recruitment upon antigenic rechallenge into local and/or systemic responses. The critical role of T cell trafficking in providing efficient T cell memory has long been a focus of interest. It is now well recognized that naive and memory T cells have different migratory pathways, and that memory T cells are heterogeneous with respect to their trafficking. We and others have observed that, long time after priming, memory T cells are preferentially found in certain niches such as the bone marrow (BM) or at the skin/mucosal site of pathogen entry, even in the absence of residual antigen. The different underlying mechanisms and peculiarities of resulting immunity are currently under study. In this review, we summarize key findings on BM and tissue-resident memory (TRM) T cells and revisit some issues in memory T cell maintenance within such niches. Moreover, we discuss BM seeding by memory T cells in the context of migration patterns and protective functions of either recirculating or TRM T cells. PMID:26909081

  18. Exploiting human memory B cell heterogeneity for improved vaccine efficacy

    Directory of Open Access Journals (Sweden)

    Noel Thomas Pauli

    2011-12-01

    Full Text Available The major goal in vaccination is establishment of long-term, prophylactic humoral memory to a pathogen. Two major components to long-lived humoral memory are plasma cells for the production of specific immunoglobulin and memory B cells that survey for their specific antigen in the periphery for later affinity maturation, proliferation, and differentiation. The study of human B cell memory has been aided by the discovery of a general marker for B cell memory, expression of CD27; however, new data suggests the existence of CD27- memory B cells as well. These recently described non-canonical memory populations have increasingly pointed to the heterogeneity of the memory compartment. The novel B memory subsets in humans appear to have unique origins, localization, and functions compared to what was considered to be a classical memory B cell. In this article, we review the known B cell memory subsets, the establishment of B cell memory in vaccination and infection, and how understanding these newly described subsets can inform vaccine design and disease treatment.

  19. IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists.

    Science.gov (United States)

    Desbois, Mélanie; Le Vu, Pauline; Coutzac, Clélia; Marcheteau, Elie; Béal, Coralie; Terme, Magali; Gey, Alain; Morisseau, Sébastien; Teppaz, Géraldine; Boselli, Lisa; Jacques, Yannick; Béchard, David; Tartour, Eric; Cassard, Lydie; Chaput, Nathalie

    2016-07-01

    Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi(+) domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)(high) T cell Ig mucin-3(+) CD8(+) T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8(+) T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8(+) T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity. PMID:27217584

  20. Trilayer Tunnel Selectors for Memristor Memory Cells.

    Science.gov (United States)

    Choi, Byung Joon; Zhang, Jiaming; Norris, Kate; Gibson, Gary; Kim, Kyung Min; Jackson, Warren; Zhang, Min-Xian Max; Li, Zhiyong; Yang, J Joshua; Williams, R Stanley

    2016-01-13

    An integrated memory cell with a mem-ristor and a trilayer crested barrier selector, showing repeatable nonlinear current-voltage switching loops is presented. The fully atomic-layer-deposited TaN1+x /Ta2 O5 /TaN1+x crested barrier selector yields a large nonlinearity (>10(4) ), high endurance (>10(8) ), low variability, and low temperature dependence. PMID:26584142

  1. Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates.

    Science.gov (United States)

    Poirier, Nicolas; Chevalier, Melanie; Mary, Caroline; Hervouet, Jeremy; Minault, David; Baker, Paul; Ville, Simon; Le Bas-Bernardet, Stephanie; Dilek, Nahzli; Belarif, Lyssia; Cassagnau, Elisabeth; Scobie, Linda; Blancho, Gilles; Vanhove, Bernard

    2016-01-01

    Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation. PMID:26597009

  2. Lineage relationship of effector and memory T cells

    OpenAIRE

    Restifo, Nicholas P; Gattinoni, Luca

    2013-01-01

    Adaptive immunity is characterized by the ability to form long-lived immunological memory. Upon re-exposure to antigen, memory T cells respond more rapidly and robustly than naïve T cells, providing better clearance of pathogens. Recent reviews have reinforced the text-book view that memory T cells arise from effector cells. Although this notion is teleologically appealing, emerging data is more consistent with a model where naïve cells directly develop into memory cells without transitioning...

  3. The nucleocapsid protein of Rift Valley fever virus is a potent human CD8+ T cell antigen and elicits memory responses.

    Directory of Open Access Journals (Sweden)

    Weidong Xu

    Full Text Available There is no licensed human vaccine currently available for Rift Valley Fever Virus (RVFV, a Category A high priority pathogen and a serious zoonotic threat. While neutralizing antibodies targeting the viral glycoproteins are protective, they appear late in the course of infection, and may not be induced in time to prevent a natural or bioterrorism-induced outbreak. Here we examined the immunogenicity of RVFV nucleocapsid (N protein as a CD8(+ T cell antigen with the potential for inducing rapid protection after vaccination. HLA-A*0201 (A2-restricted epitopic determinants were identified with N-specific CD8(+ T cells from eight healthy donors that were primed with dendritic cells transduced to express N, and subsequently expanded in vitro by weekly re-stimulations with monocytes pulsed with 59 15mer overlapping peptides (OLPs across N. Two immunodominant epitopes, VT9 (VLSEWLPVT, N(121-129 and IL9 (ILDAHSLYL, N165-173, were defined. VT9- and IL9-specific CD8(+ T cells identified by tetramer staining were cytotoxic and polyfunctional, characteristics deemed important for viral control in vivo. These peptides induced specific CD8(+ T cell responses in A2-transgenic mice, and more importantly, potent N-specific CD8(+ T cell reactivities, including VT9- and IL9-specific ones, were mounted by mice after a booster vaccination with the live attenuated RVF MP-12. Our data suggest that the RVFV N protein is a potent human T cell immunogen capable of eliciting broad, immunodominant CD8(+ T cell responses that are potentially protective. Understanding the immune responses to the nucleocapsid is central to the design of an effective RVFV vaccine irrespective of whether this viral protein is effective as a stand-alone immunogen or only in combination with other RVFV antigens.

  4. Characterising B cell numbers and memory B cells in HIV infected and uninfected Malawian adults

    Directory of Open Access Journals (Sweden)

    Gordon Stephen

    2010-09-01

    Full Text Available Abstract Background Untreated human immunodeficiency virus (HIV disease disrupts B cell populations causing reduced memory and reduced naïve resting B cells leading to increases in specific co-infections and impaired responses to vaccines. To what extent antiretroviral treatment reverses these changes in an African population is uncertain. Methods A cross-sectional study was performed. We recruited HIV-uninfected and HIV-infected Malawian adults both on and off antiretroviral therapy attending the Queen Elizabeth Central hospital in Malawi. Using flow cytometry, we enumerated B cells and characterized memory B cells and compared these measurements by the different recruitment groups. Results Overall 64 participants were recruited - 20 HIV uninfected (HIV-, 30 HIV infected ART naïve (HIV+N and 14 HIV-infected ART treated (HIV+T. ART treatment had been taken for a median of 33 months (Range 12-60 months. Compared to HIV- the HIV+N adults had low absolute number of naïve resting B cells (111 vs. 180 cells/μl p = 0.008; reduced memory B cells (27 vs. 51 cells/μl p = 0.0008. The HIV+T adults had B-cell numbers similar to HIV- except for memory B cells that remained significantly lower (30 vs. 51 cells/μl p = 0.02. In the HIV+N group we did not find an association between CD4 count and B cell numbers. Conclusions HIV infected Malawian adults have abnormal B-cell numbers. Individuals treated with ART show a return to normal in B-cell numbers but a persistent deficit in the memory subset is noted. This has important implications for long term susceptibility to co-infections and should be evaluated further in a larger cohort study.

  5. Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection.

    Directory of Open Access Journals (Sweden)

    Matthew D Martin

    2015-10-01

    Full Text Available Memory CD8 T cells confer increased protection to immune hosts upon secondary viral, bacterial, and parasitic infections. The level of protection provided depends on the numbers, quality (functional ability, and location of memory CD8 T cells present at the time of infection. While primary memory CD8 T cells can be maintained for the life of the host, the full extent of phenotypic and functional changes that occur over time after initial antigen encounter remains poorly characterized. Here we show that critical properties of circulating primary memory CD8 T cells, including location, phenotype, cytokine production, maintenance, secondary proliferation, secondary memory generation potential, and mitochondrial function change with time after infection. Interestingly, phenotypic and functional alterations in the memory population are not due solely to shifts in the ratio of effector (CD62Llo and central memory (CD62Lhi cells, but also occur within defined CD62Lhi memory CD8 T cell subsets. CD62Lhi memory cells retain the ability to efficiently produce cytokines with time after infection. However, while it is was not formally tested whether changes in CD62Lhi memory CD8 T cells over time occur in a cell intrinsic manner or are due to selective death and/or survival, the gene expression profiles of CD62Lhi memory CD8 T cells change, phenotypic heterogeneity decreases, and mitochondrial function and proliferative capacity in either a lymphopenic environment or in response to antigen re-encounter increase with time. Importantly, and in accordance with their enhanced proliferative and metabolic capabilities, protection provided against chronic LCMV clone-13 infection increases over time for both circulating memory CD8 T cell populations and for CD62Lhi memory cells. Taken together, the data in this study reveal that memory CD8 T cells continue to change with time after infection and suggest that the outcome of vaccination strategies designed to elicit

  6. Dendritic Cells Enhance HIV Infection of Memory CD4(+) T Cells in Human Lymphoid Tissues.

    Science.gov (United States)

    Reyes-Rodriguez, Angel L; Reuter, Morgan A; McDonald, David

    2016-02-01

    Dendritic cells (DCs) play a key role in controlling infections by coordinating innate and adaptive immune responses to invading pathogens. Paradoxically, DCs can increase HIV-1 dissemination in vitro by binding and transferring infectious virions to CD4(+) T cells, a process called transinfection. Transinfection has been well characterized in cultured cell lines and circulating primary T cells, but it is unknown whether DCs enhance infection of CD4(+) T cells in vivo. In untreated HIV infection, massive CD4(+) T-cell infection and depletion occur in secondary lymphoid tissues long before decline is evident in the peripheral circulation. To study the role of DCs in HIV infection of lymphoid tissues, we utilized human tonsil tissues, cultured either as tissue blocks or as aggregate suspension cultures, in single-round infection experiments. In these experiments, addition of monocyte-derived DCs (MDDCs) to the cultures increased T-cell infection, particularly in CD4(+) T cells expressing lower levels of HLA-DR. Subset analysis demonstrated that MDDCs increased HIV-1 infection of central and effector memory T-cell populations. Depletion of endogenous myeloid DCs (myDCs) from the cultures decreased memory T-cell infection, and readdition of MDDCs restored infection to predepletion levels. Using an HIV-1 fusion assay, we found that MDDCs equally increased HIV delivery into naïve, central, and effector memory T cells in the cultures, whereas predepletion of myDCs reduced fusion into memory T cells. Together, these data suggest that resident myDCs facilitate memory T-cell infection in lymphoid tissues, implicating DC-mediated transinfection in driving HIV dissemination within these tissues in untreated HIV/AIDS.

  7. Multi-layer graphene membrane based memory cell

    Science.gov (United States)

    Siahlo, Andrei I.; Popov, Andrey M.; Poklonski, Nikolai A.; Lozovik, Yurii E.; Vyrko, Sergey A.; Ratkevich, Sergey V.

    2016-10-01

    The scheme and operational principles of the nanoelectromechanical memory cell based on the bending of a multi-layer graphene membrane by the electrostatic force are proposed. An analysis of the memory cell total energy as a function of the memory cell sizes is used to determine the sizes corresponding to a bistable memory cell with the conducting ON and non-conducting OFF states and to calculate the switching voltage between the OFF and ON states. It is shown that a potential barrier between the OFF and ON states is huge for practically all sizes of a bistable memory cell which excludes spontaneous switching and allows the proposed memory cell to be used for long-term archival storage.

  8. An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation.

    Directory of Open Access Journals (Sweden)

    Yoshiko Iwai

    Full Text Available Rapid proliferation is one of the important features of memory CD8(+ T cells, ensuring rapid clearance of reinfection. Although several cytokines such as IL-15 and IL-7 regulate relatively slow homeostatic proliferation of memory T cells during the maintenance phase, it is unknown how memory T cells can proliferate more quickly than naïve T cells upon antigen stimulation. To examine antigen-specific CD8(+ T cell proliferation in recall responses in vivo, we targeted a model antigen, ovalbumin(OVA, to DEC-205(+ dendritic cells (DCs with a CD40 maturation stimulus. This led to the induction of functional memory CD8(+ T cells, which showed rapid proliferation and multiple cytokine production (IFN-gamma, IL-2, TNF-alpha during the secondary challenge to DC-targeted antigen. Upon antigen-presentation, IL-18, an IFN-gamma-inducing factor, accumulated at the DC:T cell synapse. Surprisingly, IFN-gamma receptors were required to augment IL-18 production from DCs. Mice genetically deficient for IL-18 or IFN-gamma-receptor 1 also showed delayed expansion of memory CD8(+ T cells in vivo. These results indicate that a positive regulatory loop involving IFN-gamma and IL-18 signaling contributes to the accelerated memory CD8(+ T cell proliferation during a recall response to antigen presented by DCs.

  9. T Cell Memory in the Context of Persistent Herpes Viral Infections

    Directory of Open Access Journals (Sweden)

    Nicole Torti

    2012-07-01

    Full Text Available The generation of a functional memory T cell pool upon primary encounter with an infectious pathogen is, in combination with humoral immunity, an essential process to confer protective immunity against reencounters with the same pathogen. A prerequisite for the generation and maintenance of long-lived memory T cells is the clearance of antigen after infection, which is fulfilled upon resolution of acute viral infections. Memory T cells play also a fundamental role during persistent viral infections by contributing to relative control and immuosurveillance of active replication or viral reactivation, respectively. However, the dynamics, the phenotype, the mechanisms of maintenance and the functionality of memory T cells which develop upon acute/resolved infection as opposed to chronic/latent infection differ substantially. In this review we summarize current knowledge about memory CD8 T cell responses elicited during α-, β-, and γ-herpes viral infections with major emphasis on the induction, maintenance and function of virus-specific memory CD8 T cells during viral latency and we discuss how the peculiar features of these memory CD8 T cell responses are related to the biology of these persistently infecting viruses.

  10. Human memory T cells: generation, compartmentalization and homeostasis

    OpenAIRE

    Farber, Donna L.; Yudanin, Naomi A.; Restifo, Nicholas P

    2013-01-01

    Memory T cells comprise the most abundant lymphocyte population in the body for the majority of one’s lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the decades-long exposure to multiple pathogens that occurs in humans. Here, we review studies focused on human memory T cells that reveal key properties including subset heterogeneity and diverse tissue residence in multiple mucosal and lymph...

  11. Effects of ion beams on flash memory cells

    OpenAIRE

    Obrenović Marija D.; Lazarević Đorđe R.; Dolićanin Edin Ć.; Vujisić Miloš Lj.

    2014-01-01

    This paper deals with the flash memory reliability in terms of the ionizing radiation effects. In fact, the reliability of flash memory depends on physico-chemical restrictions of electrostatic nature due to the effects of ionizing radiation. The presented results are actual as a high degree of integrated components miniaturization affects the memory sensitivity, while the role of memories in the solar cells management system for space flights is increasing...

  12. Analytical Model of Nano-Electromechanical (NEM) Nonvolatile Memory Cells

    Science.gov (United States)

    Han, Boram; Choi, Woo Young

    The fringe field effects of nano-electromechanical (NEM) nonvolatile memory cells have been investigated analytically for the accurate evaluation of NEM memory cells. As the beam width is scaled down, fringe field effect becomes more severe. It has been observed that pull-in, release and hysteresis voltage decrease more than our prediction. Also, the fringe field on cell characteristics has been discussed.

  13. Low power and reliable SRAM memory cell and array design

    CERN Document Server

    Ishibashi, Koichiro

    2011-01-01

    Success in the development of recent advanced semiconductor device technologies is due to the success of SRAM memory cells. This book addresses various issues for designing SRAM memory cells for advanced CMOS technology. To study LSI design, SRAM cell design is the best materials subject because issues about variability, leakage and reliability have to be taken into account for the design.

  14. Lineage relationship of effector and memory T cells

    Science.gov (United States)

    Restifo, Nicholas P.; Gattinoni, Luca

    2013-01-01

    Adaptive immunity is characterized by the ability to form long-lived immunological memory. Upon re-exposure to antigen, memory T cells respond more rapidly and robustly than naïve T cells, providing better clearance of pathogens. Recent reviews have reinforced the text-book view that memory T cells arise from effector cells. Although this notion is teleologically appealing, emerging data is more consistent with a model where naïve cells directly develop into memory cells without transitioning through an effector stage. A clear understanding of the lineage relationships between memory and effector cells has profound implications for the design of vaccines and for the development of effective T cell-based therapies. PMID:24148236

  15. Human memory T cells: generation, compartmentalization and homeostasis

    Science.gov (United States)

    Farber, Donna L.; Yudanin, Naomi A.; Restifo, Nicholas P.

    2014-01-01

    Memory T cells comprise the most abundant lymphocyte population in the body for the majority of one’s lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the decades-long exposure to multiple pathogens that occurs in humans. Here, we review studies focused on human memory T cells that reveal key properties including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also discuss how the function and adaptability of human memory T cells depend on spatial and temporal compartmentalization. PMID:24336101

  16. Water-responsive shape memory hybrid: Design concept and demonstration

    Directory of Open Access Journals (Sweden)

    2011-05-01

    Full Text Available Shape memory materials are featured by their ability to recover their original shapes when a particular stimulus, such as heat, light, magnetic field, even moisture/water, etc. is applied. However, it is not an easy task for non-professionals to synthesize a shape memory material which can meet all the requirements of a particular application. Even for professionals, like materials researchers, it could involve tedious trial and error procedures. In this paper, the concept of water-responsive shape memory hybrid is proposed and the advantages are demonstrated by two examples. The hybrid concept is versatile and can be easily accessed by those even without much polymer/chemistry background. Moreover, the performance of such hybrids can be well-predicted. This concept can be further extended into solvent-responsive shape memory hybrids, which can be routinely designed and realized in a Do-It-Yourself manner by almost anyone.

  17. Memory CD8+ T Cells: Orchestrators and Key Players of Innate Immunity?

    Science.gov (United States)

    Lauvau, Grégoire; Goriely, Stanislas

    2016-09-01

    Over the past decades, the dichotomy between innate and adaptive immune responses has largely dominated our understanding of immunology. Upon primary encounter with microbial pathogens, differentiation of adaptive immune cells into functional effectors usually takes several days or even longer, making them contribute to host protection only late during primary infection. However, once generated, antigen-experienced T lymphocytes can persist in the organism and constitute a pool of memory cells that mediate fast and effective protection to a recall infection with the same microbial pathogen. Herein, we challenge this classical paradigm by highlighting the "innate nature" of memory CD8+ T cells. First, within the thymus or in the periphery, naïve CD8+ T cells may acquire phenotypic and functional characteristics of memory CD8+ T cells independently of challenge with foreign antigens. Second, both the "unconventional" and the "conventional" memory cells can rapidly express protective effector functions in response to sets of inflammatory cytokines and chemokines signals, independent of cognate antigen triggering. Third, memory CD8+ T cells can act by orchestrating the recruitment, activation, and licensing of innate cells, leading to broad antimicrobial states. Thus, collectively, memory CD8+ T cells may represent important actors of innate immune defenses.

  18. Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria in the mouse.

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    Marc Bajénoff

    Full Text Available Memory CD8(+ T cells represent an important effector arm of the immune response in maintaining long-lived protective immunity against viruses and some intracellular bacteria such as Listeria monocytogenes (L.m. Memory CD8(+ T cells are endowed with enhanced antimicrobial effector functions that perfectly tail them to rapidly eradicate invading pathogens. It is largely accepted that these functions are sufficient to explain how memory CD8(+ T cells can mediate rapid protection. However, it is important to point out that such improved functional features would be useless if memory cells were unable to rapidly find the pathogen loaded/infected cells within the infected organ. Growing evidences suggest that the anatomy of secondary lymphoid organs (SLOs fosters the cellular interactions required to initiate naive adaptive immune responses. However, very little is known on how the SLOs structures regulate memory immune responses. Using Listeria monocytogenes (L.m as a murine infection model and imaging techniques, we have investigated if and how the architecture of the spleen plays a role in the reactivation of memory CD8(+ T cells and the subsequent control of L.m growth. We observed that in the mouse, memory CD8(+ T cells start to control L.m burden 6 hours after the challenge infection. At this very early time point, L.m-specific and non-specific memory CD8(+ T cells localize in the splenic red pulp and form clusters around L.m infected cells while naïve CD8(+ T cells remain in the white pulp. Within these clusters that only last few hours, memory CD8(+ T produce inflammatory cytokines such as IFN-gamma and CCL3 nearby infected myeloid cells known to be crucial for L.m killing. Altogether, we describe how memory CD8(+ T cells trafficking properties and the splenic micro-anatomy conjugate to create a spatio-temporal window during which memory CD8(+ T cells provide a local response by secreting effector molecules around infected cells.

  19. Dissociating markers of senescence and protective ability in memory T cells.

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    Martin Prlic

    Full Text Available No unique transcription factor or biomarker has been identified to reliably distinguish effector from memory T cells. Instead a set of surface markers including IL-7Rα and KLRG1 is commonly used to predict the potential of CD8 effector T cells to differentiate into memory cells. Similarly, these surface markers together with the tumor necrosis factor family member CD27 are frequently used to predict a memory T cell's ability to mount a recall response. Expression of these markers changes every time a memory cell is stimulated and repeated stimulation can lead to T cell senescence and loss of memory T cell responsiveness. This is a concern for prime-boost vaccine strategies which repeatedly stimulate T cells with the aim of increasing memory T cell frequency. The molecular cues that cause senescence are still unknown, but cell division history is likely to play a major role. We sought to dissect the roles of inflammation and cell division history in developing T cell senescence and their impact on the expression pattern of commonly used markers of senescence. We developed a system that allows priming of CD8 T cells with minimal inflammation and without acquisition of maximal effector function, such as granzyme expression, but a cell division history similar to priming with systemic inflammation. Memory cells derived from minimal effector T cells are fully functional upon rechallenge, have full access to non-lymphoid tissue and appear to be less senescent by phenotype upon rechallenge. However, we report here that these currently used biomarkers to measure senescence do not predict proliferative potential or protective ability, but merely reflect initial priming conditions.

  20. Inflammatory monocytes and neutrophils are licensed to kill during memory responses in vivo.

    Directory of Open Access Journals (Sweden)

    Emilie Narni-Mancinelli

    2011-12-01

    Full Text Available Immunological memory is a hallmark of B and T lymphocytes that have undergone a previous encounter with a given antigen. It is assumed that memory cells mediate better protection of the host upon re-infection because of improved effector functions such as antibody production, cytotoxic activity and cytokine secretion. In contrast to cells of the adaptive immune system, innate immune cells are believed to exhibit a comparable functional effector response each time the same pathogen is encountered. Here, using mice infected by the intracellular bacterium Listeria monocytogenes, we show that during a recall bacterial infection, the chemokine CCL3 secreted by memory CD8+ T cells drives drastic modifications of the functional properties of several populations of phagocytes. We found that inflammatory ly6C+ monocytes and neutrophils largely mediated memory CD8+ T cell bacteriocidal activity by producing increased levels of reactive oxygen species (ROS, augmenting the pH of their phagosomes and inducing antimicrobial autophagy. These events allowed an extremely rapid control of bacterial growth in vivo and accounted for protective immunity. Therefore, our results provide evidence that cytotoxic memory CD8+ T cells can license distinct antimicrobial effector mechanisms of innate cells to efficiently clear pathogens.

  1. Investigating the relationship between false memory formation and emotional response

    OpenAIRE

    Albrazi, Amani

    2012-01-01

    Previous research on the phenomenon known as “False Memory” has shown that there is a direct relationship between false memory formation and emotional response. Conclusions on the whole were derived from results of experiments that evaluated false memory prompted solely by stimuli that represented positive and negative emotions. Research for this thesis sought to further the discussion through the use of experiments that targeted, more specifically, the five basic emotions d...

  2. Effect of laser treatment on the attachment and viability of mesenchymal stem cell responses on shape memory NiTi alloy

    Energy Technology Data Exchange (ETDEWEB)

    Chan, C.W., E-mail: c.w.chan@qub.ac.uk [School of Mechanical and Aerospace Engineering, Queen' s University, Belfast, Northern Ireland (United Kingdom); Hussain, I. [School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln, Lincolnshire LN6 7TU (United Kingdom); Waugh, D.G.; Lawrence, J. [Laser Engineering and Manufacturing Research Group, Faculty of Science and Engineering, University of Chester, Parkgate Road, Chester, CH1 4BJ (United Kingdom); Man, H.C. [Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong (China)

    2014-09-01

    The objectives of this study were to investigate the effect of laser-induced surface features on the morphology, attachment and viability of mesenchymal stem cells (MSCs) at different periods of time, and to evaluate the biocompatibility of different zones: laser-melted zone (MZ), heat-affected zone (HAZ) and base metal (BM) in laser-treated NiTi alloy. The surface morphology and composition were studied by scanning electron microscope (SEM) and X-ray photoemission spectroscopy (XPS), respectively. The cell morphology was examined by SEM while the cell counting and viability measurements were done by hemocytometer and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. The results indicated that the laser-induced surface features, such as surface roughening, presence of anisotropic dendritic pattern and complete surface Ni oxidation were beneficial to improve the biocompatibility of NiTi as evidenced by the highest cell attachment (4 days of culture) and viability (7 days of culture) found in the MZ. The biocompatibility of the MZ was the best, followed by the BM with the HAZ being the worst. The defective and porous oxide layer as well as the coarse grained structure might attribute to the inferior cell attachment (4 days of culture) and viability (7 days of culture) on the HAZ compared with the BM which has similar surface morphology. - Highlights: • Laser-treated surface induces a more spreading cell morphology than the non-treated. • Laser-treated surface shows higher cell attachment and viability than the non-treated. • Laser surface treatment is a feasible method to improve the responses of MSCs. • The improvement is attributed to the surface features induced by laser treatment.

  3. Activated iNKT cells promote memory CD8+ T cell differentiation during viral infection.

    Directory of Open Access Journals (Sweden)

    Emma C Reilly

    Full Text Available α-Galactosylceramide (α-GalCer is the prototypical lipid ligand for invariant NKT cells. Recent studies have proposed that α-GalCer is an effective adjuvant in vaccination against a range of immune challenges, however its mechanism of action has not been completely elucidated. A variety of delivery methods have been examined including pulsing dendritic cells with α-GalCer to optimize the potential of α-GalCer. These methods are currently being used in a variety of clinical trials in patients with advanced cancer but cannot be used in the context of vaccine development against pathogens due to their complexity. Using a simple delivery method, we evaluated α-GalCer adjuvant properties, using the mouse model for cytomegalovirus (MCMV. We measured several key parameters of the immune response to MCMV, including inflammation, effector, and central memory CD8(+ T cell responses. We found that α-GalCer injection at the time of the infection decreases viral titers, alters the kinetics of the inflammatory response, and promotes both increased frequencies and numbers of virus-specific memory CD8(+ T cells. Overall, our data suggest that iNKT cell activation by α-GalCer promotes the development of long-term protective immunity through increased fitness of central memory CD8(+ T cells, as a consequence of reduced inflammation.

  4. A four-state memory cell based on magnetoelectric composite

    Institute of Scientific and Technical Information of China (English)

    SHI Zhan; WANG CuiPing; LIU XinJun; NAN OeWen

    2008-01-01

    A four-state memory can store four states in each memory cell. We designed a four-state memory cell using Co/PZT magnetoelectric composite and observed a broad magnetoelectric hysteretic output loop on applying magnetic field. Based on magnetoelectric hysteresis, we developed a read method by ap-plying a bias magnetic field on the memory cell. Results gave clearly four-state signals of 15.8, -4.4, 5.5 and -11.3 μV, which demonstrated the feasibility of our design.

  5. Robust hippocampal responsivity during retrieval of consolidated associative memory.

    Science.gov (United States)

    Hattori, Shoai; Chen, Lillian; Weiss, Craig; Disterhoft, John F

    2015-05-01

    A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories.

  6. Responsive Biomaterials: Advances in Materials Based on Shape-Memory Polymers.

    Science.gov (United States)

    Hardy, John G; Palma, Matteo; Wind, Shalom J; Biggs, Manus J

    2016-07-01

    Shape-memory polymers (SMPs) are morphologically responsive materials with potential for a variety of biomedical applications, particularly as devices for minimally invasive surgery and the delivery of therapeutics and cells for tissue engineering. A brief introduction to SMPs is followed by a discussion of the current progress toward the development of SMP-based biomaterials for clinically relevant biomedical applications.

  7. Remembering one's ID/E-ntity: E/ID protein regulation of T cell memory.

    Science.gov (United States)

    Omilusik, Kyla D; Shaw, Laura A; Goldrath, Ananda W

    2013-10-01

    Upon infection, CD8(+) T cells proliferate and differentiate into armed effector cells capable of eliminating the assaulting pathogen. Although the majority of the antigen-specific T cells will die as the immune response wanes, a few will survive indefinitely to establish the memory population and provide long-lived protection against reinfection. E protein transcription factors and their inhibitors, ID proteins, operate to balance expression of genes that control CD8(+) T cell differentiation through this process. Here, we discuss the role of ID2 and ID3 in promoting the generation and survival of effector and memory populations, particularly highlighting their reciprocal roles in shaping the CD8(+) T cell response unique to the inflammatory milieu. We further examine this coordinated control of gene expression in the context of additional transcription factors within the transcriptional network that programs CD8(+) effector and memory T cell differentiation.

  8. Distributed Shared Memory for the Cell Broadband Engine (DSMCBE)

    DEFF Research Database (Denmark)

    Larsen, Morten Nørgaard; Skovhede, Kenneth; Vinter, Brian

    2009-01-01

    in and out of non-coherent local storage blocks for each special processor element. In this paper we present a software library, namely the Distributed Shared Memory for the Cell Broadband Engine (DSMCBE). By using techniques known from distributed shared memory DSMCBE allows programmers to program the CELL...

  9. Dysfunctional memory CD8+ T cells after priming in the absence of the cell cycle regulator E2F4.

    Science.gov (United States)

    Bancos, Simona; Cao, Qingyu; Bowers, William J; Crispe, Ian Nicholas

    2009-01-01

    The transcriptional repressor E2F4 is important for cell cycle exit and terminal differentiation in epithelial cells, neuronal cells and adipocytes but its role in T lymphocytes proliferation and memory formation is not known. Herein, we investigated the function of E2F4 protein for the formation of functional murine memory T cells. Murine transgenic CD8+ T cells were infected in vitro with lentivirus vector expressing a shRNA targeted against E2F4 followed by in vitro stimulation with SIINFEKL antigenic peptide. For in vivo assays, transduced cells were injected into congenic mice which were then infected with HSV-OVA. The primary response, memory formation and secondary stimulation were determined for CD8+ lentivirus transduced cells. In the absence of E2F4 cell cycle repressor, activated CD8+ T cells underwent intensive proliferation in vitro and in vivo. These cells had the ability to differentiate into memory cells in vivo, but they were defective in recall proliferation. We show that transient suppression of E2F4 during CD8+ T cell priming enhances primary proliferation and has a negative effect on secondary stimulation. These findings demonstrate that the cell cycle repressor E2F4 is essential for the formation of functional memory T cells. A decrease in CD8+ T-lymphocyte compartment would diminish our capacity to control viral infections.

  10. Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development

    Directory of Open Access Journals (Sweden)

    Sema eKurtulus

    2013-01-01

    Full Text Available Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïve T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8+ T cells. For example, the effector CD8+ T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8+ T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8+ T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8+ T cell memory. Effector to memory transition of CD4+ T cells is less well characterized than CD8+ T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of

  11. Function of Helper T Cells in the Memory CTL-mediated Anti-tumor Immunity

    Institute of Scientific and Technical Information of China (English)

    高丰光; GermainJ.P.Fernendo; 刘文军

    2004-01-01

    Abstract To investigate the role of CD4+ helper T (Th) cells in the memory CTL-mediated anti-tumor immunity, the RAG-1 gene knock out mice were adoptively transferred with OT-1 cells to generate the memory CTL, the C57B1/6 mice immunized with the epitope peptide of OVA specific Th cells and with different adjuvants were adopfively transferred with these memory-CTLs, and then the animals were challenged with tumor cells EGT. It was found that although the simple immunization of mice with the epitope peptide of the OVA specific Th cells could generate more effect CTL, but this effect was not so strong enough to resist completely the challenges with tumor cells. Nevertheless, the memory CTL-mediated anti-tumor immune effect required the helps of Th1 and Th2 cells. The cross-regulation between Thl and Th2 cells seemed to be beneficial for the host to generate more effector CTL for mounting an efficient anti-tumor response. It concluded that the interaction between Thl and Th2 cells might be more important than the single subset of Th cells in the memory CTL-mediated anti-tumor immune response. More attention should be paid in this regard for the future studies.

  12. Non-hematopoietic cells in lymph nodes drive memory CD8 T cell inflation during murine cytomegalovirus infection.

    Directory of Open Access Journals (Sweden)

    Nicole Torti

    2011-10-01

    Full Text Available During human and murine cytomegalovirus (MCMV infection an exceptionally large virus-specific CD8 T cell pool is maintained in the periphery lifelong. This anomalous response is only seen for specific subsets of MCMV-specific CD8 T cells which are referred to as 'inflationary T cells'. How memory CD8 T cell inflation is induced and maintained is unclear, though their activated phenotype strongly suggests an involvement of persistent antigen encounter during MCMV latency. To dissect the cellular and molecular requirements for memory CD8 T cell inflation, we have generated a transgenic mouse expressing an MHC class I-restricted T cell receptor specific for an immunodominant inflationary epitope of MCMV. Through a series of adoptive transfer experiments we found that memory inflation was completely dependent on antigen presentation by non-hematopoietic cells, which are also the predominant site of MCMV latency. In particular, non-hematopoietic cells selectively induced robust proliferation of inflationary CD8 T cells in lymph nodes, where a majority of the inflationary CD8 T cells exhibit a central-memory phenotype, but not in peripheral tissues, where terminally differentiated inflationary T cells accumulate. These results indicate that continuous restimulation of central memory CD8 T cells in the lymph nodes by infected non-hematopoietic cells ensures the maintenance of a functional effector CD8 T pool in the periphery, providing protection against viral reactivation events.

  13. CD11b expression as a marker to distinguish between recently activated effector CD8(+) T cells and memory cells

    DEFF Research Database (Denmark)

    Christensen, Jeanette Erbo; Ørding Andreasen, Susanne; Christensen, Jan Pravsgaard;

    2001-01-01

    subset. Polyclonal virus-specific effector and memory CD8(+) T cells from lymphocytic choriomeningitis- and vesicular stomatitis virus-infected mice were visualized through staining for intracellular IFN-gamma or binding of MHC-peptide tetramers, and Mac-1 expression was evaluated. Naive T cells and most......CD8(+) T cells in different activation states have been difficult to identify phenotypically. In this study we have investigated whether Mac-1 (CD11b) expression can be used as a criterion to distinguish between recently activated effector cells and memory cells belonging to the CD8(+) T cell...... virus-specific memory CD8(+) T cells express little or no Mac-1 independent of the virus model employed. In contrast, the majority of CD8(+) T cells present during acute infection express a significant level of Mac-1 and, similarly, Mac-1 expression is found on secondary effectors generated in response...

  14. Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice.

    Science.gov (United States)

    Chen, Ching-I; Zhang, Li; Datta, Syamal K

    2016-01-01

    We studied effects of early and late apoptotic (necroptotic) cell products, related damage associated alarmins and TLR agonists, on hematopoietic stem and progenitor cells (HSPC). Surprisingly, normal HSPC themselves produced IL-17 and IL-21 after 1½days of stimulation, and the best stimulators were TLR 7/8 agonist; HMGB1-DNA; TLR 9 agonist, and necroptotic B cells. The stimulated HSPC expressed additional cytokines/mediators, directly causing rapid expansion of IL-17(+) memory CD4 T (Th17), and CD8 T (Tc17) cells, and antigen-experienced IL-17(+) T cells with "naïve" phenotype. In lupus marrow, HSPC were spontaneously pre-stimulated by endogenous signals to produce IL-17 and IL-21. In contrast to HSPC, megakaryocyte progenitors (MKP) did not produce IL-17, and unlike HSPC, they could process and present particulate apoptotic autoantigens to augment autoimmune memory Th17 response. Thus abnormally stimulated primitive hematopoietic progenitors augment expansion of IL-17 producing immune and autoimmune memory T cells in the bone marrow, which may affect central tolerance. PMID:26521071

  15. Memory enhancement after drinking ethanol: consolidation, interference, or response bias?

    Science.gov (United States)

    Tyson, P D; Schirmuly, M

    1994-11-01

    One explanation for memory facilitation is that alcohol has a short-term neurochemical stimulating effect on consolidating neural networks when material is learned before drinking. Contrary to the consolidation hypothesis, when the consolidation interval was manipulated the results showed that the effects of alcohol were not time dependent. Compared to placebo subjects, alcohol significantly facilitated the recall of 25 words whether administered immediately or 40 min after learning. In addition, alcohol significantly increased the memory of words associated with pictures when incidentally learned before drinking and significantly decreased incidental learning after drinking. Another explanation for memory facilitation is that alcohol's depressive physiological effect impairs the acquisition of new information, like sleeping after learning, and enhances memory by reducing subsequent interference. Consistent with the retroactive interference hypothesis, the effects of alcohol reduced interpolated interference, were greater on recall than recognition, and were immune to time delays. Contemporary theories view memory enhancement attributed to alcohol as indirectly influencing response biases and contextual cues associated with retrieval from episodic memory.

  16. Regulated selection of germinal-center cells into the memory B cell compartment.

    Science.gov (United States)

    Shinnakasu, Ryo; Inoue, Takeshi; Kometani, Kohei; Moriyama, Saya; Adachi, Yu; Nakayama, Manabu; Takahashi, Yoshimasa; Fukuyama, Hidehiro; Okada, Takaharu; Kurosaki, Tomohiro

    2016-07-01

    Despite the importance of memory B cells in protection from reinfection, how such memory cells are selected and generated during germinal-center (GC) reactions remains unclear. We found here that light-zone (LZ) GC B cells with B cell antigen receptors (BCRs) of lower affinity were prone to enter the memory B cell pool. Mechanistically, cells in this memory-prone fraction had higher expression of the transcriptional repressor Bach2 than that of their counterparts with BCRs of higher affinity. Haploinsufficiency of Bach2 resulted in reduced generation of memory B cells, independently of suppression of the gene encoding the transcription factor Blimp-1. Bach2 expression in GC cells was inversely correlated with the strength of help provided by T cells. Thus, we propose an instructive model in which weak help from T cells maintains relatively high expression of Bach2, which predisposes GC cells to enter the memory pool.

  17. Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

    Science.gov (United States)

    Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

    2015-10-01

    Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. PMID:26278659

  18. Glycyrrhiza uralensis flavonoids present in anti-asthma formula, ASHMI™, inhibit memory Th2 responses in vitro and in vivo

    OpenAIRE

    YANG, NAN; Patil, Sangita; Zhuge, Jian; Wen, Ming-Chun; Bolleddula, Jayaprakasam; Doddaga, Srinivasulu; Goldfarb, Joseph; Sampson, Hugh A.; Li, Xiu-Min

    2012-01-01

    Allergic asthma is associated with Th2-mediated inflammation. Several flavonoids were isolated from Glycyrrhiza uralensis, one of the herbs in the anti-asthma herbal medicine intervention, ASHMI. The aim of this investigation was to determine whether Glycyrrhiza uralensis flavonoids have inhibitory effects on memory Th2 responses in vitro, and antigen induced Th2 inflammation in vivo. The effects of three Glycyrrhiza uralensis flavonoids on effector memory Th2 cells, D10.G4.1 (D10 cells), wer...

  19. Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

    Science.gov (United States)

    Cubas, Rafael; van Grevenynghe, Julien; Wills, Saintedym; Kardava, Lela; Santich, Brian H; Buckner, Clarisa M; Muir, Roshell; Tardif, Virginie; Nichols, Carmen; Procopio, Francesco; He, Zhong; Metcalf, Talibah; Ghneim, Khader; Locci, Michela; Ancuta, Petronella; Routy, Jean-Pierre; Trautmann, Lydie; Li, Yuxing; McDermott, Adrian B; Koup, Rick A; Petrovas, Constantinos; Migueles, Steven A; Connors, Mark; Tomaras, Georgia D; Moir, Susan; Crotty, Shane; Haddad, Elias K

    2015-12-15

    Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

  20. Heart rate, startle response, and intrusive trauma memories.

    Science.gov (United States)

    Chou, Chia-Ying; La Marca, Roberto; Steptoe, Andrew; Brewin, Chris R

    2014-03-01

    The current study adopted the trauma film paradigm to examine potential moderators affecting heart rate (HR) as an indicator of peritraumatic psychological states and as a predictor of intrusive memories. We replicated previous findings that perifilm HR decreases predicted the development of intrusive images and further showed this effect to be specific to images rather than thoughts, and to detail rather than gist recognition memory. Moreover, a group of individuals showing both an atypical sudden reduction in HR after a startle stimulus and higher trait dissociation was identified. Only among these individuals was lower perifilm HR found to indicate higher state dissociation, fear, and anxiety, along with reduced vividness of intrusions. The current findings emphasize how peritraumatic physiological responses relate to emotional reactions and intrusive memory. The moderating role of individual difference in stress defense style was highlighted. PMID:24397333

  1. Thermomechanical Methodology for Stabilizing Shape Memory Alloy (SMA) Response

    Science.gov (United States)

    Padula, Santo A., II (Inventor)

    2016-01-01

    Methods and apparatuses for stabilizing the strain-temperature response for a shape memory alloy are provided. To perform stabilization of a second sample of the shape memory alloy, a first sample of the shape memory alloy is selected for isobaric treatment and the second sample is selected for isothermal treatment. When applying the isobaric treatment to the first sample, a constant stress is applied to the first sample. Temperature is also cycled from a minimum temperature to a maximum temperature until a strain on the first sample stabilizes. Once the strain on the first sample stabilizes, the isothermal treatment is performed on the second sample. During isothermal treatment, different levels of stress on the second sample are applied until a strain on the second sample matches the stabilized strain on the first sample.

  2. Photic memory for executive brain responses

    OpenAIRE

    Chellappa, Sarah Laxhmi; Ly, Julien; Meyer, Christelle; Balteau, Evelyne; Degueldre, Christian; Luxen, André; Phillips, Christophe; Cooper, Howard; Vandewalle, Gilles

    2014-01-01

    Light is a powerful stimulant for human alertness and cognition that can be easily administered to improve performance or counteract the negative impact of sleepiness, even during the day. Here, we show that prior exposure to longer wavelength light (orange), relative to shorter wavelength (blue), enhances the subsequent impact of light on executive brain responses. These findings emphasize the importance of light for human cognitive brain function and constitute compelling evidence in favor ...

  3. Abacavir-reactive memory T cells are present in drug naive individuals.

    Directory of Open Access Journals (Sweden)

    Andrew Lucas

    Full Text Available Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

  4. Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells.

    Science.gov (United States)

    Orent, William; Mchenry, Allison R; Rao, Deepak A; White, Charles; Klein, Hans-Ulrich; Bassil, Ribal; Srivastava, Gyan; Replogle, Joseph M; Raj, Towfique; Frangieh, Michael; Cimpean, Maria; Cuerdon, Nicole; Chibnik, Lori; Khoury, Samia J; Karlson, Elizabeth W; Brenner, Michael B; De Jager, Philip; Bradshaw, Elizabeth M; Elyaman, Wassim

    2016-01-15

    Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA. PMID:26604133

  5. A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality

    DEFF Research Database (Denmark)

    Holmkvist, P.; Roepstorff, K.; Uronen-Hansson, H.;

    2015-01-01

    Mucosal tissues contain large numbers of memory CD4+ T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4+ Tcells at barrier......, these results suggest that human memory IL-18Rα+DR3+CD4+ T cells may contribute to antigen-independent innate responses at barrier surfaces....

  6. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

    Science.gov (United States)

    Pulko, Vesna; Davies, John S; Martinez, Carmine; Lanteri, Marion C; Busch, Michael P; Diamond, Michael S; Knox, Kenneth; Bush, Erin C; Sims, Peter A; Sinari, Shripad; Billheimer, Dean; Haddad, Elias K; Murray, Kristy O; Wertheimer, Anne M; Nikolich-Žugich, Janko

    2016-08-01

    The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens. PMID:27270402

  7. Oct1 and OCA-B are selectively required for CD4 memory T cell function.

    Science.gov (United States)

    Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean

    2015-11-16

    Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. PMID:26481684

  8. Mass cytometry analysis shows that a novel memory phenotype B cell is expanded in multiple myeloma

    Science.gov (United States)

    Hansmann, Leo; Blum, Lisa; Ju, Chia-Hsin; Liedtke, Michaela; Robinson, William H.; Davis, Mark M.

    2015-01-01

    It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals and thus high resolution technologies are likely required. We used cytometry by time-of-flight (CyTOF) and next generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related pre-cancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 pre-cancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T, B, and natural killer cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0±0.7% (mean±SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27+) and naïve (CD24loCD38+) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells. PMID:25711758

  9. Working memory cells' behavior may be explained by cross-regional networks with synaptic facilitation.

    Directory of Open Access Journals (Sweden)

    Sergio Verduzco-Flores

    Full Text Available Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1 persistent fixed-frequency elevated rates above baseline, 2 elevated rates that decay throughout the tasks memory period, 3 rates that accelerate throughout the delay, and 4 patterns of inhibited firing (below baseline analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex.

  10. AMPKα1: A glucose sensor that controls CD8 T-cell memory

    OpenAIRE

    Finlay, David

    2013-01-01

    The adenosine monophosphate-activated protein kinase (AMPK) is activated by antigen receptor signals and energy stress in T cells. In many cell types, AMPK can maintain energy homeostasis and can enforce quiescence to limit energy demands. We consequently evaluated the importance of AMPK for controlling the transition of metabolically active effector CD8 T lymphocytes to the metabolically quiescent catabolic memory T cells during the contraction phase of the immune response. We show that AMPK...

  11. Thermo-Mechanical Methodology for Stabilizing Shape Memory Alloy Response

    Science.gov (United States)

    Padula, Santo

    2013-01-01

    This innovation is capable of significantly reducing the amount of time required to stabilize the strain-temperature response of a shape memory alloy (SMA). Unlike traditional stabilization processes that take days to weeks to achieve stabilized response, this innovation accomplishes stabilization in a matter of minutes, thus making it highly useful for the successful and practical implementation of SMA-based technologies in real-world applications. The innovation can also be applied to complex geometry components, not just simple geometries like wires or rods.

  12. Enumeration and Characterization of Human Memory T Cells by Enzyme-Linked Immunospot Assays

    Directory of Open Access Journals (Sweden)

    Sandra A. Calarota

    2013-01-01

    Full Text Available The enzyme-linked immunospot (ELISPOT assay has advanced into a useful and widely applicable tool for the evaluation of T-cell responses in both humans and animal models of diseases and/or vaccine candidates. Using synthetic peptides (either individually or as overlapping peptide mixtures or whole antigens, total lymphocyte or isolated T-cell subset responses can be assessed either after short-term stimulation (standard ELISPOT or after their expansion during a 10-day culture (cultured ELISPOT. Both assays detect different antigen-specific immune responses allowing the analysis of effector memory T cells and central memory T cells. This paper describes the principle of ELISPOT assays and discusses their application in the evaluation of immune correlates of clinical interest with a focus on the vaccine field.

  13. Single-Cell Memory Regulates a Neural Circuit for Sensory Behavior

    Directory of Open Access Journals (Sweden)

    Kyogo Kobayashi

    2016-01-01

    Full Text Available Unveiling the molecular and cellular mechanisms underlying memory has been a challenge for the past few decades. Although synaptic plasticity is proven to be essential for memory formation, the significance of “single-cell memory” still remains elusive. Here, we exploited a primary culture system for the analysis of C. elegans neurons and show that a single thermosensory neuron has an ability to form, retain, and reset a temperature memory. Genetic and proteomic analyses found that the expression of the single-cell memory exhibits inter-individual variability, which is controlled by the evolutionarily conserved CaMKI/IV and Raf pathway. The variable responses of a sensory neuron influenced the neural activity of downstream interneurons, suggesting that modulation of the sensory neurons ultimately determines the behavioral output in C. elegans. Our results provide proof of single-cell memory and suggest that the individual differences in neural responses at the single-cell level can confer individuality.

  14. Gamma ray effects on flash memory cell arrays

    Directory of Open Access Journals (Sweden)

    Dolićanin Edin Ć.

    2012-01-01

    Full Text Available Information stored in flash memories is physically represented by the absence or presence of charge on electrically isolated floating gates. Interaction of gamma rays with the insulators surrounding the floating gate produces effects that degrade the properties of memory cells, possibly leading to the corruption of the stored content. The cumulative nature of these effects is expressed through the total ionizing dose deposited by the gamma rays in the insulators surrounding the floating gate. Relying on both theory and experiment, we examine how the properties of cells in commercially available flash memories affect their sensitivity to gamma rays. Memory samples from several manufacturers, currently available on the market, can be compared with respect to data retention under gamma ray exposure.

  15. Decreased memory B cells and increased CD8 memory T cells in blood of breastfed children: the generation R study.

    Directory of Open Access Journals (Sweden)

    Michelle A E Jansen

    Full Text Available Breastfeeding provides a protective effect against infectious diseases in infancy. Still, immunological evidence for enhanced adaptive immunity in breastfed children remains inconclusive.To determine whether breastfeeding affects B- and T-cell memory in the first years of life.We performed immunophenotypic analysis on blood samples within a population-based prospective cohort study. Participants included children at 6 months (n=258, 14 months (n=166, 25 months (n=112 and 6 years of age (n=332 with both data on breastfeeding and blood lymphocytes. Total B- and T-cell numbers and their memory subsets were determined with 6-color flow cytometry. Mothers completed questionnaires on breastfeeding when their children were aged 2, 6, and 12 months. Multiple linear regression models with adjustments for potential confounders were performed.Per month continuation of breastfeeding, a 3% (95% CI -6, -1 decrease in CD27+IgM+, a 2% (95 CI % -5, -1 decrease in CD27+IgA+ and a 2% (95% CI -4, -1 decrease in CD27-IgG+ memory B cell numbers were observed at 6 months of age. CD8 T-cell numbers at 6 months of age were 20% (95% CI 3, 37 higher in breastfed than in non-breastfed infants. This was mainly found for central memory CD8 T cells and associated with exposure to breast milk, rather than duration. The same trend was observed at 14 months, but associations disappeared at older ages.Longer breastfeeding is associated with increased CD8 T-cell memory, but not B-cell memory numbers in the first 6 months of life. This transient skewing towards T cell memory might contribute to the protective effect against infectious diseases in infancy.

  16. Diminished Memory T-Cell Expansion Due to Delayed Kinetics of Antigen Expression by Lentivectors.

    Directory of Open Access Journals (Sweden)

    Karina Furmanov

    Full Text Available Memory CD8(+ T lymphocytes play a central role in protective immunity. In attempt to increase the frequencies of memory CD8(+ T cells, repeated immunizations with viral vectors are regularly explored. Lentivectors have emerged as a powerful vaccine modality with relatively low pre-existing and anti-vector immunity, thus, thought to be ideal for boosting memory T cells. Nevertheless, we found that lentivectors elicited diminished secondary T-cell responses that did not exceed those obtained by priming. This was not due to the presence of anti-vector immunity, as limited secondary responses were also observed following heterologous prime-boost immunizations. By dissecting the mechanisms involved in this process, we demonstrate that lentivectors trigger exceptionally slow kinetics of antigen expression, while optimal activation of lentivector-induced T cells relays on durable expression of the antigen. These qualities hamper secondary responses, since lentivector-encoded antigen is rapidly cleared by primary cytotoxic T cells that limit its presentation by dendritic cells. Indeed, blocking antigen clearance by cytotoxic T cells via FTY720 treatment, fully restored antigen presentation. Taken together, while low antigen expression is expected during secondary immunization with any vaccine vector, our results reveal that the intrinsic delayed expression kinetics of lentiviral-encoded antigen, further dampens secondary CD8(+ T-cell expansion.

  17. C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection.

    Science.gov (United States)

    Haque, Mohammad; Song, Jianyong; Fino, Kristin; Wang, Youfei; Sandhu, Praneet; Song, Xinmeng; Norbury, Christopher; Ni, Bing; Fang, Deyu; Salek-Ardakani, Shahram; Song, Jianxun

    2016-01-01

    The signalling mechanisms of costimulation in the development of memory T cells remain to be clarified. Here, we show that the transcription factor c-Myc in CD8(+) T cells is controlled by costimulatory molecules, which modulates the development of memory CD8(+) T cells. C-Myc expression was dramatically reduced in Cd28(-/-) or Ox40(-/-) memory CD8(+) T cells, and c-Myc over-expression substantially reversed the defects in the development of T-cell memory following viral infection. C-Myc regulated the expression of survivin, an inhibitor of apoptosis, which promoted the generation of virus-specific memory CD8(+) T cells. Moreover, over-expression of survivin with bcl-xL, a downstream molecule of NF-κB and intracellular target of costimulation that controls survival, in Cd28(-/-) or Ox40(-/-) CD8(+) T cells, reversed the defects in the generation of memory T cells in response to viral infection. These results identify c-Myc as a key controller of memory CD8(+) T cells from costimulatory signals.

  18. C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection.

    Science.gov (United States)

    Haque, Mohammad; Song, Jianyong; Fino, Kristin; Wang, Youfei; Sandhu, Praneet; Song, Xinmeng; Norbury, Christopher; Ni, Bing; Fang, Deyu; Salek-Ardakani, Shahram; Song, Jianxun

    2016-01-01

    The signalling mechanisms of costimulation in the development of memory T cells remain to be clarified. Here, we show that the transcription factor c-Myc in CD8(+) T cells is controlled by costimulatory molecules, which modulates the development of memory CD8(+) T cells. C-Myc expression was dramatically reduced in Cd28(-/-) or Ox40(-/-) memory CD8(+) T cells, and c-Myc over-expression substantially reversed the defects in the development of T-cell memory following viral infection. C-Myc regulated the expression of survivin, an inhibitor of apoptosis, which promoted the generation of virus-specific memory CD8(+) T cells. Moreover, over-expression of survivin with bcl-xL, a downstream molecule of NF-κB and intracellular target of costimulation that controls survival, in Cd28(-/-) or Ox40(-/-) CD8(+) T cells, reversed the defects in the generation of memory T cells in response to viral infection. These results identify c-Myc as a key controller of memory CD8(+) T cells from costimulatory signals. PMID:26791245

  19. The Effect of Cellular Stress on T and B Cell Memory Pathways in Immunized and Unimmunized BALB/c Mice*

    Science.gov (United States)

    Wang, Yufei; Rahman, Durdana; Mistry, Mukesh; Lehner, Thomas

    2016-01-01

    Immunological memory is a fundamental function of vaccination. The antigenic breakdown products of the vaccine may not persist, and undefined tonic stimulation has been proposed to maintain the specific memory. We have suggested that cellular stress agents to which the immune cells are constantly exposed may be responsible for tonic stimulation. Here we have studied four stress agents: sodium arsenite, an oxidative agent; Gramicidin, eliciting K+ efflux and calcium influx; dithiocarbamate, a metal ionophore; and aluminum hydroxide (alum), an immunological adjuvant. The aims of this study are to extend these investigations to T and B cell responses of unimmunized and ovalbumin (OVA)-immunized BALB/c mice, and furthermore, to ascertain whether stress is involved in optimal expression of memory B cells, as demonstrated in CD4+ T cells. Examination of the homeostatic pathway defined by IL-15/IL-15R (IL-15 receptor) interaction and the inflammasome pathway defined by the IL-1-IL-1R interaction between dendritic cells (DC) and CD4+ T cells suggests that both pathways are involved in the development of optimal expression of CD4+CD45RO+ memory T cells in unimmunized and OVA-immunized BALB/c mice. Furthermore, significant direct correlation was found between CD4+CD44+ memory T cells and both IL-15 of the homeostatic and IL-1β of the inflammasome pathways. However, CD19+CD27+ memory B cells in vivo seem to utilize only the IL-15/IL-15R homeostatic pathway, although the proliferative responses are enhanced by the stress agents. Altogether, stress agents may up-regulate unimmunized and OVA-immunized CD4+CD44+ memory T cells by the homeostatic and inflammasome pathways. However, the CD19+CD27+ memory B cells utilize only the homeostatic pathway. PMID:27502276

  20. Ultra-Low Voltage Class AB Switched Current Memory Cell

    DEFF Research Database (Denmark)

    Igor, Mucha

    1996-01-01

    This paper presents the theoretical basis for the design of class AB switched current memory cells employing floating-gate MOS transistors, suitable for ultra-low-voltage applications. To support the theoretical assumptions circuits based on these cells were designed using a CMOS process with...

  1. The Distribution of Human Stem Cell–like Memory T Cell in Lung Cancer

    Science.gov (United States)

    Hong, Hai; Gu, Yong; Sheng, Si Yuan; Lu, Chuan Gang; Zou, Jian Yong

    2016-01-01

    Human stem cell–like memory T (Tscm) cells are long-lived, self-renewing memory lymphocytes that can differentiate into effector cells and mediate strong antitumour response in murine model. The distribution and function of Tscm cells in human lung cancer remain unknown. In this study, we investigated the properties of human Tscm cells in the blood and lymph node of non–small cell lung cancer (NSCLC) patients. There were more CD4+ Tscm cells in blood from NSCLC patients than from healthy donors, fewer CD4+ and CD8+ TSCM cells in blood than in lymph node from NSCLC patients. To further analyze their properties, we stimulated peripheral blood mononuclear cells from NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4 and CD8 Tscm cells in blood produced interferon-γ significantly increased in NSCLC patients compare with healthy subjects. In addition, fewer Tscm cells produced interferon-γ in lymph node than in blood from NSCLC patients. Our results strongly suggest that the distribution and function of CD4 Tscm cells in NSCLC patients is upregulated. Understanding of the properties of stem-like memory T cells will supply a good rationale for designing the new adoptive immunotherapy in cancer. PMID:27244531

  2. Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice.

    Science.gov (United States)

    Ramakrishnan, Radha; Davidowitz, Andrew; Balu-Iyer, Sathy V

    2015-08-01

    A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naïve mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti-FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice.

  3. Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals.

    Science.gov (United States)

    Kim, Marie T; Kurup, Samarchith P; Starbeck-Miller, Gabriel R; Harty, John T

    2016-09-01

    As a result of the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. In this article, we show that dendritic cell (DC) immunization coupled with relatively early (days 1-3) or late (days 4-6) administration of enhanced IL-2 signals increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation and marked Bim-mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles that are more conducive to memory formation. Of note, downregulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role for CTLA-4 in downregulating B7 ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and anti-CTLA-4 blockade resulted in lower memory CD8 T cell numbers compared with the DC+early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 costimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation; thus, it should be considered in future T cell-vaccination strategies. PMID:27439516

  4. Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function.

    Science.gov (United States)

    Balmer, Maria L; Ma, Eric H; Bantug, Glenn R; Grählert, Jasmin; Pfister, Simona; Glatter, Timo; Jauch, Annaïse; Dimeloe, Sarah; Slack, Emma; Dehio, Philippe; Krzyzaniak, Magdalena A; King, Carolyn G; Burgener, Anne-Valérie; Fischer, Marco; Develioglu, Leyla; Belle, Réka; Recher, Mike; Bonilla, Weldy V; Macpherson, Andrew J; Hapfelmeier, Siegfried; Jones, Russell G; Hess, Christoph

    2016-06-21

    How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness. PMID:27212436

  5. Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination

    OpenAIRE

    Klebanoff, Christopher A.; Yu, Zhiya; Hwang, Leroy N.; Douglas C Palmer; Gattinoni, Luca; Restifo, Nicholas P

    2009-01-01

    Naive and memory CD8+ T cells can undergo programmed activation and expansion in response to a short T-cell receptor stimulus, but the extent to which in vitro programming can qualitatively substitute for an in vivo antigen stimulation remains unknown. We show that self-/tumor-reactive effector memory CD8+ T cells (TEM) programmed in vitro either with peptide-pulsed antigen-presenting cells or plate-bound anti-CD3/anti-CD28 embark on a highly stereotyped response of in vivo clonal expansion a...

  6. Cell response to surgery.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    OBJECTIVES: To describe the profound alterations in host immunity that are produced by major surgery as demonstrated by experimental and clinical studies, and to evaluate the benefits of therapeutic strategies aimed at attenuating perioperative immune dysfunction. DATA SOURCES: A review of the English-language literature was conducted, incorporating searches of the MEDLINE, EMBASE, and Cochrane collaboration databases to identify laboratory and clinical studies investigating the cellular response to surgery. STUDY SELECTION: Original articles and case reports describing immune dysfunction secondary to surgical trauma were included. DATA EXTRACTION: The results were compiled to show outcomes of different studies and were compared. DATA SYNTHESIS: Current evidence indicates that the early systemic inflammatory response syndrome observed after major surgery that is characterized by proinflammatory cytokine release, microcirculatory disturbance, and cell-mediated immune dysfunction is followed by a compensatory anti-inflammatory response syndrome, which predisposes the patient to opportunistic infection, multiple organ dysfunction syndrome, and death. Because there are currently no effective treatment options for multiple organ dysfunction syndrome, measures to prevent its onset should be initiated at an early stage. Accumulating experimental evidence suggests that targeted therapeutic strategies involving immunomodulatory agents such as interferon gamma, granulocyte colony-stimulating factor, the prostaglandin E(2) antagonist, indomethacin, and pentoxifylline may be used for the treatment of systemic inflammatory response syndrome to prevent the onset of multiple organ dysfunction syndrome. CONCLUSIONS: Surgical trauma produces profound immunological dysfunction. Therapeutic strategies directed at restoring immune homeostasis should aim to redress the physiological proinflammatory-anti-inflammatory cell imbalance associated with major surgery.

  7. The taming of the cell: shape-memory nanopatterns direct cell orientation

    Directory of Open Access Journals (Sweden)

    Ebara M

    2014-05-01

    development of spatiotemporal tunable materials to direct cell fate.Keywords: shape-memory surface, poly(ε-caprolactone, nanopatterns, temperature-responsive polymers, cell orientation

  8. Synthesis and characterization of phase change memory cells

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Phase change memory (PCM) cells based on Ge2Sb2Te5 were synthesized and investigated. Currentvoltage measurements demonstrated different final resistances. Transmission electron microscopy (TEM),high resolution electron microscopy (HREM) and the energy dispersive X-ray spectroscopy (EDS) analyses were used to characterize the microstructures of the PCM cells. The architectures,structures and defects in the cells including the deposited elemental distributions and the interfacial structures between electrodes and barrier layers were studied in detail.

  9. A Single Human Papillomavirus Vaccine Dose Improves B Cell Memory in Previously Infected Subjects.

    Science.gov (United States)

    Scherer, Erin M; Smith, Robin A; Gallego, Daniel F; Carter, Joseph J; Wipf, Gregory C; Hoyos, Manuela; Stern, Michael; Thurston, Tate; Trinklein, Nathan D; Wald, Anna; Galloway, Denise A

    2016-08-01

    Although licensed human papillomavirus (HPV) vaccines are most efficacious in persons never infected with HPV, they also reduce infection and disease in previously infected subjects, indicating natural immunity is not entirely protective against HPV re-infection. The aim of this exploratory study was to examine the B cell memory elicited by HPV infection and evaluate whether vaccination merely boosts antibody (Ab) levels in previously infected subjects or also improves the quality of B cell memory. Toward this end, the memory B cells (Bmem) of five unvaccinated, HPV-seropositive subjects were isolated and characterized, and subject recall responses to a single HPV vaccine dose were analyzed. Vaccination boosted Ab levels 24- to 930-fold (median 77-fold) and Bmem numbers 3- to 27-fold (median 6-fold). In addition, Abs cloned from naturally elicited Bmem were generally non-neutralizing, whereas all those isolated following vaccination were neutralizing. Moreover, Ab and plasmablast responses indicative of memory recall responses were only observed in two subjects. These results suggest HPV vaccination augments both the magnitude and quality of natural immunity and demonstrate that sexually active persons could also benefit from HPV vaccination. This study may have important public policy implications, especially for the older 'catch-up' group within the vaccine's target population. PMID:27423190

  10. A Single Human Papillomavirus Vaccine Dose Improves B Cell Memory in Previously Infected Subjects

    Directory of Open Access Journals (Sweden)

    Erin M. Scherer

    2016-08-01

    Full Text Available Although licensed human papillomavirus (HPV vaccines are most efficacious in persons never infected with HPV, they also reduce infection and disease in previously infected subjects, indicating natural immunity is not entirely protective against HPV re-infection. The aim of this exploratory study was to examine the B cell memory elicited by HPV infection and evaluate whether vaccination merely boosts antibody (Ab levels in previously infected subjects or also improves the quality of B cell memory. Toward this end, the memory B cells (Bmem of five unvaccinated, HPV-seropositive subjects were isolated and characterized, and subject recall responses to a single HPV vaccine dose were analyzed. Vaccination boosted Ab levels 24- to 930-fold (median 77-fold and Bmem numbers 3- to 27-fold (median 6-fold. In addition, Abs cloned from naturally elicited Bmem were generally non-neutralizing, whereas all those isolated following vaccination were neutralizing. Moreover, Ab and plasmablast responses indicative of memory recall responses were only observed in two subjects. These results suggest HPV vaccination augments both the magnitude and quality of natural immunity and demonstrate that sexually active persons could also benefit from HPV vaccination. This study may have important public policy implications, especially for the older ‘catch-up’ group within the vaccine's target population.

  11. Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection.

    Directory of Open Access Journals (Sweden)

    Erika J Crosby

    2014-02-01

    Full Text Available One of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. While persistent memory T cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. To address this issue, we utilized lymphocytic choriomeningitis virus (LCMV and Listeria monocytogenes immune mice to investigate whether bystander memory T cells influence Leishmania major infection. Despite similar parasite burdens, LCMV and Listeria immune mice exhibited a significant increase in leishmanial lesion size compared to mice infected with L. major alone. This increased lesion size was due to a severe inflammatory response, consisting not only of monocytes and neutrophils, but also significantly more CD8 T cells. Many of the CD8 T cells were LCMV specific and expressed gzmB and NKG2D, but unexpectedly expressed very little IFN-γ. Moreover, if CD8 T cells were depleted in LCMV immune mice prior to challenge with L. major, the increase in lesion size was lost. Strikingly, treating with NKG2D blocking antibodies abrogated the increased immunopathology observed in LCMV immune mice, showing that NKG2D engagement on LCMV specific memory CD8 T cells was required for the observed phenotype. These results indicate that bystander memory CD8 T cells can participate in an unrelated immune response and induce immunopathology through an NKG2D dependent mechanism without providing increased protection.

  12. Human memory CD8+ T-cells exhibit an intrinsic metabolic advantage as reflected by increased mitochondrial functionality and high glycolytic potential

    OpenAIRE

    Gubser, Patrick Marc

    2013-01-01

    Intrinsic differences between na•ve and memory CD8+ T-cells affect both quality and quantity of cognate antigen response. Cellular immune function and metabolic pathways are closely linked. The metabolic repertoire of na•ve and memory T-cells remains largely unknown. Here we assessed key metabolic features of human na•ve and effector-memory CD8+ T-cells under basal, metabolic stress, and activating conditions. Basal mitochondrial respiration was similar in both subsets. Memory cells, how...

  13. Thermomechanical response of shape memory alloy hybrid composites

    Science.gov (United States)

    Turner, Travis L.

    2000-10-01

    This study examines the use of embedded shape memory alloy (SMA) actuators for adaptive control of the themomechanical response of composite structures. Control of static and dynamic responses are demonstrated including thermal buckling, thermal post-buckling, vibration, sonic fatigue, and acoustic transmission. A thermomechanical model is presented for analyzing such shape memory alloy hybrid composite (SMAHC) structures exposed to thermal and mechanical loads. Also presented are (1) fabrication procedures for SMAHC specimens, (2) characterization of the constituent materials for model quantification, (3) development of the test apparatus for conducting static and dynamic experiments on specimens with and without SMA, (4) discussion of the experimental results, and (5) validation of the analytical and numerical tools developed in the study. The constitutive model developed to describe the mechanics of a SMAHC lamina captures the material nonlinearity with temperature of the SMA and matrix material if necessary. It is in a form that is amenable to commercial finite element (FE) code implementation. The model is valid for constrained, restrained, or free recovery configurations with appropriate measurements of fundamental engineering properties. This constitutive model is used along with classical lamination theory and the FE method to formulate the equations of motion for panel-type structures subjected to steady-state thermal and dynamic mechanical loads. Mechanical loads that are considered include acoustic pressure, inertial (base acceleration), and concentrated forces. Four solution types are developed from the governing equations including thermal buckling, thermal post-buckling, dynamic response, and acoustic transmission/radiation. These solution procedures are compared with closed-form and/or other known solutions to benchmark the numerical tools developed in this study. Practical solutions for overcoming fabrication issues and obtaining repeatable

  14. Mechanical memory

    Science.gov (United States)

    Gilkey, Jeffrey C.; Duesterhaus, Michelle A.; Peter, Frank J.; Renn, Rosemarie A.; Baker, Michael S.

    2006-08-15

    A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.

  15. Modulation of network excitability by persistent activity: how working memory affects the response to incoming stimuli.

    Directory of Open Access Journals (Sweden)

    Elisa M Tartaglia

    2015-02-01

    Full Text Available Persistent activity and match effects are widely regarded as neuronal correlates of short-term storage and manipulation of information, with the first serving active maintenance and the latter supporting the comparison between memory contents and incoming sensory information. The mechanistic and functional relationship between these two basic neurophysiological signatures of working memory remains elusive. We propose that match signals are generated as a result of transient changes in local network excitability brought about by persistent activity. Neurons more active will be more excitable, and thus more responsive to external inputs. Accordingly, network responses are jointly determined by the incoming stimulus and the ongoing pattern of persistent activity. Using a spiking model network, we show that this mechanism is able to reproduce most of the experimental phenomenology of match effects as exposed by single-cell recordings during delayed-response tasks. The model provides a unified, parsimonious mechanistic account of the main neuronal correlates of working memory, makes several experimentally testable predictions, and demonstrates a new functional role for persistent activity.

  16. Immune memory responses to HBV vaccine 13-18 years after primary vaccination.

    Science.gov (United States)

    Hou, L; Li, W; Wei, X; Zhou, Y; Zhuo, Y; Wu, H; Shen, B

    2015-01-01

    The aim of this study was to evaluate the immune memory response 13-18 years after an hepatitis B virus (HBV) vaccine by performing a specific in vitro stimulation experiment. Thirty healthy volunteers who had been inoculated 13-18 years ago with the HBV vaccine were collected from the physical examination center. Peripheral blood mononuclear cells were stimulated with 50 ng/mL recombinant HBsAg. An ELISA kit was used for the detection of antibodies that were produced by these cells in vitro. It was found that even 13-18 years after inoculation with the HBV vaccine, an anamnestic antibody response still existed, and was not correlated with the serum antibody levels (r = -0.177, P = 0.377). In conclusion, our data showed that the individuals after inoculation, including those with anti-HBs B cells. PMID:26345774

  17. A novel whole-cell mechanism for long-term memory enhancement.

    Directory of Open Access Journals (Sweden)

    Iris Reuveni

    Full Text Available Olfactory-discrimination learning was shown to induce a profound long-lasting enhancement in the strength of excitatory and inhibitory synapses of pyramidal neurons in the piriform cortex. Notably, such enhancement was mostly pronounced in a sub-group of neurons, entailing about a quarter of the cell population. Here we first show that the prominent enhancement in the subset of cells is due to a process in which all excitatory synapses doubled their strength and that this increase was mediated by a single process in which the AMPA channel conductance was doubled. Moreover, using a neuronal-network model, we show how such a multiplicative whole-cell synaptic strengthening in a sub-group of cells that form a memory pattern, sub-serves a profound selective enhancement of this memory. Network modeling further predicts that synaptic inhibition should be modified by complex learning in a manner that much resembles synaptic excitation. Indeed, in a subset of neurons all GABAA-receptors mediated inhibitory synapses also doubled their strength after learning. Like synaptic excitation, Synaptic inhibition is also enhanced by two-fold increase of the single channel conductance. These findings suggest that crucial learning induces a multiplicative increase in strength of all excitatory and inhibitory synapses in a subset of cells, and that such an increase can serve as a long-term whole-cell mechanism to profoundly enhance an existing Hebbian-type memory. This mechanism does not act as synaptic plasticity mechanism that underlies memory formation but rather enhances the response of already existing memory. This mechanism is cell-specific rather than synapse-specific; it modifies the channel conductance rather than the number of channels and thus has the potential to be readily induced and un-induced by whole-cell transduction mechanisms.

  18. A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy

    OpenAIRE

    Turtle, Cameron J.; Swanson, Hillary M.; Fujii, Nobuharu; Estey, Elihu H.; Riddell, Stanley R.

    2009-01-01

    The mechanisms that maintain human T cell memory during normal and perturbed homeostasis are not fully understood. The repeated induction of profound lymphocytopenia in patients undergoing multiple cycles of cytotoxic chemotherapy infrequently results in severe infections with viruses controlled by memory T cells, suggesting that some memory T cells survive chemotherapy and restore immunity. Here we identify a distinct subpopulation of memory CD8+ T cells with the ability to rapidly efflux an...

  19. Synthesis and characterization of phase change memory cells

    Institute of Scientific and Technical Information of China (English)

    WANG Ke; HAN XiaoDong; ZHANG Ze; WU LiangCai; LIU Bo; SONG ZhiTang; FENG SongLin

    2009-01-01

    Phase change memory (PCM) cells based on Ge2Sb2Te5 were synthesized and Investigated. Current-voltage measurements demonstrated different final resistances. Transmission electron microscopy (TEM), high resolution electron microscopy (HREM) and the energy dispersive X-ray spectroscopy (EDS) analyses were used to characterize the microstructures of the PCM ceils. The architectures, structures and defects in the cells including the deposited elemental distributions and the interracial structures between electrodes and barrier layers were studied in detail.

  20. Freeze-thaw lysates of Plasmodium falciparum-infected red blood cells induce differentiation of functionally competent regulatory T cells from memory T cells

    OpenAIRE

    Finney, Olivia C; Lawrence, Emma; Gray, Alice P; Njie, Madi; Riley, Eleanor M.; Walther, Michael

    2012-01-01

    In addition to naturally occurring regulatory T (nTreg) cells derived from the thymus, functionally competent Treg cells can be induced in vitro from peripheral blood lymphocytes in response to TCR stimulation with cytokine costimulation. Using these artificial stimulation conditions, both naïve as well as memory CD4+ T cells can be converted into induced Treg (iTreg) cells, but the cellular origin of such iTreg cells in vivo or in response to more physiologic stimulation with pathogen-derive...

  1. A novel tri-control gate surrounding gate transistor (TCG-SGT) nonvolatile memory cell for flash memory

    Science.gov (United States)

    Ohba, Takuya; Nakamura, Hiroki; Sakuraba, Hiroshi; Masuoka, Fujio

    2006-06-01

    In this paper, we propose for the first time a novel device structure known as the tri-control gate surrounding gate transistor (TCG-SGT) nonvolatile memory cell for Flash memory. In the TCG-SGT nonvolatile memory cell, the control gate, floating gate, drain and source are arranged vertically on the substrate. In addition, the control gate covers the outside of the floating gate. The body region is isolated from the substrate by the source region located at the bottom of the silicon pillar. In addition, we derive the coupling ratio of the TCG-SGT nonvolatile memory cell and compare it with the coupling ratio of the conventional floating channel (FC)-SGT Flash memory cell. The TCG-SGT nonvolatile memory cell architecture produces a capacitive-coupling ratio that is substantially higher than the capacitive-coupling ratio produced by conventional Flash memory devices, which would mean significant improvements in device performance. Finally, through process simulation, we also propose a potential fabrication process of the TCG-SGT nonvolatile memory cell structure.

  2. BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells.

    Science.gov (United States)

    Badr, Gamal; Borhis, Gwenoline; Lefevre, Eric A; Chaoul, Nada; Deshayes, Frederique; Dessirier, Valérie; Lapree, Genevieve; Tsapis, Andreas; Richard, Yolande

    2008-03-01

    B-cell-activating factor of the TNF family, (BAFF), and a proliferation-inducing ligand (APRIL) regulate B-lymphocyte survival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the activation of PI3K/AKT, NF-kappaB, and p38MAPK pathways. BAFF had similar effects on the chemotaxis of naive and memory B cells in response to CCL21 but increased more strongly that of memory B cells to CXCL13 than that of naive B cells. Our findings indicate a previously unreported role for the BAFF/BAFF-R pair in mature B-cell chemotaxis. The synergy between CXCL13 and BAFF produced by stromal cells and follicular dendritic cells may have important implications for B-cell homeostasis, the development of normal B-cell areas, and for the formation of germinal center-like follicles that may be observed in various autoimmune diseases.

  3. Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells.

    Directory of Open Access Journals (Sweden)

    Shan He

    Full Text Available BACKGROUND: Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized. DESIGN AND METHODS: Using lymphocytic choriomeningitis virus (LCMV peptide gp33-specific CD8(+ T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo. RESULTS: Antigen-activated CD8(+ T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS. These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells. CONCLUSIONS: Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy.

  4. Splenectomy alters distribution and turnover but not numbers or protective capacity of de novo generated memory CD8 T cells.

    Directory of Open Access Journals (Sweden)

    Marie eKim

    2014-11-01

    Full Text Available The spleen is a highly compartmentalized lymphoid organ that allows for efficient antigen presentation and activation of immune responses. Additionally, the spleen itself functions to remove senescent red blood cells, filter bacteria, and sequester platelets. Splenectomy, commonly performed after blunt force trauma or splenomegaly, has been shown to increase risk of certain bacterial and parasitic infections years after removal of the spleen. Although previous studies report defects in memory B cells and IgM titers in splenectomized patients, the effect of splenectomy on CD8 T cell responses and memory CD8 T cell function remains ill defined. Using TCR-transgenic P14 cells, we demonstrate that homeostatic proliferation and representation of pathogen-specific memory CD8 T cells in the blood are enhanced in splenectomized compared to sham surgery mice. Surprisingly, despite the enhanced turnover, splenectomized mice displayed no changes in total memory CD8 T cell numbers nor impaired protection against lethal dose challenge with Listeria monocytogenes. Thus, our data suggest that memory CD8 T cell maintenance and function remain intact in the absence of the spleen.

  5. Endurance characteristics of phase change memory cells

    Science.gov (United States)

    Ruru, Huo; Daolin, Cai; Chen, Bomy; Yifeng, Chen; Yuchan, Wang; Yueqing, Wang; Hongyang, Wei; Qing, Wang; Yangyang, Xia; Dan, Gao; Zhitang, Song

    2016-05-01

    The endurance characteristics of phase change memory are studied. With operational cycles, the resistances of reset and set states gradually change to the opposite direction. What is more, the operational conditions that are needed are also discussed. The failure and the changes are concerned with the compositional change of the phase change material. An abnormal phenomenon that the threshold voltage decreases slightly at first and then increases is observed, which is due to the coaction of interface contact and growing active volume size changing. Project supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA09020402), the National Key Basic Research Program of China (Nos. 2013CBA01900, 2010CB934300, 2011CBA00607, 2011CB932804), the National Integrate Circuit Research Program of China (No. 2009ZX02023-003), the National Natural Science Foundation of China (No. 61176122, 61106001, 61261160500, 61376006), and the Science and Technology Council of Shanghai (Nos. 12nm0503701, 13DZ2295700, 12QA1403900, 13ZR1447200, 14ZR1447500).

  6. Origin of CD8+ Effector and Memory T Cell Subsets

    Institute of Scientific and Technical Information of China (English)

    Christian Stemberger; Michael Neuenhahn; Veit R.Buchholz; Dirk H.Busch

    2007-01-01

    It is well accepted that CD8+ T cells play a pivotal role in providing protection against infection with intracellular pathogens and some tumors. In many cases protective immunity is maintained for long periods of time (immunological memory). Over the past years, it has become evident that in order to fulfill these multiple tasks,distinct subsets of effector and memory T cells have to be generated. Until today, however, little is known about the underlying mechanisms of subset differentiation and the timing of lineage fate decisions. In this context, it is of special importance to determine at which level of clonal expansion functional and phenotypical heterogeneity is achieved. Different models for T cell subset diversification have been proposed; these differ mainly in the time point during priming and clonal expansion (prior, during, or beyond the first cell division) when differentiation programs are induced. Recently developed single-cell adoptive transfer technology has allowed us to demonstrate that individual precursor cell still bears the full plasticity to develop into a plethora different T cell subsets. This observation targets the shaping of T cell subset differentiation towards factors that are still operative beyond the first cell division. These findings have important implications for vaccine development, as the modulation of differentiation patterns towards distinct subsets could become a powerful strategy to enhance the efficacy and quality of vaccines.

  7. Establishment of Functional B Cell Memory Against Parvovirus B19 Capsid Proteins May be Associated With Resolution of Persistent Infection

    OpenAIRE

    Corcoran, A; Crowley, B.; Dewhurst, C.; Pizer, B L; Doyle, Sean

    2006-01-01

    Parvovirus B19 (B19) infection can occur during acute lymphoblastic leukemia and persistent viral infection can occur despite intravenous immunoglobulin administration. Here, evidence is presented that resolution of persistent B19 infection in an acute lymphoblastic leukemia patient may be associated with the simultaneous strengthening of antigen-specific B cell memory against the B19 capsid protein VP2 and diminution in the memory response against the B19 non-structural protein 1 (NS1). Dete...

  8. Identification of Functional Human Splenic Memory B Cells by Expression of CD148 and CD27

    OpenAIRE

    Tangye, Stuart G.; Liu, Yong-Jun; Aversa, Gregorio; Phillips, Joseph H.; Vries, Jan E. de

    1998-01-01

    Memory B cells isolated from human tonsils are characterized by an activated cell surface phenotype, localization to mucosal epithelium, expression of somatically mutated immunoglobulin (Ig) variable (V) region genes, and a preferential differentiation into plasma cells in vitro. In spleens of both humans and rodents, a subset of memory B cells is believed to reside in the marginal zone of the white pulp. Similar to tonsil-derived memory B cells, splenic marginal zone B cells can be distingui...

  9. Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells

    Science.gov (United States)

    Marsland, Benjamin J.; Harris, Nicola L.; Camberis, Mali; Kopf, Manfred; Hook, Sarah M.; Le Gros, Graham

    2004-04-01

    CD8+ memory T cells have recently been recognized as playing a key role in natural immunity against unrelated viral infections, a phenomenon referred to as "heterologous antiviral immunity." We now provide data that the cellular immunological interactions that underlie such heterologous immunity can play an equally important role in regulating T helper 2 immune responses and protecting mucosal surfaces from allergen-induced inflammation. Our data show that CD8+ T cells, either retained in the lung after infection with influenza virus, or adoptively transferred via the intranasal route can suppress allergic airway inflammation. The suppression is mediated by IFN-, which acts to reduce the activation level, T helper 2 cytokine production, airways hyperresponsiveness, and migration of allergen-specific CD4+ T cells into the lung, whereas the systemic and draining lymph node responses remain unchanged. Of note, adoptive transfer of previously activated transgenic CD8+ T cells conferred protection against allergic airway inflammation, even in the absence of specific-antigen. Airway resident CD8+ T cells produced IFN- when directly exposed to conditioned media from activated dendritic cells or the proinflammatory cytokines IL-12 and IL-18. Taken together these data indicate that effector/memory CD8+ T cells present in the airways produce IFN- after inflammatory stimuli, independent of specific-antigen, and as a consequence play a key role in modifying the degree and frequency of allergic responses in the lung.

  10. Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection.

    Directory of Open Access Journals (Sweden)

    Sandrine Peruchon

    Full Text Available BACKGROUND: Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART. Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV mac251-infected Cynomolgus macaques. METHODS AND FINDINGS: Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.. We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD(-CD27(+ B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8(+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus-B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. CONCLUSIONS: These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid

  11. Cellular memory and, hematopoietic stem cell aging

    NARCIS (Netherlands)

    Kamminga, Leonie M.; de Haan, Gerald

    2006-01-01

    Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss sever

  12. A Distinct Lung-Interstitium-Resident Memory CD8+ T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection

    Directory of Open Access Journals (Sweden)

    Pavlo Gilchuk

    2016-08-01

    Full Text Available The nature and anatomic location of the protective memory CD8+ T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8+ T cells and their role in lower airway infections. Memory CD8+ T cells elicited by local intranasal, but not systemic, vaccination with an engineered non-replicative CD8+ T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3LO resident memory CD8+ T (Trm cell population that preferentially localizes to the pulmonary interstitium. Because they are positioned close to the mucosa, where infection occurs, interstitial Trm cells act before inflammation can recruit circulating memory CD8+ T cells into the lung tissue. This results in a local protective immune response as early as 1 day post-infection. Hence, vaccine strategies that induce lung interstitial Trm cells may confer better protection against respiratory pathogens.

  13. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells.

    Science.gov (United States)

    Snyder, Christopher M; Cho, Kathy S; Bonnett, Elizabeth L; van Dommelen, Serani; Shellam, Geoffrey R; Hill, Ann B

    2008-10-17

    During persistent murine cytomegalovirus (MCMV) infection, the T cell response is maintained at extremely high intensity for the life of the host. These cells closely resemble human CMV-specific cells, which compose a major component of the peripheral T cell compartment in most people. Despite a phenotype that suggests extensive antigen-driven differentiation, MCMV-specific T cells remain functional and respond vigorously to viral challenge. We hypothesized that a low rate of antigen-driven proliferation would account for the maintenance of this population. Instead, we found that most of these cells divided only sporadically in chronically infected hosts and had a short half-life in circulation. The overall population was supported, at least in part, by memory T cells primed early in infection, as well as by recruitment of naive T cells at late times. Thus, these data show that memory inflation is maintained by a continuous replacement of short-lived, functional cells during chronic MCMV infection.

  14. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    Directory of Open Access Journals (Sweden)

    Aisling F Brown

    Full Text Available Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI. These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

  15. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    Science.gov (United States)

    Brown, Aisling F; Murphy, Alison G; Lalor, Stephen J; Leech, John M; O'Keeffe, Kate M; Mac Aogáin, Micheál; O'Halloran, Dara P; Lacey, Keenan A; Tavakol, Mehri; Hearnden, Claire H; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P; van Wamel, Willem J; Foster, Timothy J; Geoghegan, Joan A; Lavelle, Ed C; Rogers, Thomas R; McLoughlin, Rachel M

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

  16. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    LENUS (Irish Health Repository)

    Brown, Aisling F

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

  17. Use it or lose it: establishment and persistence of T cell memory

    Directory of Open Access Journals (Sweden)

    Katherine eKedzierska

    2012-11-01

    Full Text Available Pre-existing T cell memory provides substantial protection against viral, bacterial and parasitic infections. The generation of protective T cell memory constitutes a primary goal for cell-mediated vaccines, thus understanding the mechanistic basis of memory development and maintenance are of major importance. The widely accepted idea that T cell memory pools are directly descended from the effector populations has been challenged by recent reports that provide evidence for the early establishment of T cell memory and suggest that the putative memory precursor T cells do not undergo full expansion to effector status. Moreover, it appears that once the memory T cells are established early in life, they can persist for the lifetime of an individual. This is in contrast to the reported waning of naïve T cell immunity with age. Thus, in the elderly, immune memory that was induced at an early age may be more robust than recently induced memory, despite the necessity for long persistence. The present review discusses the mechanisms underlying the early establishment of immunological memory and the subsequent persistence of memory T cell pools in animal models and humans.

  18. Antigen availability determines CD8⁺ T cell-dendritic cell interaction kinetics and memory fate decisions.

    Science.gov (United States)

    Henrickson, Sarah E; Perro, Mario; Loughhead, Scott M; Senman, Balimkiz; Stutte, Susanne; Quigley, Michael; Alexe, Gabriela; Iannacone, Matteo; Flynn, Michael P; Omid, Shaida; Jesneck, Jonathan L; Imam, Sabrina; Mempel, Thorsten R; Mazo, Irina B; Haining, W Nicholas; von Andrian, Ulrich H

    2013-09-19

    T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8⁺ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics. PMID:24054328

  19. The Breadth of Expandable Memory CD8+ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

    Science.gov (United States)

    Ndhlovu, Zaza M.; Stampouloglou, Eleni; Cesa, Kevin; Mavrothalassitis, Orestes; Alvino, Donna Marie; Li, Jonathan Z.; Wilton, Shannon; Karel, Daniel; Piechocka-Trocha, Alicja; Chen, Huabiao; Pereyra, Florencia

    2015-01-01

    ABSTRACT Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8+ T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P = 0.01) as well as treated progressors (P = 0.0003). Nef- and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P = 0.9 for Nef as determined by a Kruskal-Wallis test; P = 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r = −0.6; P = 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8+ T cell feature that would be desirable in a vaccine-induced T cell response. IMPORTANCE Many studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8+ T lymphocytes, is at least

  20. Differences between naive and memory T cell phenotype in Malawian and UK adolescents: a role for Cytomegalovirus?

    Directory of Open Access Journals (Sweden)

    Wallace Diana

    2008-10-01

    Full Text Available Abstract Background Differences in degree of environmental exposure to antigens in early life have been hypothesized to lead to differences in immune status in individuals from different populations, which may have implications for immune responses in later years. Methods Venous blood from HIV-negative adolescents and blood from the umbilical cords of babies, born to HIV-negative women, post-delivery was collected and analysed using flow cytometry. T cell phenotype was determined from peripheral blood lymphocytes and cytomegalovirus (CMV seropositivity was assessed by ELISA in adolescents. Results HIV-negative Malawian adolescents were shown to have a lower percentage of naïve T cells (CD45RO-CD62Lhi CD11alo, a higher proportion of memory T cells and a higher percentage of CD28- memory (CD28-CD45RO+ T cells compared to age-matched UK adolescents. Malawian adolescents also had a lower percentage of central memory (CD45RA-CCR7+ T cells and a higher percentage of stable memory (CD45RA+CCR7- T cells than UK adolescents. All of the adolescents tested in Malawi were seropositive for CMV (59/59, compared to 21/58 (36% of UK adolescents. CMV seropositivity in the UK was associated with a reduced percentage of naïve T cells and an increased percentage of CD28- memory T cells in the periphery. No differences in the proportions of naïve and memory T cell populations were observed in cord blood samples from the two sites. Conclusion It is likely that these differences between Malawian and UK adolescents reflect a greater natural exposure to various infections, including CMV, in the African environment and may imply differences in the ability of these populations to induce and maintain immunological memory to vaccines and natural infections.

  1. Influenza Vaccination Generates Cytokine-Induced Memory-like NK Cells: Impact of Human Cytomegalovirus Infection.

    Science.gov (United States)

    Goodier, Martin R; Rodriguez-Galan, Ana; Lusa, Chiara; Nielsen, Carolyn M; Darboe, Alansana; Moldoveanu, Ana L; White, Matthew J; Behrens, Ron; Riley, Eleanor M

    2016-07-01

    Human NK cells are activated by cytokines, immune complexes, and signals transduced via activating ligands on other host cells. After vaccination, or during secondary infection, adaptive immune responses can enhance both cytokine-driven and Ab-dependent NK cell responses. However, induction of NK cells for enhanced function after in vitro exposure to innate inflammatory cytokines has also been reported and may synergize with adaptive signals to potentiate NK cell activity during infection or vaccination. To test this hypothesis, we examined the effect of seasonal influenza vaccination on NK cell function and phenotype in 52 previously unvaccinated individuals. Enhanced, IL-2-dependent, NK cell IFN-γ responses to Influenza A/California/7/2009 virus were detected up to 4 wk postvaccination and higher in human CMV (HCMV)-seronegative (HCMV(-)) individuals than in HCMV-seropositive (HCMV(+)) individuals. By comparison, robust NK cell degranulation responses were observed both before and after vaccination, due to high titers of naturally occurring anti-influenza Abs in human plasma, and did not differ between HCMV(+) and HCMV(-) subjects. In addition to these IL-2-dependent and Ab-dependent responses, NK cell responses to innate cytokines were also enhanced after influenza vaccination; this was associated with proliferation of CD57(-) NK cells and was most evident in HCMV(+) subjects. Similar enhancement of cytokine responsiveness was observed when NK cells were cocultured in vitro with Influenza A/California/7/2009 virus, and this was at least partially dependent upon IFN-αβR2. In summary, our data indicate that attenuated or live viral vaccines promote cytokine-induced memory-like NK cells and that this process is influenced by HCMV infection. PMID:27233958

  2. Influenza Vaccination Generates Cytokine-Induced Memory-like NK Cells: Impact of Human Cytomegalovirus Infection

    Science.gov (United States)

    Goodier, Martin R.; Rodriguez-Galan, Ana; Lusa, Chiara; Nielsen, Carolyn M.; Darboe, Alansana; Moldoveanu, Ana L.; White, Matthew J.; Behrens, Ron

    2016-01-01

    Human NK cells are activated by cytokines, immune complexes, and signals transduced via activating ligands on other host cells. After vaccination, or during secondary infection, adaptive immune responses can enhance both cytokine-driven and Ab-dependent NK cell responses. However, induction of NK cells for enhanced function after in vitro exposure to innate inflammatory cytokines has also been reported and may synergize with adaptive signals to potentiate NK cell activity during infection or vaccination. To test this hypothesis, we examined the effect of seasonal influenza vaccination on NK cell function and phenotype in 52 previously unvaccinated individuals. Enhanced, IL-2–dependent, NK cell IFN-γ responses to Influenza A/California/7/2009 virus were detected up to 4 wk postvaccination and higher in human CMV (HCMV)-seronegative (HCMV−) individuals than in HCMV-seropositive (HCMV+) individuals. By comparison, robust NK cell degranulation responses were observed both before and after vaccination, due to high titers of naturally occurring anti-influenza Abs in human plasma, and did not differ between HCMV+ and HCMV− subjects. In addition to these IL-2–dependent and Ab-dependent responses, NK cell responses to innate cytokines were also enhanced after influenza vaccination; this was associated with proliferation of CD57− NK cells and was most evident in HCMV+ subjects. Similar enhancement of cytokine responsiveness was observed when NK cells were cocultured in vitro with Influenza A/California/7/2009 virus, and this was at least partially dependent upon IFN-αβR2. In summary, our data indicate that attenuated or live viral vaccines promote cytokine-induced memory-like NK cells and that this process is influenced by HCMV infection. PMID:27233958

  3. Transgenerational stress memory is not a general response in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Ales Pecinka

    Full Text Available Adverse conditions can trigger DNA damage as well as DNA repair responses in plants. A variety of stress factors are known to stimulate homologous recombination, the most accurate repair pathway, by increasing the concentration of necessary enzymatic components and the frequency of events. This effect has been reported to last into subsequent generations not exposed to the stress. To establish a basis for a genetic analysis of this transgenerational stress memory, a broad range of treatments was tested for quantitative effects on homologous recombination in the progeny. Several Arabidopsis lines, transgenic for well-established recombination traps, were exposed to 10 different physical and chemical stress treatments, and scored for the number of somatic homologous recombination (SHR events in the treated generation as well as in the two subsequent generations that were not treated. These numbers were related to the expression level of genes involved in homologous recombination and repair. SHR was enhanced after the majority of treatments, confirming previous data and adding new effective stress types, especially interference with chromatin. Compounds that directly modify DNA stimulated SHR to values exceeding previously described induction rates, concomitant with an induction of genes involved in SHR. In spite of the significant stimulation in the stressed generations, the two subsequent non-treated generations only showed a low and stochastic increase in SHR that did not correlate with the degree of stimulation in the parental plants. Transcripts coding for SHR enzymes generally returned to pre-treatment levels in the progeny. Thus, transgenerational effects on SHR frequency are not a general response to abiotic stress in Arabidopsis and may require special conditions.

  4. Differential role of ICAM ligands in determination of human memory T cell differentiation

    Directory of Open Access Journals (Sweden)

    Mitchell Dennis

    2007-01-01

    Full Text Available Abstract Background Leukocyte Function Antigen-1 (LFA-1 is a primary adhesion molecule that plays important roles in T cell activation, leukocyte recirculation, and trans-endothelial migration. By applying a multivariate intracellular phospho-proteomic analysis, we demonstrate that LFA-1 differentially activates signaling molecules. Results Signal intensity was dependent on both ICAM ligand and LFA-1 concentration. In the presence of CD3 and CD28 stimulation, ICAM-2 and ICAM-3 decreased TGFβ1 production more than ICAM-1. In long-term differentiation experiments, stimulation with ICAM-3, CD3, and CD28 generated IFNγ producing CD4+CD45RO+CD62L-CD11aBrightCD27- cells that had increased expression of intracellular BCL2, displayed distinct chemokine receptor profiles, and exhibited distinct migratory characteristics. Only CD3/CD28 with ICAM-3 generated CD4+CD45RO+CD62L-CD11aBrightCD27- cells that were functionally responsive to chemotaxis and exhibited higher frequencies of cells that signaled to JNK and ERK1/2 upon stimulation with MIP3α. Furthermore, these reports identify that the LFA-1 receptor, when presented with multiple ligands, can result in distinct T cell differentiation states and suggest that the combinatorial integration of ICAM ligand interactions with LFA-1 have functional consequences for T cell biology. Conclusion Thus, the ICAM ligands, differentially modulate LFA-1 signaling in T cells and potentiate the development of memory human T cells in vitro. These findings are of importance in a mechanistic understanding of memory cell differentiation and ex vivo generation of memory cell subsets for therapeutic applications.

  5. Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma.

    Science.gov (United States)

    Schuberth, P C; Jakka, G; Jensen, S M; Wadle, A; Gautschi, F; Haley, D; Haile, S; Mischo, A; Held, G; Thiel, M; Tinguely, M; Bifulco, C B; Fox, B A; Renner, C; Petrausch, U

    2013-04-01

    The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.

  6. PD-1 Blockade Expands Intratumoral Memory T Cells

    DEFF Research Database (Denmark)

    Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse;

    2016-01-01

    Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multi......Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed...

  7. Stress Response Recruits the Hippocampal Endocannabinoid System for the Modulation of Fear Memory

    Science.gov (United States)

    Alvares, Lucas de Oliveira; Engelke, Douglas Senna; Diehl, Felipe; Scheffer-Teixeira, Robson; Haubrich, Josue; Cassini, Lindsey de Freitas; Molina, Victor Alejandro; Quillfeldt, Jorge Alberto

    2010-01-01

    The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress…

  8. The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections.

    Directory of Open Access Journals (Sweden)

    Greta E Weiss

    2010-05-01

    Full Text Available Immunity to Plasmodium falciparum (Pf malaria is only acquired after years of repeated infections and wanes rapidly without ongoing parasite exposure. Antibodies are central to malaria immunity, yet little is known about the B-cell biology that underlies the inefficient acquisition of Pf-specific humoral immunity. This year-long prospective study in Mali of 185 individuals aged 2 to 25 years shows that Pf-specific memory B-cells and antibodies are acquired gradually in a stepwise fashion over years of repeated Pf exposure. Both Pf-specific memory B cells and antibody titers increased after acute malaria and then, after six months of decreased Pf exposure, contracted to a point slightly higher than pre-infection levels. This inefficient, stepwise expansion of both the Pf-specific memory B-cell and long-lived antibody compartments depends on Pf exposure rather than age, based on the comparator response to tetanus vaccination that was efficient and stable. These observations lend new insights into the cellular basis of the delayed acquisition of malaria immunity.

  9. Memory CD4+ T cells are required for optimal NK cell effector functions against the opportunistic fungal pathogen Pneumocystis murina.

    Science.gov (United States)

    Kelly, Michelle N; Zheng, Mingquan; Ruan, Sanbao; Kolls, Jay; D'Souza, Alain; Shellito, Judd E

    2013-01-01

    Little is known about the role of NK cells or their interplay with other immune cells during opportunistic infections. Using our murine model of Pneumocystis pneumonia, we found that loss of NK cells during immunosuppression results in substantial Pneumocystis lung burden. During early infection of C57B/6 CD4(+) T cell-depleted mice, there were significantly fewer NK cells in the lung tissue compared with CD4(+) T cell-intact animals, and the NK cells present demonstrated decreased upregulation of the activation marker NKp46 and production of the effector cytokine, IFN-γ. Furthermore, coincubation studies revealed a significant increase in fungal killing when NK cells were combined with CD4(+) T cells compared with either cell alone, which was coincident with a significant increase in perforin production by NK cells. Finally, however, we found through adoptive transfer that memory CD4(+) T cells are required for significant NK cell upregulation of the activation marker NK group 2D and production of IFN-γ, granzyme B, and perforin during Pneumocystis infection. To the best of our knowledge, this study is the first to demonstrate a role for NK cells in immunity to Pneumocystis pneumonia, as well as to establish a functional relationship between CD4(+) T cells and NK cells in the host response to an opportunistic fungal pathogen.

  10. Long-term persistence of T cell memory to HBsAg after hepatitis B vaccination

    Institute of Scientific and Technical Information of China (English)

    Ru-Xiang Wang; Greet J. Boland; Jan van Hattum; Gijsbert C. de Gast

    2004-01-01

    AIM: To determine if the T cell memory to HBsAg can persist for a long time after hepatitis B (HB) vaccination.METHODS: Thirty one vaccine recipients who were healthcare workers (18 females and 13 males aged 34-58 years) from Utrecht University Hospital, Netherlands, and had previously Received a standard course of vaccination for hepatitis B were investigated and another 9 unvaccinated healthy volunteers from the same hospital were used as the control. Blood samples were taken just before the experiment to test serum anti-HBs levels and the subjects were classified into different groups according to their serum titers of anti-HBs and vaccination history. Their peripheral blood mononuclear cells (pBrvMc) were isolated from freshly heparinized venous blood and the proliferative response of Tlymphocytes to the recombinant hepatitis B surface antigen(HBsAg) was investigated.RESULTS: Positive serum anti-HBs was found in 61.3%(19/31) vaccine recipients and a significant in vitro lymphocyte proliferative response to recombinant HBsAg was observed in all the vaccinees with positive anti-HBs. Serum anti-HBs level ≤10 IU/L was found in 38.7% (12/31)subjects. In this study, we specially focused on lymphocyte proliferative response to recombinant HBsAg in those vaccine recipients with serum anti-HBsAg less than 10 IU/L.Most of them had Received a standard course of vaccination about 10 years before. T lymphocyte proliferative response was found positive in 7 of the 12 vaccine recipients. These results confirmed that HBsAg-specific memory T cells remained detectable in the circulation for a long time after vaccination, even when serum anti-HBs level had been undetectable.CONCLUSION: The T cell memory to HBsAg can persist for at least 10 years after HB vaccination. Further booster injection is not necessary in healthy responders to HB vaccine.

  11. Outsourcing Memory in Response to an Aging Population.

    Science.gov (United States)

    Ross, Michael; Schryer, Emily

    2015-11-01

    With baby boomers entering old age and longevity increasing, policymakers have focused on the physical, social, and health needs of older persons. We urge policymakers to consider cognitive aging as well, particularly normal, age-related memory decline. Psychological scientists attribute memory decline mainly to cognitive overload stemming from age-related reductions in sensory capacities, speed of cognitive processing, and the ability to filter out irrelevant information. Even in the absence of decline, however, memory is imperfect and forgetting can be especially consequential for older adults. For example, forgetting to take prescription medicines is an age-related problem largely because older adults tend to ingest many more prescription drugs. We propose that policymakers focus on increasing environmental support for memory that can reduce the burden on cognitive resources and thus improve recall. In providing environmental support, policymakers need to pay careful attention to potential age-related changes in physical and cognitive capacity, as well as behavior.

  12. Heart rate, startle response, and intrusive trauma memories

    OpenAIRE

    Chou, C. Y.; Marca, R. L.; Steptoe, A; Brewin, C. R.

    2014-01-01

    The current study adopted the trauma film paradigm to examine potential moderators affecting heart rate (HR) as an indicator of peritraumatic psychological states and as a predictor of intrusive memories. We replicated previous findings that perifilm HR decreases predicted the development of intrusive images and further showed this effect to be specific to images rather than thoughts, and to detail rather than gist recognition memory. Moreover, a group of individuals showing both an atypical ...

  13. Proteins of Leishmania (Viannia shawi confer protection associated with Th1 immune response and memory generation

    Directory of Open Access Journals (Sweden)

    Passero Luiz Felipe D

    2012-03-01

    Full Text Available Abstract Background Leishmania (Viannia shawi parasite was first characterized in 1989. Recently the protective effects of soluble leishmanial antigen (SLA from L. (V. shawi promastigotes were demonstrated using BALB/c mice, the susceptibility model for this parasite. In order to identify protective fractions, SLA was fractionated by reverse phase HPLC and five antigenic fractions were obtained. Methods F1 fraction was purified from L. (V. shawi parasite extract by reverse phase HPLC. BALB/c mice were immunized once a week for two consecutive weeks by subcutaneous routes in the rump, using 25 μg of F1. After 1 and 16 weeks of last immunization, groups were challenged in the footpad with L. (V. shawi promastigotes. After 2 months, those same mice were sacrificed and parasite burden, cellular and humoral immune responses were evaluated. Results The F1 fraction induced a high degree of protection associated with an increase in IFN-γ, a decrease in IL-4, increased cell proliferation and activation of CD8+T lymphocytes. Long-term protection was acquired in F1-immunized mice, associated with increased CD4+ central memory T lymphocytes and activation of both CD4+ and CD8+ T cells. In addition, F1-immunized groups showed an increase in IgG2a levels. Conclusions The inductor capability of antigens to generate memory lymphocytes that can proliferate and secrete beneficial cytokines upon infection could be an important factor in the development of vaccine candidates against American Tegumentary Leishmaniasis.

  14. Radiation-induced alterations in murine lymphocyte homing patterns. II. Recovery and function of memory cells in LBN rats

    International Nuclear Information System (INIS)

    Suspensions of lymph node cells from dinitrophenylated bovine gamma globulin (DNP-BGG)-immune LBN F1 hybrid rats (Lewis X Brown Norway) were prepared, irradiated, and injected intravenously into unirradiated syngeneic intermediate hosts and irradiated syngeneic adoptive controls. After allowance of 24 hr for homing to occur, the intermediate hosts were killed and cell preparations from the lymph nodes and spleen were injected intravenously into separate irradiated LBN final host groups. All control and experimental groups were challenged (DNP-BGG saline iv) 24 hr after the injection of the lymphoid cells. Rats were bled on Days 7, 11, and 14 after challenge and the antigen-binding capacity (ABC) of the serum was determined. After correction for the fraction of the total cell population transferred from the intermediate host, the peak ABC of the final hosts was related to the number of memory cells present. It was thus possible to determine the relative distribution of the memory cell population to the spleen and lymph nodes of the intermediate hosts. In the intermediate control animals, irradiated memory cells provided a secondary antibody response which was delayed but not suppressed when compared to unirradiated cells. In intermediate hosts, the homing of lymph node memory cells to the spleen and lymph nodes was significantly reduced by an exposure to 200 R of x radiation

  15. T cell therapies-are T memory stem cells the answer?

    Science.gov (United States)

    Flynn, Jacqueline K; Gorry, Paul R

    2015-10-01

    T memory stem cells (TSCM) are the earliest developmental stage of memory T cells, displaying stem cell-like properties and exhibiting a gene profile between naive and central memory (CM) T cells. Their long-lifespan, robust proliferative potential and self-renewal capacity has generated much research and clinical interest particularly for therapeutic use. Here, we discuss recent findings published in Science Translational Medicine by Biasco and colleagues [2015 Feb 4;7(273):273ra13], which provided evidence for the persistence of TSCM in humans for up to 12 years after infusion of genetically modified lymphocytes, and we examine the implications for the development of novel immunotherapies using TSCM. PMID:26605297

  16. The contribution of epigenetic memory to immunologic memory.

    Science.gov (United States)

    Zediak, Valerie P; Wherry, E John; Berger, Shelley L

    2011-04-01

    Memory T lymphocytes are distinct from antigen-inexperienced naïve T cells in that memory T cells can respond more rapidly when they re-encounter a pathogen. Work over the past decade has begun to define the epigenetic underpinnings of the transcriptional component of the memory T cell response. An emerging theme is the persistence of an active chromatin signature at relevant gene loci in resting memory T cells, even when those genes are transcriptionally inactive. This gives strength to the concept of gene poising, and has shown that memory T lymphocytes are an ideal model in which to further define various mechanisms of epigenetic poising.

  17. Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers

    Science.gov (United States)

    Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high-affinity IgG responses. In chronic infections characterized by a high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to downregulation and apoptosis. Anaplasma ...

  18. In vivo proliferation of naïve and memory influenza-specific CD8(+) T cells

    DEFF Research Database (Denmark)

    Flynn, K J; Riberdy, J M; Christensen, Jan Pravsgaard;

    1999-01-01

    days. The greatly expanded population of CD8(+)NPP(+) memory T cells in the lymphoid tissue of secondarily challenged mice declines progressively in mean prevalence over the ensuing 100 days, despite the fact that at least some of these lymphocytes continue to cycle. The recall of cell......The virus-specific CD8(+) T cell response has been analyzed through the development, effector, and recovery phases of primary and secondary influenza pneumonia. Apparently, most, if not all, memory T cells expressing clonotypic receptors that bind a tetrameric complex of influenza nucleoprotein (NP......)(366-374) peptide+H-2D(b) (NPP) are induced to divide during the course of this localized respiratory infection. The replicative phase of the recall response ends about the time that virus can no longer be recovered from the lung, whereas some primary CD8(+)NPP(+) T cells may proliferate for a few more...

  19. Neem leaf glycoprotein promotes dual generation of central and effector memory CD8(+) T cells against sarcoma antigen vaccine to induce protective anti-tumor immunity.

    Science.gov (United States)

    Ghosh, Sarbari; Sarkar, Madhurima; Ghosh, Tithi; Guha, Ipsita; Bhuniya, Avishek; Saha, Akata; Dasgupta, Shayani; Barik, Subhasis; Bose, Anamika; Baral, Rathindranath

    2016-03-01

    We have previously shown that Neem Leaf Glycoprotein (NLGP) mediates sustained tumor protection by activating host immune response. Now we report that adjuvant help from NLGP predominantly generates CD44(+)CD62L(high)CCR7(high) central memory (TCM; in lymph node) and CD44(+)CD62L(low)CCR7(low) effector memory (TEM; in spleen) CD8(+) T cells of Swiss mice after vaccination with sarcoma antigen (SarAg). Generated TCM and TEM participated either to replenish memory cell pool for sustained disease free states or in rapid tumor eradication respectively. TCM generated after SarAg+NLGP vaccination underwent significant proliferation and IL-2 secretion following SarAg re-stimulation. Furthermore, SarAg+NLGP vaccination helps in greater survival of the memory precursor effector cells at the peak of the effector response and their maintenance as mature memory cells, in comparison to single modality treatment. Such response is corroborated with the reduced phosphorylation of FOXO in the cytosol and increased KLF2 in the nucleus associated with enhanced CD62L, CCR7 expression of lymph node-resident CD8(+) T cells. However, spleen-resident CD8(+) T memory cells show superior efficacy for immediate memory-to-effector cell conversion. The data support in all aspects that SarAg+NLGP demonstrate superiority than SarAg vaccination alone that benefits the host by rapid effector functions whenever required, whereas, central-memory cells are thought to replenish the memory cell pool for ultimate sustained disease free survival till 60 days following post-vaccination tumor inoculation.

  20. Relations of nostalgia with music to emotional response and recall of autobiographical memory

    OpenAIRE

    Kobayashi, Asami; Iwanaga, Makoto; Seiwa, Hidetoshi

    2002-01-01

    Previous researches suggest that musical mood and preferences affects on emotional response, and that context of music also affects on musical-dependent memory. We often feel 'nostalgia' when listening to old familiar tunes. Nostalgia is related to eliciting positive emotions, recall of autobiographical memory and positive evaluations for recall contents. The present study aimed to examine effects of musical mood, preference and nostalgia on emotional responses, the amounts of recall of autob...

  1. A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

    Science.gov (United States)

    Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

    2015-07-31

    Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. PMID:26144899

  2. Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies

    DEFF Research Database (Denmark)

    Muellenbeck, Matthias F; Ueberheide, Beatrix; Amulic, Borko;

    2013-01-01

    . We show at the single cell level that natural Pf infection induces the development of classical memory B cells (CM) and atypical memory B cells (AtM) that produce broadly neutralizing antibodies against blood stage Pf parasites. CM and AtM contribute to anti-Pf serum IgG production, but only AtM show...

  3. Activation of a Temporal Memory in Purkinje Cells by the mGluR7 Receptor

    Directory of Open Access Journals (Sweden)

    Fredrik Johansson

    2015-12-01

    Full Text Available Cerebellar Purkinje cells can learn to respond to a conditioned stimulus with an adaptively timed pause in firing. This response was usually ascribed to long-term depression of parallel fiber to Purkinje cell synapses but has recently been shown to be due to a previously unknown form of learning involving an intrinsic cellular timing mechanism. Here, we investigate how these responses are elicited. They are resistant to blockade of GABAergic inhibition, suggesting that they are caused by glutamate release rather than by a changed balance between GABA and glutamate. We show that the responses are abolished by antagonists of the mGlu7 receptor but not significantly affected by other glutamate antagonists. These results support the existence of a distinct learning mechanism, different from changes in synaptic strength. They also demonstrate in vivo post-synaptic inhibition mediated by glutamate and show that the mGlu7 receptor is involved in activating intrinsic temporal memory.

  4. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells.

    Science.gov (United States)

    Madroñal, Noelia; Delgado-García, José M; Fernández-Guizán, Azahara; Chatterjee, Jayanta; Köhn, Maja; Mattucci, Camilla; Jain, Apar; Tsetsenis, Theodoros; Illarionova, Anna; Grinevich, Valery; Gross, Cornelius T; Gruart, Agnès

    2016-01-01

    The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. PMID:26988806

  5. Normally-off type nonvolatile static random access memory with perpendicular spin torque transfer-magnetic random access memory cells and smallest number of transistors

    Science.gov (United States)

    Tanaka, Chika; Abe, Keiko; Noguchi, Hiroki; Nomura, Kumiko; Ikegami, Kazutaka; Fujita, Shinobu

    2014-01-01

    In this paper, we present a novel nonvolatile-random access memory (RAM) cell design based on a “normally-off memory architecture” using a perpendicular spin torque transfer-magnetic random access memory (STT-MRAM) based on a four-transistors static random access memory (SRAM) in order to reduce the operating power of mobile processors. After the cell design concept and basic operation are proposed, a stable and reliable operation for read/write is confirmed by circuit simulation.

  6. Impairment of pneumococcal antigen specific isotype-switched Igg memory B-cell immunity in HIV infected Malawian adults.

    Directory of Open Access Journals (Sweden)

    Oluwadamilola H Iwajomo

    Full Text Available Pneumococcal disease is associated with a particularly high morbidity and mortality amongst adults in HIV endemic countries. Our previous findings implicating a B-cell defect in HIV-infected children from the same population led us to comprehensively characterize B-cell subsets in minimally symptomatic HIV-infected Malawian adults and investigate the isotype-switched IgG memory B-cell immune response to the pneumococcus. We show that similar to vertically acquired HIV-infected Malawian children, horizontally acquired HIV infection in these adults is associated with IgM memory B-cell (CD19(+ CD27(+ IgM(+ IgD(+ depletion, B-cell activation and impairment of specific IgG B-cell memory to a range of pneumococcal proteins. Our data suggest that HIV infection affects both T-cell independent and T-cell dependent B-cell maturation, potentially leading to impairment of humoral responses to extracellular pathogens such as the pneumococcus, and thus leaving this population susceptible to invasive disease.

  7. Characterization of Memory B-Cells from Thymus and its Impact for DLBCL Classification

    DEFF Research Database (Denmark)

    Bergkvist, Kim Steve; Nørgaard, Martin Agge; Bøgsted, Martin;

    2016-01-01

    The rare memory B-cells in thymus are considered the cell of origin for primary mediastinal large B-cell lymphoma (PMBL). The goals for the present study were to characterize the normal memory B-cell compartment in thymus and support its association to primary mediastinal B-cell lymphoma. Seven...... paired human tissue samples from thymus and sternum bone marrow were harvested during cardiac surgery. B-cell subsets were phenotyped by Euroflow standard and FACS-sorted for microarray analysis on the Human Exon 1.0 ST Arrays platform. Differentially expressed genes between thymus and bone marrow memory...... B-cells were identified and correlated to the molecular subclasses of diffuse large B-cell lymphoma. Within thymus, 4% (median, range 2-14%) of the CD45(+) haematopoietic cells were CD19(+) B-cells with a major fraction being CD27(+)/CD38(-) memory B-cells (median 80%, range 76-93%). The bone marrow...

  8. Thermoelectric Responsive Shape Memory Graphene/Hydro-Epoxy Composites for Actuators

    Directory of Open Access Journals (Sweden)

    Yongkun Wang

    2016-08-01

    Full Text Available A series of thermoelectric responsive shape memory hydro-epoxy (H-EP composites filled with different contents of graphene were developed and characterized. Compared with traditional actuation materials, these novel shape memory composites exhibit attractive properties, such as light weight, large deformation, good processability and high response speed, making them good candidates for actuator materials. The effect of graphene content on the shape memory composites was studied in terms of mechanical, dynamic mechanical analysis (DMA, electrical properties, and thermoelectric responsive shape memory test. The results show that when graphene content was 2 wt %, the bend strength of the composite improved by about 47% with a storage modulus larger than other composites. The shape recovery ratio of the composites was about 100%, and the shape recovery speed increased with the increment of graphene content, applied voltage, and temperature. Due to the excellent actuation performance, the graphene/hydro-epoxy composite has potential applications in the actuator in the future.

  9. On the effects of geometry, defects, and material asymmetry on the mechanical response of shape memory alloy cellular lattice structures

    Science.gov (United States)

    Karamooz Ravari, M. R.; Nasr Esfahani, S.; Taheri Andani, M.; Kadkhodaei, M.; Ghaei, A.; Karaca, H.; Elahinia, M.

    2016-02-01

    Shape memory alloy (such as NiTi) cellular lattice structures are a new class of advanced materials with many potential applications. The cost of fabrication of these structures however is high. It is therefore necessary to develop modeling methods to predict the functional behavior of these alloys before fabrication. The main aim of the present study is to assess the effects of geometry, microstructural imperfections and material asymmetric response of dense shape memory alloys on the mechanical response of cellular structures. To this end, several cellular and dense NiTi samples are fabricated using a selective laser melting process. Both cellular and dense specimens were tested in compression in order to obtain their stress-strain response. For modeling purposes, a three -dimensional (3D) constitutive model based on microplane theory which is able to describe the material asymmetry was employed. Five finite element models based on unit cell and multi-cell methods were generated to predict the mechanical response of cellular lattices. The results show the considerable effects of the microstructural imperfections on the mechanical response of the cellular lattice structures. The asymmetric material response of the bulk material also affects the mechanical response of the corresponding cellular structure.

  10. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults.

    Science.gov (United States)

    Sünram-Lea, Sandra I; Owen, Lauren; Finnegan, Yvonne; Hu, Henglong

    2011-08-01

    It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.

  11. Prior high corticosterone exposure reduces activation of immature neurons in the ventral hippocampus in response to spatial and nonspatial memory.

    Science.gov (United States)

    Workman, Joanna L; Chan, Melissa Y T; Galea, Liisa A M

    2015-03-01

    Chronic stress or chronically high glucocorticoids attenuate adult hippocampal neurogenesis by reducing cell proliferation, survival, and differentiation in male rodents. Neurons are still produced in the dentate gyrus during chronically high glucocorticoids, but it is not known whether these new neurons are appropriately activated in response to spatial memory. Thus, the goal of this study was to determine whether immature granule neurons generated during chronically high glucocorticoids (resulting in a depressive-like phenotype) are differentially activated by spatial memory retrieval. Male Sprague Dawley rats received either 40 mg/kg corticosterone (CORT) or vehicle for 18 days prior to behavioral testing. Rats were tested in the forced swim test (FST) and then tested in a spatial (hippocampus-dependent) or cued (hippocampus-independent) Morris Water Maze. Tissue was then processed for doublecortin (DCX) to identify immature neurons and zif268, an immediate early gene product. As expected, CORT increased depressive-like behavior (greater immobility in the FST) however, prior CORT modestly enhanced spatial learning and memory compared with oil. Prior CORT reduced the number of DCX-expressing cells and proportion of DCX-expressing cells colabeled for zif268, but only in the ventral hippocampus. Prior CORT shifted the proportion of cells in the ventral hippocampus away from postmitotic cells and toward immature, proliferative cells, likely due to the fact that postmitotic cells were produced and matured during CORT exposure but proliferative cells were produced after high CORT exposure ceased. Compared with cue training, spatial training slightly increased DCX-expressing cells and shifted cells toward the postmitotic stage in the ventral hippocampus. These data suggest that the effects of CORT and spatial training on immature neurons are more pronounced in the ventral hippocampus. Further, high CORT reduced activation of immature neurons, suggesting that exposure

  12. Theoretical study of SET operation in carbon nanotube memory cell

    Science.gov (United States)

    Stopa, Michael; Rueckes, Thomas

    2016-04-01

    We present results of self-consistent electronic structure calculations for an electromechanical memory cell consisting of a carbon nanotube (CNT) fabric between titanium leads to elucidate the mechanism whereby the applied bias works to close the current gaps in the CNT fabric. We demonstrate that the asymmetry in the bias conditions required to achieve the “SET” operation of the cell (changing it from a high resistivity to low resistivity) results from the nature of a voltage drop in a compensated semiconducting material and depends sensitively on the background charge as well as on the position of the layer where the conducting gaps occur. The calculations provide insight into the behavior of the material and suggest possible fabrication strategies to modify the functionality.

  13. Splenectomy associated changes in IgM memory B cells in an adult spleen registry cohort.

    Directory of Open Access Journals (Sweden)

    Paul U Cameron

    Full Text Available Asplenic patients have a lifelong risk of overwhelming post-splenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells. The clinical value of quantitation of memory B cells as an indicator of splenic abnormality or risk of infection has been unclear. To assess changes in B cell sub-populations after splenectomy we studied patients recruited to a spleen registry (n = 591. A subset of 209 adult asplenic or hyposplenic subjects, and normal controls (n = 140 were tested for IgM memory B cells. We also determined a changes in IgM memory B cells with time after splenectomy using the cross-sectional data from patients on the registry and b the kinetics of changes in haematological markers associated with splenectomy(n = 45. Total B cells in splenectomy patients did not differ from controls, but memory B cells, IgM memory B cells and switched B cells were significantly (p<0.001 reduced. The reduction was similar for different indications for splenectomy. Changes of asplenia in routine blood films including presence of Howell-Jolly bodies (HJB, occurred early (median 25 days and splenectomy associated thrombocytosis and lymphocytosis peaked by 50 days. There was a more gradual decrease in IgM memory B cells reaching a stable level within 6 months after splenectomy. IgM memory B cells as proportion of B cells was the best discriminator between splenectomized patients and normal controls and at the optimal cut-off of 4.53, showed a true positive rate of 95% and false positive rate of 20%. In a survey of 152 registry patients stratified by IgM memory B cells around this cut-off there was no association with minor infections and no registry patients experienced OPSI during the study. Despite significant changes after splenectomy, conventional measures of IgM memory cells have limited clinical utility in this population.

  14. The effects of cell phone conversations on the attention and memory of bystanders.

    Directory of Open Access Journals (Sweden)

    Veronica V Galván

    Full Text Available The pervasive use of cell phones impacts many people-both cell phone users and bystanders exposed to conversations. This study examined the effects of overhearing a one-sided (cell phone conversation versus a two-sided conversation on attention and memory. In our realistic design, participants were led to believe they were participating in a study examining the relationship between anagrams and reading comprehension. While the participant was completing an anagram task, the researcher left the room and participants overheard a scripted conversation, either two confederates talking with each other or one confederate talking on a cell phone. Upon the researcher's return, the participant took a recognition memory task with words from the conversation, and completed a questionnaire measuring the distracting nature of the conversation. Participants who overheard the one-sided conversation rated the conversation as significantly higher in distractibility than those who overheard the two-sided conversation. Also, participants in the one-sided condition scored higher on the recognition task. In particular they were more confident and accurate in their responses to words from the conversation than participants in the two-sided condition. However, participants' scores on the anagram task were not significantly different between conditions. As in real world situations, individual participants could pay varying amounts of attention to the conversation since they were not explicitly instructed to ignore it. Even though the conversation was irrelevant to the anagram task and contained less words and noise, one-sided conversations still impacted participants' self-reported distractibility and memory, thus showing people are more attentive to cell phone conversations than two-sided conversations. Cell phone conversations may be a common source of distraction causing negative consequences in workplace environments and other public places.

  15. Streptococcus induces circulating CLA(+) memory T-cell-dependent epidermal cell activation in psoriasis.

    Science.gov (United States)

    Ferran, Marta; Galván, Ana B; Rincón, Catalina; Romeu, Ester R; Sacrista, Marc; Barboza, Erika; Giménez-Arnau, Ana; Celada, Antonio; Pujol, Ramon M; Santamaria-Babí, Luis F

    2013-04-01

    Streptococcal throat infection is associated with a specific variant of psoriasis and with HLA-Cw6 expression. In this study, activation of circulating psoriatic cutaneous lymphocyte-associated antigen (CLA)(+) memory T cells cultured together with epidermal cells occurred only when streptococcal throat extracts were added. This triggered the production of Th1, Th17, and Th22 cytokines, as well as epidermal cell mediators (CXCL8, CXCL9, CXCL10, and CXCL11). Streptococcal extracts (SEs) did not induce any activation with either CLA(-) cells or memory T cells cultured together with epidermal cells from healthy subjects. Intradermal injection of activated culture supernatants into mouse skin induced epidermal hyperplasia. SEs also induced activation when we used epidermal cells from nonlesional skin of psoriatic patients with CLA(+) memory T cells. Significant correlations were found between SE induced upregulation of mRNA expression for ifn-γ, il-17, il-22, ip-10, and serum level of antistreptolysin O in psoriatic patients. This study demonstrates the direct involvement of streptococcal infection in pathological mechanisms of psoriasis, such as IL-17 production and epidermal cell activation.

  16. Dexamethasone and Monophosphoryl Lipid A-Modulated Dendritic Cells Promote Antigen-Specific Tolerogenic Properties on Naive and Memory CD4+ T Cells

    Science.gov (United States)

    Maggi, Jaxaira; Schinnerling, Katina; Pesce, Bárbara; Hilkens, Catharien M.; Catalán, Diego; Aguillón, Juan C.

    2016-01-01

    Tolerogenic dendritic cells (DCs) are a promising tool to control T cell-mediated autoimmunity. Here, we evaluate the ability of dexamethasone-modulated and monophosphoryl lipid A (MPLA)-activated DCs [MPLA-tolerogenic DCs (tDCs)] to exert immunomodulatory effects on naive and memory CD4+ T cells in an antigen-specific manner. For this purpose, MPLA-tDCs were loaded with purified protein derivative (PPD) as antigen and co-cultured with autologous naive or memory CD4+ T cells. Lymphocytes were re-challenged with autologous PPD-pulsed mature DCs (mDCs), evaluating proliferation and cytokine production by flow cytometry. On primed-naive CD4+ T cells, the expression of regulatory T cell markers was evaluated and their suppressive ability was assessed in autologous co-cultures with CD4+ effector T cells and PPD-pulsed mDCs. We detected that memory CD4+ T cells primed by MPLA-tDCs presented reduced proliferation and proinflammatory cytokine expression in response to PPD and were refractory to subsequent stimulation. Naive CD4+ T cells were instructed by MPLA-tDCs to be hyporesponsive to antigen-specific restimulation and to suppress the induction of T helper cell type 1 and 17 responses. In conclusion, MPLA-tDCs are able to modulate antigen-specific responses of both naive and memory CD4+ T cells and might be a promising strategy to “turn off” self-reactive CD4+ effector T cells in autoimmunity.

  17. Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

    OpenAIRE

    Cheuk, Stanley; Wikén, Maria; Blomqvist, Lennart; Nylén, Susanne; Talme, Toomas; Ståhle, Mona; Eidsmo, Liv

    2014-01-01

    Psoriasis is a common and chronic inflammatory skin disease in which T cells play a key role. Effective treatment heals the skin without scarring, but typically psoriasis recurs in previously affected areas. A pathogenic memory within the skin has been proposed, but the nature of such site-specific disease memory is unknown. Tissue-resident memory T (TRM) cells have been ascribed a role in immunity after resolved viral skin infections. Because of their localization in the epidermal compartmen...

  18. Quantitative Analysis of Memristance Defined Exponential Model for Multi-bits Titanium Dioxide Memristor Memory Cell

    OpenAIRE

    DAOUD, A. A. D.; DESSOUKI, A. A. S.; ABUELENIN, S. M.

    2016-01-01

    The ability to store multiple bits in a single memristor based memory cell is a key feature for high-capacity memory packages. Studying multi-bit memristor circuits requires high accuracy in modelling the memristance change. A memristor model based on a novel definition of memristance is proposed. A design of a single memristor memory cell using the proposed model for the platinum electrodes titanium dioxide memristor is illustrated. A specific voltage pulse is used with varyi...

  19. High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway.

    Science.gov (United States)

    Hara, Yasushi; Tashiro, Yasuyuki; Murakami, Akikazu; Nishimura, Miyuki; Shimizu, Takeyuki; Kubo, Masato; Burrows, Peter D; Azuma, Takachika

    2015-12-01

    During a T cell-dependent immune response, B cells undergo clonal expansion and selection and the induction of isotype switching and somatic hypermutation (SHM). Although somatically mutated IgM(+) memory B cells have been reported, it has not been established whether they are really high affinity B cells. We tracked (4-hydroxy-3-nitrophenyl) acetyl hapten-specific GC B cells from normal immunized mice based on affinity of their B cell receptor (BCR) and performed BCR sequence analysis. SHM was evident by day 7 postimmunization and increased with time, such that high affinity IgM(+) as well as IgG(+) memory B cells continued to be generated up to day 42. In contrast, class-switch recombination (CSR) was almost completed by day 7 and then the ratio of IgG1(+)/IgM(+) GC B cells remained unchanged. Together these findings suggest that IgM(+) B cells undergo SHM in the GC to generate high affinity IgM(+) memory cells and that this process continues even after CSR is accomplished. PMID:26514429

  20. Acute Alcohol Effects on Contextual Memory BOLD Response: Differences Based on Fragmentary Blackout History

    Science.gov (United States)

    Wetherill, Reagan R.; Schnyer, David M.; Fromme, Kim

    2011-01-01

    Background Contextual memory, or memory for source details, is an important aspect of episodic memory and has been implicated in alcohol-induced fragmentary blackouts (FB). Little is known, however, about how neural functioning during contextual memory processes may differ between individuals with and without a history of fragmentary blackouts. This study examined whether neural activation during a contextual memory task differed by history of fragmentary blackout and acute alcohol consumption. Methods Twenty-four matched individuals with (FB+; n = 12) and without (FB−; n = 12) a history of FBs were recruited from a longitudinal study of alcohol use and behavioral risks and completed a laboratory beverage challenge followed by two functional magnetic resonance imaging (fMRI) sessions under no alcohol and alcohol [breath alcohol concentration (BrAC) = 0.08%] conditions. Task performance and brain hemodynamic activity during a block design contextual memory task were examined across 48 fMRI sessions. Results Groups demonstrated no differences in performance on the contextual memory task, yet exhibited different brain response patterns after alcohol intoxication. A significant FB group by beverage interaction emerged in bilateral dorsolateral prefrontal cortex and posterior parietal cortex with FB− individuals showing greater BOLD response after alcohol exposure (p blackouts. PMID:22420742

  1. Tissue-Resident Memory T Cells and Fixed Immune Surveillance in Nonlymphoid Organs.

    Science.gov (United States)

    Carbone, Francis R

    2015-07-01

    T cell immunity is often defined in terms of memory lymphocytes that use the blood to access a range of organs. T cells are involved in two patterns of recirculation. In one, the cells shuttle back and forth between blood and secondary lymphoid organs, whereas in the second, memory cells recirculate between blood and nonlymphoid tissues. The latter is a means by which blood T cells control peripheral infection. It is now clear that there exists a distinct memory T cell subset that is absent from blood but found within nonlymphoid tissues. These nonrecirculating tissue-resident memory T (TRM) cells develop within peripheral compartments and never spread beyond their point of lodgement. This review examines fixed immune surveillance by TRM cells, highlighting features that make them potent controllers of infection in nonlymphoid tissues. These features provide clues about TRM cell specialization, such as their ability to deal with sequestered, persisting infections confined to peripheral compartments.

  2. Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma

    OpenAIRE

    Kim, Byung-Seok; Kim, Il-Kyu; Park, Young-Jun; Kim, Yun-Sun; Kim, Yeon-Jeong; Chang, Woo-Sung; Lee, Yoon-Sook; Kweon, Mi-Na; Chung, Yeonseok; Kang, Chang-Yuil

    2010-01-01

    Genetic and epigenetic programming of T helper (Th) cell subsets during their polarization from naive Th cells establishes long-lived memory Th cells that stably maintain their lineage signatures. However, whether memory Th cells can be redifferentiated into another Th lineage is unclear. In this study, we show that Ag-specific memory Th cells were redifferentiated into Foxp3+ T cells by TGF-β when stimulated in the presence of all-trans retinoic acid and rapamycin. The “converted” Foxp3+ T c...

  3. Memory CD4+ T cells do not induce graft-versus-host disease.

    Science.gov (United States)

    Anderson, Britt E; McNiff, Jennifer; Yan, Jun; Doyle, Hester; Mamula, Mark; Shlomchik, Mark J; Shlomchik, Warren D

    2003-07-01

    Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Donor T cells that accompany stem cell grafts cause GVHD by attacking recipient tissues; therefore, all patients receive GVHD prophylaxis by depletion of T cells from the allograft or through immunosuppressant drugs. In addition to providing a graft-versus-leukemia effect, donor T cells are critical for reconstituting T cell-mediated immunity. Ideally, immunity to infectious agents would be transferred from donor to host without GVHD. Most donors have been exposed to common pathogens and have an increased precursor frequency of memory T cells against pathogenic antigens. We therefore asked whether memory CD62L-CD44+ CD4+ T cells would induce less GVHD than unfractionated or naive CD4+ T cells. Strikingly, we found that memory CD4 cells induced neither clinical nor histologic GVHD. This effect was not due to the increased number of CD4+CD25+ regulatory T cells found in the CD62L-CD44+ fraction because memory T cells depletion of these cells did not cause GVHD. Memory CD4 cells engrafted and responded to antigen both in vivo and in vitro. If these murine results are applicable to human alloSCT, selective administration of memory T cells could greatly improve post-transplant immune reconstitution.

  4. Memory strategy training in children with cerebral infarcts related to sickle cell disease.

    Science.gov (United States)

    Yerys, Benjamin E; White, Desirée A; Salorio, Cynthia F; McKinstry, Robert; Moinuddin, Asif; DeBaun, Michael

    2003-06-01

    Cerebral infarcts occur in approximately 30% of children with sickle cell disease (SCD), but little information exists regarding remediation of associated cognitive deficits. The authors examined the benefits of training children with infarcts to use memory strategies. Six children with SCD-related infarcts received academic tutoring; three of these children received additional training in memory strategies (silent rehearsal to facilitate short-term memory and semantic organization to facilitate long-term memory). The performance of children receiving strategy training appeared to improve more than that of children receiving only tutoring. Memory in children with SCD-related infarcts may be enhanced through strategy training. PMID:12794531

  5. Age-related memory impairments due to reduced blood glucose responses to epinephrine

    OpenAIRE

    Morris, Ken A.; Chang, Qing; Mohler, Eric G.; Gold, Paul E.

    2009-01-01

    Increases in blood glucose levels are an important component of the mechanisms by which epinephrine enhances memory formation. The present experiments addressed the hypothesis that a dysfunction in the blood glucose response to circulating epinephrine contributes to age-related memory impairments. Doses of epinephrine and glucagon that significantly increased blood glucose levels in young adult rats were far less effective at doing so in two-year-old rats. In young rats, epinephrine and gluco...

  6. Working Memory and Response Inhibition in Patients With Bipolar I Disorder During Euthymic Period

    OpenAIRE

    Farahmand, Zahra; Tehrani-Doost, Mehdi; Amini, Homayoun; Mohammadi, Abolfazl; Mirzaei, Mosleh; Mohamadzadeh, Azar

    2015-01-01

    Background: Several cognitive domains, including attention, memory, and executive functions are impaired in bipolar disorder. Objectives: This study aimed to investigate two executive functions (working memory and response inhibition) in patients with bipolar I disorder during remission of the symptoms. Patients and Methods: In this case-control design, 30 bipolar I patients (18 to 45 years old) were matched with 30 ones in the control group in terms of age, gender, and education. The patient...

  7. Out-of-Sequence Preventative Cell Dispatching for Multicast Input-Queued Space-Memory-Memory Clos-Network

    DEFF Research Database (Denmark)

    Yu, Hao; Ruepp, Sarah Renée; Berger, Michael Stübert

    2011-01-01

    independently, the desynchronized static round-robin (DSRR) cell dispatching scheme can evenly distribute cells to the central switching modules, however, its frequent change of the input switching module connection pattern causes a serious OOS problem to the IQ-SMM architecture. Therefore large reassembly......This paper proposes two out-of-sequence (OOS) preventative cell dispatching algorithms for the multicast input-queued space-memory-memory (IQ-SMM) Clos-network switch architecture, i.e. the multicast flow-based DSRR (MF-DSRR) and the multicast flow-based round-robin (MFRR). Treating each cell...... buffers are required at the output ports and high reassembly delay can degrade the multicast services. MF-DSRR can reduce the OOS problem and leverages the principle of DSRR to obtain a low complexity, however it fails to eliminate the in-packet OOS where cells of the same packet are disordered. Using...

  8. Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection.

    Science.gov (United States)

    Fiege, Jessica K; Beura, Lalit K; Burbach, Brandon J; Shimizu, Yoji

    2016-09-15

    During acute infections, naive Ag-specific CD8 T cells are activated and differentiate into effector T cells, most of which undergo contraction after pathogen clearance. A small population of CD8 T cells persists as memory to protect against future infections. We investigated the role of adhesion- and degranulation-promoting adapter protein (ADAP) in promoting CD8 T cell responses to a systemic infection. Naive Ag-specific CD8 T cells lacking ADAP exhibited a modest expansion defect early after Listeria monocytogenes or vesicular stomatitis virus infection but comparable cytolytic function at the peak of response. However, reduced numbers of ADAP-deficient CD8 T cells were present in the spleen after the peak of the response. ADAP deficiency resulted in a greater frequency of CD127(+) CD8 memory precursors in secondary lymphoid organs during the contraction phase. Reduced numbers of ADAP-deficient killer cell lectin-like receptor G1(-) CD8 resident memory T (TRM) cell precursors were present in a variety of nonlymphoid tissues at the peak of the immune response, and consequently the total numbers of ADAP-deficient TRM cells were reduced at memory time points. TRM cells that did form in the absence of ADAP were defective in effector molecule expression. ADAP-deficient TRM cells exhibited impaired effector function after Ag rechallenge, correlating with defects in their ability to form T cell-APC conjugates. However, ADAP-deficient TRM cells responded to TGF-β signals and recruited circulating memory CD8 T cells. Thus, ADAP regulates CD8 T cell differentiation events following acute pathogen challenge that are critical for the formation and selected functions of TRM cells in nonlymphoid tissues. PMID:27521337

  9. Editorial: T cell memory, bone marrow, and aging: the good news

    OpenAIRE

    Effros, Rita B

    2012-01-01

    Discussion on the accumulating evidence that bone marrow in old age is not simply the place where immune cells are generated but the where certain memory cells selectively return to provide a set of distinct immune functions during old age.

  10. Characterization of electrical contacts for phase change memory cells

    NARCIS (Netherlands)

    Roy, Deepu

    2011-01-01

    Advancements in integrated circuits demand an increasing requirement for a faster, low-cost non-volatile memory with improved scaling potential. Phase change memory is an important emerging memory technology qualifying these requirements. With dimensional scaling, the contacts are scaled by F2, ther

  11. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function

    Science.gov (United States)

    Sukumar, Madhusudhanan; Liu, Jie; Ji, Yun; Subramanian, Murugan; Crompton, Joseph G.; Yu, Zhiya; Roychoudhuri, Rahul; Palmer, Douglas C.; Muranski, Pawel; Karoly, Edward D.; Mohney, Robert P.; Klebanoff, Christopher A.; Lal, Ashish; Finkel, Toren; Restifo, Nicholas P.; Gattinoni, Luca

    2013-01-01

    Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell–based therapies against chronic infectious diseases and cancer. PMID:24091329

  12. Phenotypic characterization of bovine memory cells responding to mycobacteria in IFNγ enzyme linked immunospot assays.

    Science.gov (United States)

    Blunt, Laura; Hogarth, Philip J; Kaveh, Daryan A; Webb, Paul; Villarreal-Ramos, Bernardo; Vordermeier, Hans Martin

    2015-12-16

    Bovine tuberculosis (bTB) remains a globally significant veterinary health problem. Defining correlates of protection can accelerate the development of novel vaccines against TB. As the cultured IFNγ ELISPOT (cELISPOT) assay has been shown to predict protection and duration of immunity in vaccinated cattle, we sought to characterize the phenotype of the responding T-cells. Using expression of CD45RO and CD62L we purified by cytometric cell sorting four distinct CD4(+) populations: CD45RO(+)CD62L(hi), CD45RO(+)CD62L(lo), CD45RO(-)CD62L(hi) and CD45RO(-)CD62L(lo) (although due to low and inconsistent cell recovery, this population was not considered further in this study), in BCG vaccinated and Mycobacterium bovis infected cattle. These populations were then tested in the cELISPOT assay. The main populations contributing to production of IFNγ in the cELISPOT were of the CD45RO(+)CD62L(hi) and CD45RO(+)CD62L(lo) phenotypes. These cell populations have been described in other species as central and effector memory cells, respectively. Following in vitro culture and flow cytometry we observed plasticity within the bovine CD4(+) T-cell phenotype. Populations switched phenotype, increasing or decreasing expression of CD45RO and CD62L within 24h of in vitro stimulation. After 14 days all IFNγ producing CD4(+) T cells expressed CD45RO regardless of the original phenotype of the sorted population. No differences were detected in behavior of cells derived from BCG-vaccinated animals compared to cells derived from naturally infected animals. In conclusion, although multiple populations of CD4(+) T memory cells from both BCG vaccinated and M. bovis infected animals contributed to cELISPOT responses, the dominant contributing population consists of central-memory-like T cells (CD45RO(+)CD62L(hi)).

  13. Pharmacologic Induction of CD8+ T Cell Memory: Better Living Through Chemistry

    OpenAIRE

    Gattinoni, Luca; Klebanoff, Christopher A.; Restifo, Nicholas P

    2009-01-01

    The generation of a robust population of memory T cells is critical for effective vaccine and cell-based therapies to prevent and treat infectious diseases and cancer. A series of recent papers have established a new, cell-intrinsic approach in which small molecules target key metabolic and developmental pathways to enhance the formation and maintenance of highly functional CD8+ memory T cells. These findings raise the exciting new possibility of using small molecules, many of which are alrea...

  14. Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits CD8+ T cell memory formation

    Science.gov (United States)

    Ji, Yun; Pos, Zoltan; Rao, Mahadev; Klebanoff, Christopher A.; Yu, Zhiya; Sukumar, Madhusudhanan; Reger, Robert N.; Palmer, Douglas C.; Borman, Zachary A.; Muranski, Pawel; Wang, Ena; Schrump, David S.; Marincola, Francesco M.; Restifo, Nicholas P.; Gattinoni, Luca

    2011-01-01

    Blimp-1 is a transcriptional repressor that promotes the differentiation of CD8+ T cells into short-lived KLRG-1+ effector cells (SLEC), but how it operates remains poorly defined. Here we show that Blimp-1 binds and represses the Id3 promoter in SLEC. Repression of Id3 by Blimp-1 was dispensable for SLEC development but limited their capacity to persist as memory cells. Enforced expression of Id3 was sufficient to rescue SLEC survival and enhanced recall responses. Id3 function was mediated in part through inhibition of E2a transcriptional activity and induction of genes regulating genome stability. These findings identify a Blimp-1-Id3-E2a axis as a key molecular switch that determines whether effector CD8+ T cells are programmed to die or enter the memory pool. PMID:22057288

  15. Nicotinic modulation of hippocampal cell signaling and associated effects on learning and memory.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2016-03-01

    The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits.

  16. Qualitative and quantitative analysis of adenovirus type 5 vector-induced memory CD8 T cells: not as bad as their reputation.

    Science.gov (United States)

    Steffensen, Maria Abildgaard; Holst, Peter Johannes; Steengaard, Sanne Skovvang; Jensen, Benjamin Anderschou Holbech; Bartholdy, Christina; Stryhn, Anette; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

    2013-06-01

    It has been reported that adenovirus (Ad)-primed CD8 T cells may display a distinct and partially exhausted phenotype. Given the practical implications of this claim, we decided to analyze in detail the quality of Ad-primed CD8 T cells by directly comparing these cells to CD8 T cells induced through infection with lymphocytic choriomeningitis virus (LCMV). We found that localized immunization with intermediate doses of Ad vector induces a moderate number of functional CD8 T cells which qualitatively match those found in LCMV-infected mice. The numbers of these cells may be efficiently increased by additional adenoviral boosting, and, importantly, the generated secondary memory cells cannot be qualitatively differentiated from those induced by primary infection with replicating virus. Quantitatively, DNA priming prior to Ad vaccination led to even higher numbers of memory cells. In this case, the vaccination led to the generation of a population of memory cells characterized by relatively low CD27 expression and high CD127 and killer cell lectin-like receptor subfamily G member 1 (KLRG1) expression. These memory CD8 T cells were capable of proliferating in response to viral challenge and protecting against infection with live virus. Furthermore, viral challenge was followed by sustained expansion of the memory CD8 T-cell population, and the generated memory cells did not appear to have been driven toward exhaustive differentiation. Based on these findings, we suggest that adenovirus-based prime-boost regimens (including Ad serotype 5 [Ad5] and Ad5-like vectors) represent an effective means to induce a substantially expanded, long-lived population of high-quality transgene-specific memory CD8 T cells.

  17. Examination of various WMS-III logical memory scores in the assessment of response bias.

    Science.gov (United States)

    Bortnik, Kirsty E; Boone, Kyle B; Marion, Sarah D; Amano, Stacy; Ziegler, Elizabeth; Cottingham, Maria E; Victor, Tara L; Zeller, Michelle A

    2010-02-01

    The assessment of response validity during neuropsychological evaluation is an integral part of the testing process. Research has increasingly focused on the use of "embedded" effort measures (derived from standard neuropsychological tasks) because they do not require additional administration time and are less likely to be identified as effort indicators by test takers because of their primary focus as measures of cognitive function. The current study examined the clinical utility of various WMS-III Logical Memory scores in detecting response bias, as well as the Rarely Missed Index, an embedded effort indicator derived from the WMS-III Logical Memory Delayed Recognition subtest. The Rarely Missed Index cut-off only identified 24.1% of 63 non-credible participants (at >/=90% specificity in 125 credible patients), and cut-offs for other Logical Memory variables were in fact found to be more sensitive to non-credible performance. A new indicator, consisting of the weighted combination of the two most sensitive Logical Memory subtest scores (Logical Memory II raw score and Logical Memory Delayed Recognition raw score), was associated with 53% to 60% sensitivity, and thus may be an effective adjunct when utilized in conjunction with other validated effort indicators and collateral information in identifying non-credible performance.

  18. Effects of working memory demand on neural mechanisms of motor response selection and control.

    Science.gov (United States)

    Barber, Anita D; Caffo, Brian S; Pekar, James J; Mostofsky, Stewart H

    2013-08-01

    Inhibitory control commonly recruits a number of frontal regions: pre-supplementary motor area (pre-SMA), frontal eye fields (FEFs), and right-lateralized posterior inferior frontal gyrus (IFG), dorsal anterior insula (DAI), dorsolateral prefrontal cortex (DLPFC), and inferior frontal junction (IFJ). These regions may directly implement inhibitory motor control or may be more generally involved in executive control functions. Two go/no-go tasks were used to distinguish regions specifically recruited for inhibition from those that additionally show increased activity with working memory demand. The pre-SMA and IFG were recruited for inhibition in both tasks and did not have greater activation for working memory demand on no-go trials, consistent with a role in inhibitory control. Activation in pre-SMA also responded to response selection demand and was increased with working memory on go trials specifically. The bilateral FEF and right DAI were commonly active for no-go trials. The FEF was also recruited to a greater degree with working memory demand on go trials and may bias top-down information when stimulus-response mappings change. The DAI, additionally responded to increased working memory demand on both go and no-go trials and may be involved in accessing sustained task information, alerting, or autonomic changes when cognitive demands increase. DLPFC activation was consistent with a role in working memory retrieval on both go and no-go trials. The inferior frontal junction, on the other hand, had greater activation with working memory specifically for no-go trials and may detect salient stimuli when the task requires frequent updating of working memory representations.

  19. Neural Stem Cell Grafting Counteracts Hippocampal Injury-Mediated Impairments in Mood, Memory, and Neurogenesis

    OpenAIRE

    Hattiangady, Bharathi; Shetty, Ashok K.

    2012-01-01

    Hippocampal injury typically leads to mood and memory impairments associated with reduced and aberrant neurogenesis in the dentate gyrus. This study examined whether subventricular zone-neural stem cell (SVZ-NSC) grafting after hippocampal injury would counteract impairments in mood, memory, and neurogenesis. Analyses through forced swim, water maze, and novel object recognition tests revealed significant impairments in mood and memory function in animals that underwent injury and sham-grafti...

  20. Protective Antigen-Specific Memory B Cells Persist Years after Anthrax Vaccination and Correlate with Humoral Immunity

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    Lori Garman

    2014-08-01

    Full Text Available Anthrax Vaccine Adsorbed (AVA generates short-lived protective antigen (PA specific IgG that correlates with in vitro toxin neutralization and protection from Bacillus anthracis challenge. Animal studies suggest that when PA-specific IgG has waned, survival after spore challenge correlates with an activation of PA-specific memory B cells. Here, we characterize the quantity and the longevity of AVA-induced memory B cell responses in humans. Peripheral blood mononuclear cells (PBMCs from individuals vaccinated ≥3 times with AVA (n = 50 were collected early (3–6 months, n = 27 or late after their last vaccination (2–5 years, n = 23, pan-stimulated, and assayed by ELISPOT for total and PA-specific memory B cells differentiated into antibody secreting cells (ASCs. PA-specific ASC percentages ranged from 0.02% to 6.25% (median: 1.57% and did not differ between early and late post-vaccination individuals. PA-specific ASC percentages correlated with plasma PA-specific IgG (r = 0.42, p = 0.03 and toxin neutralization (r = 0.52, p = 0.003 early post vaccination. PA-specific ASC percentages correlated with supernatant anti-PA both early (r = 0.60, p = 0.001 and late post vaccination (r = 0.71, p < 0.0001. These data suggest PA-specific memory B cell responses are long-lived and can be estimated after recent vaccination by the magnitude and neutralization capacity of the humoral response.

  1. The effects of centrally administered fluorocitrate via inhibiting glial cells on working memory in rats

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Although prefrontal and hippocampal neurons are critical for spatial working memory,the function of glial cells in spatial working memory remains uncertain.In this study we investigated the function of glial cells in rats’ working memory.The glial cells of rat brain were inhibited by intracerebroventricular(icv) injection of fluorocitrate(FC).The effects of FC on the glial cells were examined by using electroencephalogram(EEG) recordings and delayed spatial alternation tasks.After icv injection of 10 μL of 0.5 nmol/L or 5 nmol/L FC,the EEG power spectrum recorded from the hippocampus increased,but the power spectrum for the prefrontal cortex did not change,and working memory was unaffected.Following an icv injection of 10 μL of 20 nmol/L FC,the EEG power spectra in both the prefrontal cortex and the hippocampus increased,and working memory improved.The icv injection of 10 μL of 50 nmol/L FC,the EEG power spectra in both the prefrontal cortex and in the hippocampus decreased,and working memory was impaired.These results suggest that spatial working memory is affected by centrally administered FC,but only if there are changes in the EEG power spectrum in the prefrontal cortex.Presumably,the prefrontal glial cells relate to the working memory.

  2. Adenoviral Vector Vaccination Induces a Conserved Program of CD8+ T Cell Memory Differentiation in Mouse and Man

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    Beatrice Bolinger

    2015-11-01

    Full Text Available Following exposure to vaccines, antigen-specific CD8+ T cell responses develop as long-term memory pools. Vaccine strategies based on adenoviral vectors, e.g., those developed for HCV, are able to induce and sustain substantial CD8+ T cell populations. How such populations evolve following vaccination remains to be defined at a transcriptional level. We addressed the transcriptional regulation of divergent CD8+ T cell memory pools induced by an adenovector encoding a model antigen (beta-galactosidase. We observe transcriptional profiles that mimic those following infection with persistent pathogens, murine and human cytomegalovirus (CMV. Key transcriptional hallmarks include upregulation of homing receptors and anti-apoptotic pathways, driven by conserved networks of transcription factors, including T-bet. In humans, an adenovirus vaccine induced similar CMV-like phenotypes and transcription factor regulation. These data clarify the core features of CD8+ T cell memory following vaccination with adenovectors and indicate a conserved pathway for memory development shared with persistent herpesviruses.

  3. Human sensory-evoked responses differ coincident with either "fusion-memory" or "flash-memory", as shown by stimulus repetition-rate effects

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    Baird Bill

    2006-02-01

    Full Text Available Abstract Background: A new method has been used to obtain human sensory evoked-responses whose time-domain waveforms have been undetectable by previous methods. These newly discovered evoked-responses have durations that exceed the time between the stimuli in a continuous stream, thus causing an overlap which, up to now, has prevented their detection. We have named them "A-waves", and added a prefix to show the sensory system from which the responses were obtained (visA-waves, audA-waves, somA-waves. Results: When A-waves were studied as a function of stimulus repetition-rate, it was found that there were systematic differences in waveshape at repetition-rates above and below the psychophysical region in which the sensation of individual stimuli fuse into a continuity. The fusion phenomena is sometimes measured by a "Critical Fusion Frequency", but for this research we can only identify a frequency-region [which we call the STZ (Sensation-Transition Zone]. Thus, the A-waves above the STZ differed from those below the STZ, as did the sensations. Study of the psychophysical differences in auditory and visual stimuli, as shown in this paper, suggest that different stimulus features are detected, and remembered, at stimulation rates above and below STZ. Conclusion: The results motivate us to speculate that: 1 Stimulus repetition-rates above the STZ generate waveforms which underlie "fusion-memory" whereas rates below the STZ show neuronal processing in which "flash-memory" occurs. 2 These two memories differ in both duration and mechanism, though they may occur in the same cell groups. 3 The differences in neuronal processing may be related to "figure" and "ground" differentiation. We conclude that A-waves provide a novel measure of neural processes that can be detected on the human scalp, and speculate that they may extend clinical applications of evoked response recordings. If A-waves also occur in animals, it is likely that A-waves will provide

  4. High-throughput gene expression profiling of memory differentiation in primary human T cells

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    Russell Kate

    2008-08-01

    Full Text Available Abstract Background The differentiation of naive T and B cells into memory lymphocytes is essential for immunity to pathogens. Therapeutic manipulation of this cellular differentiation program could improve vaccine efficacy and the in vitro expansion of memory cells. However, chemical screens to identify compounds that induce memory differentiation have been limited by 1 the lack of reporter-gene or functional assays that can distinguish naive and memory-phenotype T cells at high throughput and 2 a suitable cell-line representative of naive T cells. Results Here, we describe a method for gene-expression based screening that allows primary naive and memory-phenotype lymphocytes to be discriminated based on complex genes signatures corresponding to these differentiation states. We used ligation-mediated amplification and a fluorescent, bead-based detection system to quantify simultaneously 55 transcripts representing naive and memory-phenotype signatures in purified populations of human T cells. The use of a multi-gene panel allowed better resolution than any constituent single gene. The method was precise, correlated well with Affymetrix microarray data, and could be easily scaled up for high-throughput. Conclusion This method provides a generic solution for high-throughput differentiation screens in primary human T cells where no single-gene or functional assay is available. This screening platform will allow the identification of small molecules, genes or soluble factors that direct memory differentiation in naive human lymphocytes.

  5. Genome-wide RNA profiling of long-lasting stem cell-like memory CD8 T cells induced by Yellow Fever vaccination in humans

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    Silvia A. Fuertes Marraco

    2015-09-01

    Full Text Available The live-attenuated Yellow Fever (YF vaccine YF-17D induces a broad and polyfunctional CD8 T cell response in humans. Recently, we identified a population of stem cell-like memory CD8 T cells induced by YF-17D that persists at stable frequency for at least 25 years after vaccination. The YF-17D is thus a model system of human CD8 T cell biology that furthermore allows to track and study long-lasting and antigen-specific human memory CD8 T cells. Here, we describe in detail the sample characteristics and preparation of a microarray dataset acquired for genome-wide gene expression profiling of long-lasting YF-specific stem cell-like memory CD8 T cells, compared to the reference CD8 T cell differentiation subsets from total CD8 T cells. We also describe the quality controls, annotations and exploratory analyses of the dataset. The microarray data is available from the Gene Expression Omnibus (GEO public repository with accession number GSE65804.

  6. Genome-wide RNA profiling of long-lasting stem cell-like memory CD8 T cells induced by Yellow Fever vaccination in humans.

    Science.gov (United States)

    Fuertes Marraco, Silvia A; Soneson, Charlotte; Delorenzi, Mauro; Speiser, Daniel E

    2015-09-01

    The live-attenuated Yellow Fever (YF) vaccine YF-17D induces a broad and polyfunctional CD8 T cell response in humans. Recently, we identified a population of stem cell-like memory CD8 T cells induced by YF-17D that persists at stable frequency for at least 25 years after vaccination. The YF-17D is thus a model system of human CD8 T cell biology that furthermore allows to track and study long-lasting and antigen-specific human memory CD8 T cells. Here, we describe in detail the sample characteristics and preparation of a microarray dataset acquired for genome-wide gene expression profiling of long-lasting YF-specific stem cell-like memory CD8 T cells, compared to the reference CD8 T cell differentiation subsets from total CD8 T cells. We also describe the quality controls, annotations and exploratory analyses of the dataset. The microarray data is available from the Gene Expression Omnibus (GEO) public repository with accession number GSE65804. PMID:26484272

  7. Circadian control of antigen-specific T cell responses

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    Nobis CC

    2016-09-01

    Full Text Available Chloé C Nobis,1–3 Nathalie Labrecque,2–4 Nicolas Cermakian1,5–8 1Douglas Mental Health University Institute, 2Maisonneuve-Rosemont Hospital Research Centre, 3Department of Microbiology, Infectious Diseases and Immunology, 4Department of Medicine, University of Montreal, 5Department of Psychiatry, 6Department of Microbiology and Immunology, 7Department of Neurology and Neurosurgery, 8Department of Physiology, McGill University, Montreal, QC, Canada Abstract: The immune system is composed of two arms, the innate and the adaptive immunity. While the innate response constitutes the first line of defense and is not specific for a particular pathogen, the adaptive response is highly specific and allows for long-term memory of the pathogen encounter. T lymphocytes (or T cells are central players in the adaptive immune response. Various aspects of T cell functions vary according to the time of day. Circadian clocks located in most tissues and cell types generate 24-hour rhythms of various physiological processes. These clocks are based on a set of clock genes, and this timing mechanism controls rhythmically the expression of numerous other genes. Clock genes are expressed in cells of the immune system, including T cells. In this review, we provide an overview of the circadian control of the adaptive immune response, with emphasis on T cells, including their development, trafficking, response to antigen, and effector functions. Keywords: circadian clock, adaptive immune response, T lymphocyte, antigen, cytokine, proliferation

  8. Generation-by-generation dissection of the response function in long memory epidemic processes

    Science.gov (United States)

    Saichev, A. I.; Sornette, D.

    2010-06-01

    In a number of natural and social systems, the response to an exogenous shock relaxes back to the average level according to a long-memory kernel ~1/t1+θ with 0 ≤ θ response function ~1/t1-θ. Surprisingly, this means that the shorter the memory of the bare kernel (the larger 1+θ), the longer the memory of the response function (the smaller 1-θ). Here, we present a detailed investigation of this paradoxical behavior based on a generation-by-generation decomposition of the total response function, the use of Laplace transforms and of “anomalous” scaling arguments. The paradox is explained by the fact that the number of triggered generations grows anomalously with time at ~ tθ so that the contributions of active generations up to time t more than compensate the shorter memory associated with a larger exponent θ. This anomalous scaling results fundamentally from the property that the expected waiting time is infinite for 0 ≤ θ ≤ 1. The techniques developed here are also applied to the case θ > 1 and we find in this case that the total renormalized response is a constant for t < 1/(1-n) followed by a cross-over to ~1/t1+θ for t ≫ 1/(1-n).

  9. Higher numbers of memory B-cells and Th2-cytokine skewing in high responders to hepatitis B vaccination.

    Science.gov (United States)

    Doedée, A M C M; Kannegieter, N; Öztürk, K; van Loveren, H; Janssen, R; Buisman, A M

    2016-04-27

    In the present study, differences in hepatitis B surface antigen (HBsAg)-specific memory B-cell responses between low and high responders to hepatitis B vaccine (HepB), based on levels of antibodies against HBsAg (anti-HBs), were determined. In addition, HBsAg specific T-cell responses between high (anti-HBs level >20,000 IU/L) and low (anti-HBs level cells, plasma immunoglobulin G (Ig) levels, and T-cell cytokine concentrations were measured in low and high responders directly before and one month after the second booster vaccination. In advance, an Enzyme-linked Immunosorbent Spot (ELISpot) Assay was optimized for the determination of HBsAg-specific B-cell responses. The number of HBsAg-specific B-cells was significantly higher (pcells were significantly correlated (RS=0.66, pcell response showed the same values in the low and high responder group and did not change by the booster vaccination with HepB. However, a significant correlation (RS=0.6975, p=0.007) between the IL-13 levels and the plasma IgG levels post-booster was found. Subsequently, the IL-13 level in the high-responder group post-booster was significantly higher compared to the low-responder group. Since activation of the B-cell response after vaccination is induced by Th2 cells and IL-13 is produced by these cells, we conclude that the difference in HBsAg-specific Th2 cells is involved in determining the differences in anti-HBs level and memory B-cell numbers between low and high responders.

  10. Decreased numbers of CD4+ naive and effector memory T cells, and CD8+ naïve T cells, are associated with trichloroethylene exposure

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    H Dean eHosgood

    2012-01-01

    Full Text Available Trichloroethylene (TCE is a volatile chlorinated organic compound that is commonly used as a solvent for lipophilic compounds. Although recognized as an animal carcinogen, TCE’s carcinogenic potential in humans is still uncertain. We have carried out a cross-sectional study of 80 workers exposed to TCE and 96 unexposed controls matched on age and sex in Guangdong, China to study TCE’s early biologic effects. We previously reported that the total lymphocyte count and each of the major lymphocyte subsets (i.e., CD4+ T cells, CD8+ T cells, natural killer (NK cells, and B cells were decreased in TCE-exposed workers compared to controls, suggesting a selective effect on lymphoid progenitors and/or lymphocyte survival. To explore which T lymphocyte subsets are affected, we investigated the effect of TCE exposure on the numbers of CD4+ naïve and memory T cells, CD8+ naïve and memory T cells, and regulatory T cells by FACS analysis. Linear regression of each subset was used to test for differences between exposed workers and controls adjusting for potential confounders. We observed that CD4+ and CD8+ naïve T cell counts were about 8% (p = 0.056 and 17% (p = 0.0002 lower, respectively, among exposed workers. CD4+ effector memory T cell counts were decreased by about 20% among TCE exposed workers compared to controls (p = 0.001. The selective targeting of TCE on CD8+ naïve and possibly CD4+ naive T cells, and CD4+ effector memory T cells, provide further insights into the immunosuppression-related response of human immune cells upon TCE exposure.

  11. Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques.

    Science.gov (United States)

    Okoye, Afam A; Rohankhedkar, Mukta; Konfe, Audrie L; Abana, Chike O; Reyes, Matthew D; Clock, Joseph A; Duell, Derick M; Sylwester, Andrew W; Sammader, Partha; Legasse, Alfred W; Park, Byung S; Axthelm, Michael K; Nikolich-Žugich, Janko; Picker, Louis J

    2015-11-01

    Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naive T cells (TN) associated with decline in thymic output and export of new cells into the peripheral T cell pool. Because the lymphotropic cytokine IL-7 plays crucial roles in both development of TN in the thymus and TN homeostasis in the periphery, we sought to determine the extent to which therapeutic administration of IL-7 could reverse TN deficiency in aging rhesus macaques (RM), either by enhancement of the demonstrably reduced thymopoiesis or by peripheral TN expansion. Our results indicate that treatment of both adult (8-15 y) and old (>20 y) RM with recombinant simian IL-7 (rsIL-7) results in only transient increases in peripheral CD4(+) and CD8(+) TN numbers with no long-term benefit, even with repeated therapy. This transient effect was due to peripheral TN expansion and not enhanced thymic function, and appeared to be limited by induction of IL-7 nonresponsiveness. However, rsIL-7 therapy had a more promising effect on the central memory T cell (TCM) population (both CD4(+) and CD8(+)) in adult and old RM, doubling the numbers of these cells in circulation and maintaining this larger population long term. IL-7 therapy did not reduce TCR diversity of the memory T cell compartment, suggesting that rsIL-7-induced expansion was symmetrical. Thus, although rsIL-7 failed to counter age-associated TN loss, the ability of this therapy to expand clonotypically diverse CD4(+) and CD8(+) TCM populations might potentially improve adaptive immune responsiveness in the elderly. PMID:26416281

  12. ICOS is required for the generation of both central and effector CD4+ memory T‐cell populations following acute bacterial infection

    Science.gov (United States)

    Marriott, Clare L.; Carlesso, Gianluca; Herbst, Ronald

    2015-01-01

    Interactions between ICOS and ICOS ligand (ICOSL) are essential for the development of T follicular helper (Tfh) cells and thus the formation and maintenance of GC reactions. Given the conflicting reports on the requirement of other CD4+ T‐cell populations for ICOS signals, we have employed a range of in vivo approaches to dissect requirements for ICOS signals in mice during an endogenous CD4+ T‐cell response and contrasted this with CD28 signals. Genetic absence of ICOSL only modestly reduced the total number of antigen‐specific CD4+ T cells at the peak of the primary response, but resulted in a severely diminished number of both T central memory and T effector memory cells. Treatment with blocking anti‐ICOS mAb during the primary response recapitulated these effects and caused a more substantial reduction than blocking CD28 signals with CTLA4Ig. During the memory phase of the response further signals through ICOS or CD28 were not required for survival. However, upon secondary challenge only Tfh cell expansion remained heavily ICOS‐dependent, while CD28 signals were required for optimal expansion of all subsets. These data demonstrate the importance of ICOS signals specifically for memory CD4+ T‐cell formation, while highlighting the potential of therapeutically targeting this pathway. PMID:25754933

  13. Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory.

    Science.gov (United States)

    Kitamura, Takashi; Sun, Chen; Martin, Jared; Kitch, Lacey J; Schnitzer, Mark J; Tonegawa, Susumu

    2015-09-23

    Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions, but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory. PMID:26402611

  14. Effector and Central Memory Poly-functional CD4+ and CD8+ T cells are Boosted upon ZOSTAVAX® Vaccination

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    Kalpit A Vora

    2015-10-01

    Full Text Available ZOSTAVAX® is a live attenuated varicella-zoster virus (VZV vaccine that is licensed for the protection of individuals ≥ 50 years against shingles, and its most common complication, post-herpetic neuralgia. While IFN responses increase upon vaccination, the quality of the T cell response has not been elucidated. By using polychromatic flow cytometry, we characterized the breadth, magnitude, and quality of ex vivo CD4+ and CD8+ T cell responses induced 3 – 4 weeks after ZOSTAVAX vaccination of healthy adults. We show, for the first time that the highest frequencies of VZV-specific CD4+ T cells were poly-functional CD154+IFNγ+IL-2+TNFα+ cells, which were boosted upon vaccination. The CD4+ T cells were broadly reactive to several VZV proteins, with IE63 ranking the highest amongst them in the fold-rise of poly-functional cells, followed by IE62, gB, ORF9, and gE. We identified a novel poly-functional ORF9-specific CD8+ T cell population in 62% of the subjects, and these were boosted upon vaccination. Poly-functional CD4+ and CD8+ T cells produced significantly higher levels of IFNγ, IL-2, and TNFα compared to mono-functional cells. After vaccination, a boost in the expression of IFN by poly-functional IE63-and ORF9-specific CD4+ T cells, and IFNγ, IL-2, and TNFα by ORF9-specific poly-functional CD8+ T cells was observed. Responding poly-functional T cells exhibited both effector (CCR7−CD45RA−CD45RO+, and central (CCR7+CD45RA−CD45RO+ memory phenotypes, which expressed comparable levels of cytokines. Altogether, our studies demonstrate that a boost in memory poly-functional CD4+ T cells, and ORF9-specific CD8+ T cells may contribute towards ZOSTAVAX efficacy.

  15. Efficient Methods To Isolate Human Monoclonal Antibodies from Memory B Cells and Plasma Cells.

    Science.gov (United States)

    Corti, Davide; Lanzavecchia, Antonio

    2014-10-01

    In this article, we highlight the advantages of isolating human monoclonal antibodies from the human memory B cells and plasma cell repertoires by using high-throughput cellular screens. Memory B cells are immortalized with high efficiency using Epstein-Barr virus (EBV) in the presence of a toll-like receptor (TLR) agonist, while plasma cells are maintained in single-cell cultures by using interleukin 6 (IL-6) or stromal cells. In both cases, multiple parallel assays, including functional assays, can be used to identify rare cells that produce antibodies with unique properties. Using these methods, we have isolated potent and broadly neutralizing antibodies against a variety of viruses, in particular, a pan-influenza-A-neutralizing antibody and an antibody that neutralizes four different paramyxoviruses. Given the high throughput and the possibility of directly screening for function (rather than just binding), these methods are instrumental to implement a target-agnostic approach to identify the most effective antibodies and, consequently, the most promising targets for vaccine design. This approach is exemplified by the identification of unusually potent cytomegalovirus-neutralizing antibodies that led to the identification of the target, a pentameric complex that we are developing as a candidate vaccine. PMID:26104354

  16. Antigen-dependent proliferation and cytokine induction in respiratory syncytial virus-infected cotton rats reflect the presence of effector-memory T cells

    International Nuclear Information System (INIS)

    Respiratory syncytial virus (RSV) is a major cause of lower airway disease in infants and children. Immunity to RSV is not long lasting, resulting in re-occurring infections throughout life. Effective long-lived immunity results when central-memory T cells that proliferate vigorously and secrete IL-2 are present. In contrast, effector-memory T cells that mainly produce IFN-γ, facilitate virus clearance but are not long lived. To identify the type of memory response induced after RSV-A (Long) infection, we characterized the kinetics of the antigen-specific immune response and identified the types of cytokines induced. RSV-specific lymphocytic proliferation following primary and secondary infection was similar, and in both cases responses waned within a short period of time. In addition, mRNA for IFN-γ but not IL-2 was induced in RSV-specific CD4+ T cells. This supports the idea that the presence of effector-memory rather than central-memory T cells contributes to the ineffectiveness of the immune response to RSV

  17. Cutting edge: CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal.

    Science.gov (United States)

    Chaix, Julie; Nish, Simone A; Lin, Wen-Hsuan W; Rothman, Nyanza J; Ding, Lei; Wherry, E John; Reiner, Steven L

    2014-08-01

    Central memory (CM) CD8(+) T cells "remember" prior encounters because they maintain themselves through cell division in the absence of ongoing challenge (homeostatic self-renewal), as well as reproduce the CM fate while manufacturing effector cells during secondary Ag encounters (rechallenge self-renewal). We tested the consequence of conditional deletion of the bone marrow homing receptor CXCR4 on antiviral T cell responses. CXCR4-deficient CD8(+) T cells have impaired memory cell maintenance due to defective homeostatic proliferation. Upon rechallenge, however, CXCR4-deficient T cells can re-expand and renew the CM pool while producing secondary effector cells. The critical bone marrow-derived signals essential for CD8(+) T cell homeostatic self-renewal appear to be dispensable to yield self-renewing, functionally asymmetric cell fates during rechallenge.

  18. PERFORMANCE COMPARISON OF CELL-BASED AND PACKET-BASED SWITCHING SCHEMES FOR SHARED MEMORY SWITCHES

    Institute of Scientific and Technical Information of China (English)

    Xi Kang; Ge Ning; Feng Chongxi

    2004-01-01

    Shared Memory (SM) switches are widely used for its high throughput, low delay and efficient use of memory. This paper compares the performance of two prominent switching schemes of SM packet switches: Cell-Based Switching (CBS) and Packet-Based Switching (PBS).Theoretical analysis is carried out to draw qualitative conclusion on the memory requirement,throughput and packet delay of the two schemes. Furthermore, simulations are carried out to get quantitative results of the performance comparison under various system load, traffic patterns,and memory sizes. Simulation results show that PBS has the advantage of shorter time delay while CBS has lower memory requirement and outperforms in throughput when the memory size is limited. The comparison can be used for tradeoff between performance and complexity in switch design.

  19. The taming of the cell: shape-memory nanopatterns direct cell orientation

    Science.gov (United States)

    Ebara, Mitsuhiro; Uto, Koichiro; Idota, Naokazu; Hoffman, John M; Aoyagi, Takao

    2014-01-01

    We report here that the direction of aligned cells on nanopatterns can be tuned to a perpendicular direction without use of any biochemical reagents. This was enabled by shape-memory activation of nanopatterns that transition from a memorized temporal pattern to the original permanent pattern by heating. The thermally induced shape-memory nanopatterns were prepared by chemically crosslinking semi-crystalline poly(ε-caprolactone) (PCL) in a mold to show shape-memory effects over its melting temperature (Tm = 33°C). Permanent surface patterns were first generated by crosslinking the PCL macromonomers in a mold, and temporary surface patterns were then embossed onto the permanent patterns. The temporary surface patterns could be easily triggered to transition quickly to the permanent surface patterns by a 37°C heat treatment, while surface wettability was independent of temperature. To investigate the role of dynamic and reversible surface nanopatterns on cell alignment on the PCL films before and after a topographic transition, NIH 3T3 fibroblasts were seeded on fibronectin-coated PCL films with a temporary grooved topography (grooves with a height of 300 nm and width of 2 μm were spaced 9 μm apart). Interestingly, cells did not change their direction immediately after the surface transition. However, cell alignment was gradually lost with time, and finally cells realigned parallel to the permanent grooves that emerged. The addition of a cytoskeletal inhibitor prevented realignment. These results clearly indicate that cells can sense dynamic changes in the surrounding environments and spontaneously adapt to a new environment by remodeling their cytoskeleton. These findings will serve as the basis for new development of spatiotemporal tunable materials to direct cell fate. PMID:24872707

  20. Cortisol response and psychological distress predict susceptibility to false memories for a trauma film.

    Science.gov (United States)

    Monds, Lauren A; Paterson, Helen M; Ali, Sinan; Kemp, Richard I; Bryant, Richard A; McGregor, Iain S

    2016-10-01

    For eyewitness testimony to be considered reliable, it is important to ensure memory remains accurate following the event. As many testimonies involve traumatic, as opposed to neutral, events, it is important to consider the role of distress in susceptibility to false memories. The aim of this study was to investigate whether cortisol response following a stressor would be associated with susceptibility to false memories. Psychological distress responses were also investigated, specifically, dissociation, intrusions, and avoidance. Participants were allocated to one of three conditions: those who viewed a neutral film (N = 35), those who viewed a real trauma film (N = 35), and a trauma "reappraisal" group where participants were told the film was not real (N = 35). All received misinformation about the film in the form of a narrative. Participants provided saliva samples (to assess cortisol) and completed distress and memory questionnaires. Cortisol response was a significant predictor of the misinformation effect. Dissociation and avoidance were related to confabulations. In conclusion, following a stressor an individual may differ with regard to their psychological response to the event, and also whether they experience a cortisol increase. This may affect whether they are more distressed later on, and also whether they remember the event accurately.

  1. Selective and Protracted Effect of Nifedipine on Fear Memory Extinction Correlates with Induced Stress Response

    Science.gov (United States)

    Waltereit, Robert; Mannhardt, Sonke; Nescholta, Sabine; Maser-Gluth, Christiane; Bartsch, Dusan

    2008-01-01

    Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage…

  2. The Drosophila cell adhesion molecule Klingon is required for long-term memory formation and is regulated by Notch

    OpenAIRE

    Matsuno, Motomi; Horiuchi, Junjiro; Tully, Tim; Saitoe, Minoru

    2008-01-01

    The ruslan (rus) mutant was previously identified in a behavioral screen for mutants defective in long-lasting memory, which consists of two consolidated memory types, anesthesia-resistant memory, and protein synthesis-dependent long-term memory (LTM). We demonstrate here that rus is a new allele of klingon (klg), which encodes a homophilic cell adhesion molecule. Klg is acutely required for LTM but not anesthesia-resistant memory formation, and Klg expression increases upon LTM induction. LT...

  3. Memristive behavior in a junctionless flash memory cell

    Energy Technology Data Exchange (ETDEWEB)

    Orak, Ikram [Vocational School of Health Services, Bingöl University, 12000 Bingöl (Turkey); Department of Physics, Faculty of Science and Art, Bingöl University, 12000 Bingöl (Turkey); Ürel, Mustafa; Dana, Aykutlu, E-mail: aykutlu@unam.bilkent.edu.tr [UNAM Institute of Materials Science and Nanotechnology, Bilkent University, 06800 Ankara (Turkey); Bakan, Gokhan [Faculty of Engineering, Antalya International University, 07190 Antalya (Turkey)

    2015-06-08

    We report charge storage based memristive operation of a junctionless thin film flash memory cell when it is operated as a two terminal device by grounding the gate. Unlike memristors based on nanoionics, the presented device mode, which we refer to as the flashristor mode, potentially allows greater control over the memristive properties, allowing rational design. The mode is demonstrated using a depletion type n-channel ZnO transistor grown by atomic layer deposition (ALD), with HfO{sub 2} as the tunnel dielectric, Al{sub 2}O{sub 3} as the control dielectric, and non-stoichiometric silicon nitride as the charge storage layer. The device exhibits the pinched hysteresis of a memristor and in the unoptimized device, R{sub off}/R{sub on} ratios of about 3 are presented with low operating voltages below 5 V. A simplified model predicts R{sub off}/R{sub on} ratios can be improved significantly by adjusting the native threshold voltage of the devices. The repeatability of the resistive switching is excellent and devices exhibit 10{sup 6 }s retention time, which can, in principle, be improved by engineering the gate stack and storage layer properties. The flashristor mode can find use in analog information processing applications, such as neuromorphic computing, where well-behaving and highly repeatable memristive properties are desirable.

  4. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory.

    Science.gov (United States)

    Oliveira, Giacomo; Ruggiero, Eliana; Stanghellini, Maria Teresa Lupo; Cieri, Nicoletta; D'Agostino, Mattia; D'Agostino, Mattio; Fronza, Raffaele; Lulay, Christina; Dionisio, Francesca; Mastaglio, Sara; Greco, Raffaella; Peccatori, Jacopo; Aiuti, Alessandro; Ambrosi, Alessandro; Biasco, Luca; Bondanza, Attilio; Lambiase, Antonio; Traversari, Catia; Vago, Luca; von Kalle, Christof; Schmidt, Manfred; Bordignon, Claudio; Ciceri, Fabio; Bonini, Chiara

    2015-12-01

    Long-lasting immune protection from pathogens and cancer requires the generation of memory T cells able to survive long-term. To unravel the immunological requirements for long-term persistence of human memory T cells, we characterized and traced, over several years, T lymphocytes genetically modified to express the thymidine kinase (TK) suicide gene that were infused in 10 patients after haploidentical hematopoietic stem cell transplantation (HSCT). At 2 to 14 years after infusion and in the presence of a broad and resting immune system, we could still detect effectors/effector memory (TEM/EFF), central memory (TCM), and stem memory (TSCM) TK(+) cells, circulating at low but stable levels in all patients. Longitudinal analysis of cytomegalovirus (CMV)- and Flu-specific TK(+) cells indicated that antigen recognition was dominant in driving in vivo expansion and persistence at detectable levels. The amount of infused TSCM cells positively correlated with early expansion and with the absolute counts of long-term persisting gene-marked cells. By combining T cell sorting with sequencing of integration (IS), TCRα and TCRβ clonal markers, we showed that T cells retrieved long-term were enriched in clones originally shared in different memory T cell subsets, whereas dominant long-term clonotypes appeared to preferentially originate from infused TSCM and TCM clones. Together, these results indicate that long-term persistence of gene-modified memory T cells after haploidentical HSCT is influenced by antigen exposure and by the original phenotype of infused cells. Cancer adoptive immunotherapy might thus benefit from cellular products enriched in lymphocytes with an early-differentiated phenotype. PMID:26659572

  5. Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Lianjun Zhang

    2016-02-01

    Full Text Available Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs and memory precursor cells (MPECs. The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2, regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memorycells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memorycells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.

  6. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming

    NARCIS (Netherlands)

    Kwakkenbos, Mark J.; Diehl, Sean A.; Yasuda, Etsuko; Bakker, Arjen Q.; van Geelen, Caroline M. M.; Lukens, Michaël; van Bleek, Grada M.; Widjojoatmodjo, Myra N.; Bogers, Willy M. J. M.; Mei, Henrik; Radbruch, Andreas; Scheeren, Ferenc A.; Spits, Hergen; Beaumont, Tim

    2010-01-01

    The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced

  7. Item Response Theory Analyses of the Cambridge Face Memory Test (CFMT)

    OpenAIRE

    Cho, Sun-Joo; Wilmer, Jeremy; Herzmann, Grit; McGugin, Rankin; Fiset, Daniel; Van Gulick, Ana E.; Ryan, Katie; Gauthier, Isabel

    2015-01-01

    We evaluated the psychometric properties of the Cambridge face memory test (CFMT; Duchaine & Nakayama, 2006). First, we assessed the dimensionality of the test with a bi-factor exploratory factor analysis (EFA). This EFA analysis revealed a general factor and three specific factors clustered by targets of CFMT. However, the three specific factors appeared to be minor factors that can be ignored. Second, we fit a unidimensional item response model. This item response model showed that the CFMT...

  8. Low Velocity Impact Response Analysis of Shape Memory Alloy Reinforced Composite Beam

    Institute of Scientific and Technical Information of China (English)

    WU Yongdong; ZHONG Weifang; WU Guorong; ZOU Jing

    2005-01-01

    The low velocity impact responses of shape memory alloy ( SMA ) reinforced composite beams were analyzed by employing the finite element method. The finite element dynamic equation was solved by the Newmark direct integration method, the impact contact force was determined using the Hertzian contact law, and the influence of SMA fibers on stiffness matrix is studied. Numerical results show that the SMA fibers can effectively improve the low velocity impact response property of composite beam.

  9. Generation-by-Generation Dissection of the Response Function in Long Memory Epidemic Processes

    CERN Document Server

    Saichev, A

    2009-01-01

    In a number of natural and social systems, the response to an exogenous shock relaxes back to the average level according to a long-memory kernel $\\sim 1/t^{1+\\theta}$ with $0 \\leq \\theta 1$ and we find in this case that the total renormalized response is a {\\bf constant} for $t < 1/(1-n)$ followed by a cross-over to $\\sim 1/t^{1+\\theta}$ for $t \\gg 1/(1-n)$.

  10. Discrete-Slots Models of Visual Working-Memory Response Times

    OpenAIRE

    Donkin, Christopher; Nosofsky, Robert M.; Gold, Jason M.; Richard M Shiffrin

    2013-01-01

    Much recent research has aimed to establish whether visual working memory (WM) is better characterized by a limited number of discrete all-or-none slots or by a continuous sharing of memory resources. To date, however, researchers have not considered the response-time (RT) predictions of discrete-slots versus shared-resources models. To complement the past research in this field, we formalize a family of mixed-state, discrete-slots models for explaining choice and RTs in tasks of visual WM ch...

  11. Qualitative and quantitative analysis of adenovirus type 5 vector-induced memory CD8 T cells

    DEFF Research Database (Denmark)

    Steffensen, Maria Abildgaard; Holst, Peter Johannes; Steengaard, Sanne Skovvang;

    2013-01-01

    It has been reported that adenovirus (Ad) primed CD8 T cells may display a distinct and partially exhausted phenotype. Given the practical implications of this claim, we decided to analyze in detail the quality of Ad-primed CD8 T cells directly comparing these cells to CD8 T cells induced through...... adenoviral boosting and, importantly, the generated secondary memory cells cannot be qualitatively differentiated from those induced by primary infection with replicating virus. Quantitatively, DNA priming prior to Ad-vaccination will lead to even higher numbers of memory cells. In this case, the vaccination...... an effective means to induce a substantially expanded, long-lived population of high-quality transgene-specific memory CD8 T cells....

  12. Place Cell Networks in Pre-weanling Rats Show Associative Memory Properties from the Onset of Exploratory Behavior.

    Science.gov (United States)

    Muessig, L; Hauser, J; Wills, T J; Cacucci, F

    2016-08-01

    Place cells are hippocampal pyramidal cells that are active when an animal visits a restricted area of the environment, and collectively their activity constitutes a neural representation of space. Place cell populations in the adult rat hippocampus display fundamental properties consistent with an associative memory network: the ability to 1) generate new and distinct spatial firing patterns when encountering novel spatial contexts or changes in sensory input ("remapping") and 2) reinstate previously stored firing patterns when encountering a familiar context, including on the basis of an incomplete/degraded set of sensory cues ("pattern completion"). To date, it is unknown when these spatial memory responses emerge during brain development. Here, we show that, from the age of first exploration (postnatal day 16) onwards, place cell populations already exhibit these key features: they generate new representations upon exposure to a novel context and can reactivate familiar representations on the basis of an incomplete set of sensory cues. These results demonstrate that, as early as exploratory behaviors emerge, and despite the absence of an adult-like grid cell network, the developing hippocampus processes incoming sensory information as an associative memory network. PMID:27282394

  13. Influence of thermal memory on the thermoelastic bending component of photoacoustic response

    Directory of Open Access Journals (Sweden)

    Nešić Mioljub V.

    2011-01-01

    Full Text Available In this work, thermoelastic component of the photoacoustic response is derived, including thermal memory of the material. The comparison between this model and the classic one, which does not account for the influence of thermal memory is made. It has been noticed that the two models tend to overlap at very high and very low frequencies of the light modulation spectrum, while in the middle range some deviations become more apparent, which proves that thermal memory must be taken into account. It has also been shown that the limits of this range are the function of heat propagation velocity and thickness of the sample. Based upon the processing of obtained data, it has been concluded that the characteristics of the output signal, in the range of the interest, are highly influenced by thermal dynamic qualities, like heat diffusivity and thermal relaxation time, as well as the sample thickness.

  14. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function

    OpenAIRE

    Sukumar, Madhusudhanan; Liu, Jie; Ji, Yun; Subramanian, Murugan; Crompton, Joseph G.; Yu, Zhiya; Roychoudhuri, Rahul; Palmer, Douglas C.; Muranski, Pawel; Karoly, Edward D; Mohney, Robert P.; Klebanoff, Christopher A.; Lal, Ashish; Finkel, Toren; Restifo, Nicholas P.

    2013-01-01

    Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had ...

  15. Quantifying susceptibility of CD4+ stem memory T-cells to infection by laboratory adapted and clinical HIV-1 strains.

    Science.gov (United States)

    Flynn, Jacqueline K; Paukovics, Geza; Cashin, Kieran; Borm, Katharina; Ellett, Anne; Roche, Michael; Jakobsen, Martin R; Churchill, Melissa J; Gorry, Paul R

    2014-02-10

    CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP) reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM), central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs.

  16. Quantifying Susceptibility of CD4+ Stem Memory T-Cells to Infection by Laboratory Adapted and Clinical HIV-1 Strains

    Directory of Open Access Journals (Sweden)

    Jacqueline K. Flynn

    2014-02-01

    Full Text Available CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1 infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM, central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs.

  17. Diet-Induced Weight Loss Alters Functional Brain Responses during an Episodic Memory Task

    Directory of Open Access Journals (Sweden)

    Carl-Johan Boraxbekk

    2015-07-01

    Full Text Available Objective: It has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women. Methods: 20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 months. We used functional magnetic resonance imaging to examine brain function during an episodic memory task as well as anthropometric and biochemical data before and after the interventions. Results: Episodic memory performance improved significantly (p = 0.010 after the dietary interventions. Concomitantly, brain activity increased in the anterior part of the right hippocampus during memory encoding, without differences between diets. This was associated with decreased levels of plasma free fatty acids (FFA. Brain activity increased in pre-frontal cortex and superior/middle temporal gyri. The magnitude of increase correlated with waist circumference reduction. During episodic retrieval, brain activity decreased in inferior and middle frontal gyri, and increased in middle/superior temporal gyri. Conclusions: Diet-induced weight loss, associated with decreased levels of plasma FFA, improves episodic memory linked to increased hippocampal activity.

  18. Epidermal Fatty Acid Binding Protein (E-FABP) Is Not Required for the Generation or Maintenance of Effector and Memory T Cells following Infection with Listeria monocytogenes.

    Science.gov (United States)

    Li, Bing; Schmidt, Nathan W

    2016-01-01

    Following activation of naïve T cells there are dynamic changes in the metabolic pathways used by T cells to support both the energetic needs of the cell and the macromolecules required for growth and proliferation. Among other changes, lipid metabolism undergoes dynamic transitions between fatty acid oxidation and fatty acid synthesis as cells progress from naïve to effector and effector to memory T cells. The hydrophobic nature of lipids requires that they be bound to protein chaperones within a cell. Fatty acid binding proteins (FABPs) represent a large class of lipid chaperones, with epidermal FABP (E-FABP) expressed in T cells. The objective of this study was to determine the contribution of E-FABP in antigen-specific T cell responses. Following infection with Listeria monocytogenes, we observed similar clonal expansion, contraction and formation of memory CD8 T cells in WT and E-FABP-/- mice, which also exhibited similar phenotypic and functional characteristics. Analysis of Listeria-specific CD4 T cells also revealed no defect in the expansion, contraction, and formation of memory CD4 T cells in E-FABP-/- mice. These data demonstrate that E-FABP is dispensable for antigen-specific T cell responses following a bacterial infection. PMID:27588422

  19. The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

    Science.gov (United States)

    Chen, Tsan-Ju; Chen, Shun-Sheng; Wang, Dean-Chuan; Hung, Hui-Shan

    2016-11-01

    Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc. PMID:26895748

  20. Differential gene expression by integrin β7+ and β7- memory T helper cells

    Directory of Open Access Journals (Sweden)

    Yang Yee

    2004-07-01

    Full Text Available Abstract Background The cell adhesion molecule integrin α4β7 helps direct the migration of blood lymphocytes to the intestine and associated lymphoid tissues. We hypothesized that β7+ and β7- blood memory T helper cells differ in their expression of genes that play a role in the adhesion or migration of T cells. Results RNA was prepared from β7+ and β7- CD4+ CD45RA- blood T cells from nine normal human subjects and analyzed using oligonucleotide microarrays. Of 21357 genes represented on the arrays, 16 were more highly expressed in β7+ cells and 18 were more highly expressed in β7- cells (≥1.5 fold difference and adjusted P + memory/effector T cells than on β7- cells. Conclusions Memory/effector T cells that express integrin β7 have a distinct pattern of expression of a set of gene transcripts. Several of these molecules can affect cell adhesion or chemotaxis and are therefore likely to modulate the complex multistep process that regulates trafficking of CD4+ memory T cell subsets with different homing behaviors.

  1. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

    Science.gov (United States)

    Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony J.; Yamamoto, Tori N.; Cruz, Anthony C.; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Thomas, Stacy K.; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Siegel, Richard M.; Restifo, Nicholas P.

    2015-01-01

    Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell–T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory–induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell–based immunotherapies. PMID:26657860

  2. Co-administration of IL-1+IL-6+TNF-α with Mycobacterium tuberculosis infected macrophages vaccine induces better protective T cell memory than BCG.

    Directory of Open Access Journals (Sweden)

    Vijender Singh

    Full Text Available BCG has been administered globally for more than 75 years, yet tuberculosis (TB continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb and Salmonella typhimurium by utilizing infected macrophages (IM. In short-term experiments (30 days, substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1+IL-6+TNF-α and IL-7+IL-15 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL-1+IL-6+TNF-α (IM-1.6.α and IL-7+IL-15 (IM-7.15. The mice were then rested for a reasonably large period (240 days to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.α but not IM-7.15 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CD8 T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1.6.α was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb

  3. Sustained CD8+ T cell memory inflation after infection with a single-cycle cytomegalovirus.

    Directory of Open Access Journals (Sweden)

    Christopher M Snyder

    2011-10-01

    Full Text Available Cytomegalovirus (CMV is a β-herpesvirus that establishes a lifelong latent or persistent infection. A hallmark of chronic CMV infection is the lifelong persistence of large numbers of virus-specific CD8+ effector/effector memory T cells, a phenomenon called "memory inflation". How the virus continuously stimulates these T cells without being eradicated remains an enigma. The prevailing view is that CMV establishes a low grade "smoldering" infection characterized by tiny bursts of productive infection which are rapidly extinguished, leaving no detectable virus but replenishing the latent pool and leaving the immune system in a highly charged state. However, since abortive reactivation with limited viral gene expression is known to occur commonly, we investigated the necessity for virus reproduction in maintaining the inflationary T cell pool. We inhibited viral replication or spread in vivo using two different mutants of murine CMV (MCMV. First, famcyclovir blocked the replication of MCMV encoding the HSV Thymidine Kinase gene, but had no impact on the CD8+ T cell memory inflation once the infection was established. Second, MCMV that lacks the essential glycoprotein L, and thus is completely unable to spread from cell to cell, also drove memory inflation if the virus was administered systemically. Our data suggest that CMV which cannot spread from the cells it initially infects can repeatedly generate viral antigens to drive memory inflation without suffering eradication of the latent genome pool.

  4. Memory T cell subsets in tuberculosis: what should we be targeting?

    Science.gov (United States)

    Henao-Tamayo, Marcela; Ordway, Diane J; Orme, Ian M

    2014-09-01

    The purpose of vaccination is to establish a stable population of long lived memory T cells. In the context of tuberculosis, the BCG vaccine has been widely used for well over 60 years, but during that time its weaknesses, particularly its ineffectiveness in adults, has been increasingly recognized. In this commentary we review what is known about memory T cells, both in general and in the context of their role in expressing specific acquired resistance to tuberculosis. Current knowledge indicates that both effector memory and central memory can be generated, depending on the experimental conditions, but both in animal models and in clinical studies it is clear that effector memory T cells are the predominant subset. These issues are of importance, given the concerted effort to make new TB vaccines, not all of which may work in precisely the same manner. At the present time whether a TB vaccine would work better if it targeted one specific T cell subset rather than another is as yet completely unknown, and this is now further complicated by new evidence that suggests other subsets such as IL-17 secreting CD4 T cells and cells with stem cell-like qualities may also play important roles.

  5. Age related differences in dynamics of specific memory B cell populations after clinical pertussis infection.

    Directory of Open Access Journals (Sweden)

    Inonge van Twillert

    Full Text Available For a better understanding of the maintenance of immune mechanisms to Bordetella pertussis (Bp in relation to age, we investigated the dynamic range of specific B cell responses in various age-groups at different time points after a laboratory confirmed pertussis infection. Blood samples were obtained in a Dutch cross sectional observational study from symptomatic pertussis cases. Lymphocyte subpopulations were phenotyped by flowcytometry before and after culture. Memory B (Bmem cells were differentiated into IgG antibody secreting cells (ASC by polyclonal stimulation and detected by an ELISPOT assay specific for pertussis antigens pertussis toxin (Ptx, filamentous haemagglutinin (FHA and pertactin (Prn. Bp antigen specific IgG concentrations in plasma were determined using multiplex technology. The majority of subjects having experienced a clinical pertussis episode demonstrated high levels of both Bp specific IgG and Bmem cell levels within the first 6 weeks after diagnosis. Significantly lower levels were observed thereafter. Waning of cellular and humoral immunity to maintenance levels occurred within 9 months after antigen encounter. Age was found to determine the maximum but not base-line frequencies of Bmem cell populations; higher levels of Bmem cells specific for Ptx and FHA were reached in adults and (pre- elderly compared to under-fours and schoolchildren in the first 6 weeks after Bp exposure, whereas not in later phases. This age effect was less obvious for specific IgG levels. Nonetheless, subjects' levels of specific Bmem cells and specific IgG were weakly correlated. This is the first study to show that both age and closeness to last Bp encounter impacts the size of Bp specific Bmem cell and plasma IgG levels.

  6. Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells.

    Science.gov (United States)

    Herrmann, A; Rice, M; Lévy, R; Pizer, B L; Losty, P D; Moss, D; Sée, V

    2015-01-01

    Therapies targeting cancer metastasis are challenging owing to the complexity of the metastatic process and the high number of effectors involved. Although tumour hypoxia has previously been associated with increased aggressiveness as well as resistance to radio- and chemotherapy, the understanding of a direct link between the level and duration of hypoxia and the individual steps involved in metastasis is still missing. Using live imaging in a chick embryo model, we have demonstrated that the exposure of neuroblastoma cells to 1% oxygen for 3 days was capable of (1) enabling cell migration towards blood vessels, (2) slowing down their velocity within blood vessels to facilitate extravasation and (3) promoting cell proliferation in primary and secondary sites. We have shown that cells do not have to be hypoxic anymore to exhibit these acquired capabilities as a long-term memory of prior hypoxic exposure is kept. Furthermore, non-hypoxic cells can be influenced by neighbouring hypoxic preconditioned cells and be entrained in the metastatic progression. The acquired aggressive phenotype relies on hypoxia-inducible factor (HIF)-dependent transcription of a number of genes involved in metastasis and can be impaired by HIF inhibition. Altogether, our results demonstrate the need to consider both temporal and spatial tumour heterogeneity because cells can 'remember' an earlier environment and share their acquired phenotype with their close neighbours. As a consequence, it is necessary to monitor the correct hypoxic markers to be able to predict the consequences of the cells' history on their behaviour and their potential response to therapies. PMID:25664931

  7. Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection.

    Science.gov (United States)

    Steinbach, Karin; Vincenti, Ilena; Kreutzfeldt, Mario; Page, Nicolas; Muschaweckh, Andreas; Wagner, Ingrid; Drexler, Ingo; Pinschewer, Daniel; Korn, Thomas; Merkler, Doron

    2016-07-25

    Tissue-resident memory T cells (TRM) persist at sites of prior infection and have been shown to enhance pathogen clearance by recruiting circulating immune cells and providing bystander activation. Here, we characterize the functioning of brain-resident memory T cells (bTRM) in an animal model of viral infection. bTRM were subject to spontaneous homeostatic proliferation and were largely refractory to systemic immune cell depletion. After viral reinfection in mice, bTRM rapidly acquired cytotoxic effector function and prevented fatal brain infection, even in the absence of circulating CD8(+) memory T cells. Presentation of cognate antigen on MHC-I was essential for bTRM-mediated protective immunity, which involved perforin- and IFN-γ-dependent effector mechanisms. These findings identify bTRM as an organ-autonomous defense system serving as a paradigm for TRM functioning as a self-sufficient first line of adaptive immunity. PMID:27377586

  8. A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells

    OpenAIRE

    Juchem, Kathryn W.; Anderson, Britt E.; Zhang, Cuiling; McNiff, Jennifer M.; DEMETRIS, ANTHONY J.; Farber, Donna L.; Caton, Andrew J.; Shlomchik, Warren D.; Shlomchik, Mark J.

    2011-01-01

    Effector memory T cells (TEM) do not cause graft-versus-host disease (GVHD), though why this is has not been elucidated. To compare the fates of alloreactive naive (TN) or memory (TM) T cells, we developed a model of GVHD in which donor T cells express a transgene-encoded TCR specific for an antigenic peptide that is ubiquitously expressed in the recipient. Small numbers of naive TCR transgenic (Tg) T cells induced a robust syndrome of GVHD in transplanted recipients. We then used an establis...

  9. Protection against HPV-16-Associated Tumors Requires the Activation of CD8+ Effector Memory T Cells and the Control of Myeloid-Derived Suppressor Cells.

    Science.gov (United States)

    Diniz, Mariana O; Sales, Natiely S; Silva, Jamile R; Ferreira, Luís Carlos S

    2016-08-01

    Active anticancer immunotherapeutic approaches have been shown to induce cellular or humoral immune responses in patients, but, thus far, the observed outcomes did not ensure their recommendation for clinical use. The induction of tumor-specific CD8(+) T cells, although required for the clearance of most solid tumors, was shown to be insufficient for the development of a successful immunotherapeutic approach. The suppressive immune environment triggered by tumors, including the expansion of myeloid-derived suppressor cells (MDSC), is detrimental to the development of antitumor immune responses and precludes the generation of more promising clinical outcomes. In this work, we characterized the CD8(+) T-cell population specifically involved in the control of tumor growth and the role of MDSCs after administration of an antitumor therapeutic DNA vaccine targeting human papillomavirus type 16 (HPV-16)-associated tumors. Activation of cytotoxic high-avidity CD8(+) T cells with an effector memory phenotype was found in mice grafted with tumor cells expressing the HPV-16 oncoproteins. In addition, MDSC antibody depletion further enhanced the immunotherapeutic effects of the vaccine, resulting in the complete eradication of tumor cells. Collectively, the current results indicate that the simultaneous control of MDSCs and activation of high-avidity tumor-specific effector memory CD8(+) T cells are key features for tumor protection by immunotherapeutic approaches and deserve further testing under clinical conditions. Mol Cancer Ther; 15(8); 1920-30. ©2016 AACR. PMID:27222537

  10. Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation

    Science.gov (United States)

    Yang, Jialong; Zhang, Ping; Krishna, Sruti; Wang, Jinli; Lin, Xingguang; Huang, Hongxiang; Xie, Danli; Gorentla, Balachandra; Huang, Rick; Gao, Jimin; Li, Qi-Jing; Zhong, Xiao-Ping

    2016-01-01

    Signals from the T-cell receptor (TCR) and γ-chain cytokine receptors play crucial roles in initiating activation and effector/memory differentiation of CD8 T-cells. We report here that simultaneous deletion of both diacylglycerol kinase (DGK) α and ζ (DKO) severely impaired expansion of CD8 effector T cells and formation of memory CD8 T-cells after Listeria monocytogenes infection. Moreover, ablation of both DGKα and ζ in preformed memory CD8 T-cells triggered death and impaired homeostatic proliferation of these cells. DKO CD8 T-cells were impaired in priming due to decreased expression of chemokine receptors and migration to the draining lymph nodes. Moreover, DKO CD8 T-cells were unexpectedly defective in NFκB-mediated miR-155 transcript, leading to excessive SOCS1 expression and impaired γ-chain cytokine signaling. Our data identified a DGK-NFκB-miR-155-SOCS1 axis that bridges TCR and γ-chain cytokine signaling for robust CD8 T-cell primary and memory responses to bacterial infection. PMID:27014906

  11. The effect of liking on the memorial response to advertising: the case of small cars

    OpenAIRE

    Sergio Brasini; Marzia Freo; Giorgio Tassinari

    2013-01-01

    In marketing literature there is actually very poor evidence of how ad liking works to build its impact on memorial response to ad pressure. This study investigates the problem of the existence of carryover effects of ad liking on recall, by modelling the dynamic patterns of recall, ad pressure and liking by means of the specification of an augmented Koyck-type model and provides a methodology for assessing ad likeability ex post effectiveness on recall variables. The analysis is carried out ...

  12. Diet-Induced Weight Loss alters Functional Brain Responses during an Episodic Memory Task

    OpenAIRE

    Boraxbekk, Carl-Johan; Stomby, Andreas; Ryberg, Mats; Lindahl, Bernt; Larsson, Christel; Nyberg, Lars; Olsson, Tommy

    2015-01-01

    Objective: It has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women. Methods: 20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 mon...

  13. Fabrication, characterization and simulation of high performance Si nanowire-based non-volatile memory cells

    International Nuclear Information System (INIS)

    We report the fabrication, characterization and simulation of Si nanowire SONOS-like non-volatile memory with HfO2 charge trapping layers of varying thicknesses. The memory cells, which are fabricated by self-aligning in situ grown Si nanowires, exhibit high performance, i.e. fast program/erase operations, long retention time and good endurance. The effect of the trapping layer thickness of the nanowire memory cells has been experimentally measured and studied by simulation. As the thickness of HfO2 increases from 5 to 30 nm, the charge trap density increases as expected, while the program/erase speed and retention remain the same. These data indicate that the electric field across the tunneling oxide is not affected by HfO2 thickness, which is in good agreement with simulation results. Our work also shows that the Omega gate structure improves the program speed and retention time for memory applications.

  14. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.

    Science.gov (United States)

    Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F; Gondek, David; Alvarez, David; Basto, Pamela A; Perro, Mario; Vrbanac, Vladimir D; Tager, Andrew M; Shi, Jinjun; Yethon, Jeremy A; Farokhzad, Omid C; Langer, Robert; Starnbach, Michael N; von Andrian, Ulrich H

    2015-06-19

    Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b(+)CD103(-) dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b(-)CD103(+) DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (T(RM) cells). Optimal Ct clearance required both T(RM) seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties. PMID:26089520

  15. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

    Science.gov (United States)

    Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H. Leighton; Katz, Jonathan D.; Finkelman, Fred D.; Hildeman, David A.

    2007-01-01

    We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells. PMID:17591857

  16. TRAF3 regulates the effector function of regulatory T cells and humoral immune responses

    OpenAIRE

    Chang, Jae-Hoon; Hu, Hongbo; Jin, Jin; Puebla-Osorio, Nahum; Xiao, Yichuan; Gilbert, Brian E.; Brink, Robert; Ullrich, Stephen E.; Sun, Shao-Cong

    2014-01-01

    Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor–associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell–specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated act...

  17. Memory performance is related to the cortisol awakening response in older people, but not to the diurnal cortisol slope.

    Science.gov (United States)

    Hidalgo, Vanesa; Almela, Mercedes; Pulopulos, Matias M; Salvador, Alicia

    2016-09-01

    There are large individual differences in age-related cognitive decline. Hypothalamic-pituitary-adrenal axis (HPA-axis) functioning has been suggested as one of the mechanisms underlying these differences. This study aimed to investigate the relationships between the diurnal cortisol cycle, measured as the cortisol awakening response (CAR), and the diurnal cortisol slope (DCS) and the memory performance of healthy older people. To do so, we assessed the verbal, visual, and working memory performance of 64 participants (32 men) from 57 to 76 years old who also provided 14 saliva samples on two consecutive weekdays to determine their diurnal cortisol cycle. The CAR was linearly and negatively associated with verbal (significantly) and visual (marginally) memory domains, but not with working memory. Sex did not moderate these relationships. Furthermore, no associations were found between the DCS and any of the three memory domains assessed. Our results indicate that the two components of the diurnal cortisol cycle have different relationships with memory performance, with the CAR being more relevant than DCS in understanding the link from HPA-axis activity and regulation to different types of memory. These results suggest that the CAR is related to memory domains dependent on hippocampal functioning (i.e., declarative memory), but not to those that are more dependent on prefrontal cortex functioning (i.e., working memory). PMID:27266967

  18. Bioabsorbable radiopaque water-responsive shape memory embolization plug for temporary vascular occlusion.

    Science.gov (United States)

    Wong, Yee Shan; Salvekar, Abhijit Vijay; Zhuang, Kun Da; Liu, Hui; Birch, William R; Tay, Kiang Hiong; Huang, Wei Min; Venkatraman, Subbu S

    2016-09-01

    We describe the preparation, characterization and evaluation of a biodegradable radiopaque water-triggered shape memory embolization plug for temporary vascular occlusion. The shape memory occluding device consists of a composite of a radio-opaque filler and a poly (dl-lactide-co-glycolide) (PLGA) blend, which was coated with a crosslinked poly (ethylene glycol) diacrylate (PEGDA) hydrogel. The mechanical properties, the degradation timeframe, the effect of programming conditions on the shape memory behaviour and the extent of radio-opacity for imaging were evaluated. Based on the tests, the mechanism responsible for the water-induced shape memory effect in such an embolization plug was elucidated. Suitable materials were optimized to fabricate an embolic plug prototype and its in vitro performance was evaluated as an occlusion rate (using a custom-built set up) and its biocompatibility. Finally, a feasibility study was conducted in vivo in a rabbit model to investigate the ease of device deployment, device migration and extent of vessel occlusion. The in vivo results demonstrated that the prototypes were visible under fluoroscopy and complete vascular occlusion occurred within 2 min of deployment of the prototypes in vivo. In conclusion, the developed embolization plug enables controlled and temporary vascular embolization, and is ready for safety studies. PMID:27322962

  19. A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve

    Science.gov (United States)

    Fu, Ying; Zhang, Zhen; Sheehan, Jared; Avnir, Yuval; Ridenour, Callie; Sachnik, Thomas; Sun, Jiusong; Hossain, M. Jaber; Chen, Li-Mei; Zhu, Quan; Donis, Ruben O.; Marasco, Wayne A.

    2016-01-01

    Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of ‘universal' influenza vaccine strategies. PMID:27619409

  20. A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve.

    Science.gov (United States)

    Fu, Ying; Zhang, Zhen; Sheehan, Jared; Avnir, Yuval; Ridenour, Callie; Sachnik, Thomas; Sun, Jiusong; Hossain, M Jaber; Chen, Li-Mei; Zhu, Quan; Donis, Ruben O; Marasco, Wayne A

    2016-01-01

    Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of 'universal' influenza vaccine strategies. PMID:27619409

  1. Analysis of TANOS Memory Cells With Sealing Oxide Containing Blocking Dielectric

    OpenAIRE

    Beug, M. Florian; Melde, Thomas; Czernohorsky, Malte; Hoffmann, Raik; Paul, Jan; Knöfler, Roman; Tilke, Armin T.

    2010-01-01

    In this paper, we investigate the specific impact of an additional silicon oxide layer (sealing oxide) on top of the charge-trap nitride on the electrical performance of small dimension and large TANOS charge-trapping (CT) memory cells. We observe a significant improvement in charge retention on both our target 48-nm NAND TANOS cells and on large 5 µm long and wide memory cells. However, erase performance is partially degraded by this additional silicon dioxide top-dielectric layer. The prese...

  2. Seismic Response Control of Offshore Platform Structures with Shape Memory Alloy Dampers

    Institute of Scientific and Technical Information of China (English)

    LI Hong-nan; HE Xiao-yu; HUO Lin-sheng

    2005-01-01

    In this study, the seismic response control of offshore platform structures with Shape Memory Alloy (SMA) dampers is investigated. A new SMA damper and its restoring force model are introduced for the calculation of seismic response reduction. Based on an actual platform structure and its mechanical model, the parameters which may affect the rate of shock absorption are analyzed, such as the number, position and characteristics of the SMA dampers andthe condition of the site where the platform is located. The results show that the SMA damper is an effective control device for offshore platforms and satisfactory control can be achieved by proper selection of the parameters.

  3. Controlled surface chemistries and quantitative cell response

    Science.gov (United States)

    Plant, Anne L.

    2002-03-01

    Living cells experience a large number of signaling cues from their extracellular matrix. As a result of these inputs, a variety of intracellular signaling pathways are apparently initiated simultaneously. The vast array of alternative responses that result from the integration of these inputs suggests that it may be reasonable to look for cellular response not as an 'on' or 'off' condition but as a distribution of responses. A difficult challenge is to determine whether variations in responses from individual cells arise from the complexity of intracellular signals or are due to variations in the cell culture environment. By controlling surface chemistry so that every cell 'sees' the same chemical and physical environment, we can begin to assess how the distribution of cell response is affected strictly by changes in the chemistry of the cell culture surface. Using the gene for green fluorescent protein linked to the gene for the promoter of the extracellular matrix protein, tenascin, we can easily probe the end product in a signaling pathway that is purported to be linked to surface protein chemistry and to cell shape. Cell response to well-controlled, well-characterized, and highly reproducible surfaces prepared using soft lithography techniques are compared with more conventional ways of preparing extracellular matrix proteins for cell culture. Using fluorescence microscopy and image analysis of populations of cells on these surfaces, we probe quantitatively the relationship between surface chemistry, cell shape and variations in gene expression endpoint.

  4. Echoic memory: investigation of its temporal resolution by auditory offset cortical responses.

    Directory of Open Access Journals (Sweden)

    Makoto Nishihara

    Full Text Available Previous studies showed that the amplitude and latency of the auditory offset cortical response depended on the history of the sound, which implicated the involvement of echoic memory in shaping a response. When a brief sound was repeated, the latency of the offset response depended precisely on the frequency of the repeat, indicating that the brain recognized the timing of the offset by using information on the repeat frequency stored in memory. In the present study, we investigated the temporal resolution of sensory storage by measuring auditory offset responses with magnetoencephalography (MEG. The offset of a train of clicks for 1 s elicited a clear magnetic response at approximately 60 ms (Off-P50m. The latency of Off-P50m depended on the inter-stimulus interval (ISI of the click train, which was the longest at 40 ms (25 Hz and became shorter with shorter ISIs (2.5∼20 ms. The correlation coefficient r2 for the peak latency and ISI was as high as 0.99, which suggested that sensory storage for the stimulation frequency accurately determined the Off-P50m latency. Statistical analysis revealed that the latency of all pairs, except for that between 200 and 400 Hz, was significantly different, indicating the very high temporal resolution of sensory storage at approximately 5 ms.

  5. The role of CD4 T cell memory in generating protective immunity to novel and potentially pandemic strains of influenza

    Directory of Open Access Journals (Sweden)

    Anthony eDiPiazza

    2016-01-01

    Full Text Available Recent events have made it clear that potentially pandemic strains of influenza regularly pose a threat to human populations. Therefore, it is essential that we develop better strategies to enhance vaccine design and evaluation, to predict those that will be poor responders to vaccination and to identify those that are at particular risk of disease-associated complications following infection. Simplified animal models have revealed the discrete functions that CD4 T cells play in the developing immune response and to influenza immunity. However, humans have a complex immunological history with influenza through periodic infection and vaccination with seasonal variants, leading to the establishment of heterogeneous memory populations of CD4 T cells that participate in subsequent responses. The continual evolution of the influenza-specific CD4 T cell repertoire involves both specificity and function and overlays other restrictions on CD4 T cell activity derived from viral antigen handling and MHC class II:peptide epitope display. Together, these complexities in the influenza-specific CD4 T cell repertoire constitute a formidable obstacle to predicting protective immune response to potentially pandemic strains of influenza and in devising optimal vaccine strategies to potentiate these responses. We suggest that more precise efforts to identify and enumerate both the positive and negative contributors within the CD4 T cell compartment will aid significantly in achievement of these goals.

  6. Opposite effects of interleukin-4 on memory T helper cell development depend on interleukin-2.

    Science.gov (United States)

    Bemer, V; Motta, I; Perret, R; Truffa-Bachi, P

    1996-01-01

    We previously reported that cyclosporin A (CSA) promotes the generation of T helper memory cells during antigenic priming of murine spleen cells in vitro. More recently, we have demonstrated that interleukin-2 (IL2) has a downmodulating effect on T helper memory cell generation. The present data address the role of the other T cell growth factor, IL4, upon induction of these cells. The data presented here show that IL4 can interfere with this process: addition of rIL4 to immunosuppressed priming cultures leads to a considerable decrease in the helper activity of the recovered cells. However, in standard cultures, in which IL2 is normally produced, no effect of IL4 on T helper memory cell generation was found. Addition of IL4 has important consequences for cytokines produced upon antigenic restimulation. In standard cultures, IL4 primes for cells expressing high levels of IL2 and IL4 mRNA. Strikingly, in immunosuppressed priming cultures, IL4 counterbalances the CSA-induced blockade of the IFN gamma gene. Taken together, our results suggest that the unique role of IL4 is to drive T helper memory precursors into an IL4 production differentiation pathway. However, IL4 has a downmodulating effect on memory T helper cell induction when IL2 is not produced. These results confirm that synergy between IL2 and IL4 is mandatory for the directive role of IL4 upon IL4-producing cells. Furthermore, the finding that IL4 promotes the induction of IFN gamma in a CSA-resistant pathway represents a new tool for analysis of regulation of the IFN gamma gene.

  7. Attribution in the presence of a long-memory climate response

    Science.gov (United States)

    Rypdal, K.

    2015-11-01

    Multiple, linear regression is employed to attribute variability in the global surface temperature to various forcing components and prominent internal climatic modes. The purpose of the study is to asses how sensitive attribution is to long-range memory (LRM) in the model for the temperature response. The model response to a given forcing component is its fingerprint and is different for a zero response time (ZRT) model and one with an LRM response. The fingerprints are used as predictors in the regression scheme to express the response as a linear combination of footprints. For the instrumental period 1880-2010 CE (Common Era) the LRM response model explains 89 % of the total variance and is also favoured by information-theoretic model selection criteria. The anthropogenic footprint is relatively insensitive to LRM scaling in the response and explains almost all global warming after 1970 CE. The solar footprint is weakly enhanced by the LRM response, while the volcanic footprint is reduced by a factor of 2. The natural climate variability on multidecadal timescales has no systematic trend and is dominated by the footprint of the Atlantic Multidecadal Oscillation. The 2000-2010 CE hiatus is explained as a natural variation. A corresponding analysis for the last millennium is performed, using a Northern Hemisphere temperature reconstruction. The Little Ice Age (LIA) is explained as mainly due to volcanic cooling or as a long-memory response to a strong radiative disequilibrium during the Medieval Warm Anomaly, and it is not attributed to the low solar activity during the Maunder Minimum.

  8. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy

    Directory of Open Access Journals (Sweden)

    Vita Golubovskaya

    2016-03-01

    Full Text Available This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.; intracellular markers (FOXP3; epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic; and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.

  9. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy.

    Science.gov (United States)

    Golubovskaya, Vita; Wu, Lijun

    2016-01-01

    This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy--a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4⁺ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8⁺ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4⁺ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.

  10. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy

    Science.gov (United States)

    Golubovskaya, Vita; Wu, Lijun

    2016-01-01

    This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors. PMID:26999211

  11. Invertebrate learning and memory: Fifty years of olfactory conditioning of the proboscis extension response in honeybees.

    Science.gov (United States)

    Giurfa, Martin; Sandoz, Jean-Christophe

    2012-02-01

    The honeybee Apis mellifera has emerged as a robust and influential model for the study of classical conditioning, thanks to the existence of a powerful Pavlovian conditioning protocol, the olfactory conditioning of the proboscis extension response (PER). In 2011, the olfactory PER conditioning protocol celebrates 50 years since it was first introduced by Kimihisa Takeda in 1961. Here, we review its origins, developments, and perspectives in order to define future research avenues and necessary methodological and conceptual evolutions. We show that olfactory PER conditioning has become a versatile tool for the study of questions in extremely diverse fields in addition to the study of learning and memory and that it has allowed behavioral characterizations, not only of honeybees, but also of other insect species, for which the protocol was adapted. We celebrate, therefore, Takeda's original work and prompt colleagues to conceive and establish further robust behavioral tools for an accurate characterization of insect learning and memory at multiple levels of analysis. PMID:22251890

  12. Investigation of the Thermomechanical Response of Shape Memory Alloy Hybrid Composite Beams

    Science.gov (United States)

    Davis, Brian A.

    2005-01-01

    Previous work at NASA Langley Research Center (LaRC) involved fabrication and testing of composite beams with embedded, pre-strained shape memory alloy (SMA) ribbons. That study also provided comparison of experimental results with numerical predictions from a research code making use of a new thermoelastic model for shape memory alloy hybrid composite (SMAHC) structures. The previous work showed qualitative validation of the numerical model. However, deficiencies in the experimental-numerical correlation were noted and hypotheses for the discrepancies were given for further investigation. The goal of this work is to refine the experimental measurement and numerical modeling approaches in order to better understand the discrepancies, improve the correlation between prediction and measurement, and provide rigorous quantitative validation of the numerical model. Thermal buckling, post-buckling, and random responses to thermal and inertial (base acceleration) loads are studied. Excellent agreement is achieved between the predicted and measured results, thereby quantitatively validating the numerical tool.

  13. Switching Characteristics of Phase Change Memory Cell Integrated with Metal-Oxide Semiconductor Field Effect Transistor

    Institute of Scientific and Technical Information of China (English)

    XU Cheng; CHEN Bomy; LIU Bo; CHEN Yi-Feng; LIANG Shuang; SONG Zhi-Tang; FENG Song-Lin; WAN Xu-Dong; YANG Zuo-Ya; XIE Joseph

    2008-01-01

    A Ge2Sb2Te5 based phase change memory device cell integrated with metal-oxide semiconductor field effect transistor (MOSFET) is fabricated using standard 0.18 μm complementary metal-oxide semiconductor process technology.It shows steady switching characteristics in the dc current-voltage measurement.The phase changing phenomenon from crystalline state to amorphous state with a voltage pulse altitude of 2.0 V and pulse width of 50 ns is also obtained.These results show the feasibility of integrating phase change memory cell with MOSFET.

  14. Interleukin-27 inhibits vaccine-enhanced pulmonary disease following respiratory syncytial virus infection by regulating cellular memory responses.

    Science.gov (United States)

    Zeng, Ruihong; Zhang, Huixian; Hai, Yan; Cui, Yuxiu; Wei, Lin; Li, Na; Liu, Jianxun; Li, Caixia; Liu, Ying

    2012-04-01

    Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract disease in young children. In the 1960s, infants vaccinated with formalin-inactivated RSV developed a more severe disease characterized by excessive inflammatory immunopathology in lungs upon natural RSV infection. The fear of causing the vaccine-enhanced disease (VED) is an important obstacle for development of safe and effective RSV vaccines. The recombinant vaccine candidate G1F/M2 immunization also led to VED. It has been proved that cellular memory induced by RSV vaccines contributed to VED. Interleukin-27 (IL-27) and IL-23 regulate Th1, Th17, and/or Th2 cellular immune responses. In this study, mice coimmunized with pcDNA3-IL-27 and G1F/M2 were fully protected and, importantly, did not develop vaccine-enhanced inflammatory responses and immunopathology in lungs after RSV challenge, which was correlated with moderate Th1-, suppressed Th2-, and Th17-like memory responses activated by RSV. In contrast, G1F/M2- or pcDNA3-IL-23+G1F/M2-immunized mice, in which robust Th2- and Th17-like memory responses were induced, developed enhanced pulmonary inflammation and severe immunopathology. Mice coimmunized with G1F/M2 and the two cytokine plasmids exhibited mild inflammatory responses as well as remarkable Th1-, suppressed Th2-, and Th17-like memory responses. These results suggested that Th1-, Th2-, and Th17-like memory responses and, in particular, excessive Th2- and Th17-like memory responses were closely associated with VED; IL-27 may inhibit VED following respiratory syncytial virus infection by regulating cellular memory responses.

  15. Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance.

    Science.gov (United States)

    Murata, Kenji; Tsukahara, Tomohide; Emori, Makoto; Shibayama, Yuji; Mizushima, Emi; Matsumiya, Hiroshi; Yamashita, Keiji; Kaya, Mitsunori; Hirohashi, Yoshihiko; Kanaseki, Takayuki; Kubo, Terufumi; Himi, Tetsuo; Ichimiya, Shingo; Yamashita, Toshihiko; Sato, Noriyuki; Torigoe, Toshihiko

    2016-06-01

    High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long-living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, "young memory" T (TYM) cells. TYM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8(+)CD45RA(+)CD62L(+) T cells. TYM proliferate upon TCR stimulation, with differentiation capacity into TCM and TEM and drug resistance. Moreover, TYM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of TYM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation. PMID:27471640

  16. Deconvoluting post-transplant immunity: cell subset-specific mapping reveals pathways for activation and expansion of memory T, monocytes and B cells.

    Directory of Open Access Journals (Sweden)

    Yevgeniy A Grigoryev

    Full Text Available A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO(+CD62L(- effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant.

  17. Transplanted Bone Marrow Mesenchymal Stem Cells Improve Memory in Rat Models of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Parvin Babaei

    2012-01-01

    Full Text Available The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. In the first experiments aged animals (30 months were tested in Morris water maze (MWM and divided into two groups: impaired memory and unimpaired memory. Impaired groups were divided into two groups and cannulated bilaterally at the CA1 of the hippocampus for delivery of mesenchymal stem cells (500×103/ and PBS (phosphate buffer saline. In the second experiment, Ibotenic acid (Ibo was injected bilaterally into the nucleus basalis magnocellularis (NBM of young rats (3 months and animals were tested in MWM. Then, animals with memory impairment received the following treatments: MSCs (500×103/ and PBS. Two months after the treatments, cognitive recovery was assessed by MWM in relearning paradigm in both experiments. Results showed that MSCs treatment significantly increased learning ability and memory in both age- and Ibo-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and NBM lesions.

  18. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus

    Directory of Open Access Journals (Sweden)

    Apiwat Sirichoat

    2015-10-01

    Full Text Available Asiatic acid is a pentacyclic triterpene from Centella asiatica. Previous studies have reported that asiatic acid exhibits antioxidant and neuroprotective activities in cell culture. It also prevents memory deficits in animal models. The objective of this study was to investigate the relationship between spatial working memory and changes in cell proliferation within the hippocampus after administration of asiatic acid to male Spraque-Dawley rats. Control rats received vehicle (propylene glycol while treated rats received asiatic acid (30 mg/kg orally for 14 or 28 days. Spatial memory was determined using the novel object location (NOL test. In animals administered asiatic acid for both 14 and 28 days, the number of Ki-67 positive cells in the subgranular zone of the dentate gyrus was significantly higher than in control animals. This was associated with a significant increase in their ability to discriminate between novel and familiar object locations in a novel object discrimination task, a hippocampus-dependent spatial memory test. Administration of asiatic acid also significantly increased doublecortin (DCX and Notch1 protein levels in the hippocampus. These findings demonstrate that asiatic acid treatment may be a potent cognitive enhancer which improves hippocampal-dependent spatial memory, likely by increasing hippocampal neurogenesis.

  19. Improvement in the Shape Memory Response of Ti50.5Ni24.5Pd25 High-Temperature Shape Memory Alloy with Scandium Microalloying

    Science.gov (United States)

    Atli, K. C.; Karaman, I; Noebe, R. D.; Garg, A.; Chumlyakov, Y. I.; Kireeva, I. V.

    2010-01-01

    A Ti(50.5)Ni(24.5)Pd25 high-temperature shape memory alloy (HTSMA) is microalloyed with 0.5 at. pct scandium (Sc) to enhance its shape-memory characteristics, in particular, dimensional stability under repeated thermomechanical cycles. For both Ti(50.5)Ni(24.5)Pd25 and the Sc-alloyed material, differential scanning calorimetry is conducted for multiple cycles to characterize cyclic stability of the transformation temperatures. The microstructure is evaluated using electron microscopy, X-ray diffractometry, and wavelength dispersive spectroscopy. Isobaric thermal cycling experiments are used to determine transformation temperatures, dimensional stability, and work output as a function of stress. The Sc-doped alloy displays more stable shape memory response with smaller irrecoverable strain and narrower thermal hysteresis than the baseline ternary alloy. This improvement in performance is attributed to the solid solution hardening effect of Sc.

  20. The Tower of Babel of CD8+ T-cell memory: known facts, deserted roads, muddy waters, and possible dead ends.

    Science.gov (United States)

    Rocha, Benedita; Tanchot, Corinne

    2006-06-01

    Adequate antigen stimulation can lead to permanent modifications of primed cells and to the generation of memory T cells that have astonishingly improved capacities to deal with antigen. The overall properties of memory T cells (increased survival, precocious and increased division capacities, and improved effector functions) can be used to identify this unique cell type. However, each immune response may lead to the generation of multiple primed types that do not necessarily possess all these characteristics. It is not known whether these different cell types are just side products of the immune reaction or whether they are involved in disease control. Control of different infections may involve different challenges and lead to the generation of different types of immune reactions. Our major challenge is to unravel this complexity, but we must overcome our handicapped experimental tests and our imperfect a priori definitions. PMID:16824127

  1. Defensive Responses to Early Memories with Peers: a Possible Pathway to Disordered Eating.

    Science.gov (United States)

    Ferreira, Cláudia; Marta-Simões, Joana; Trindade, Inês A

    2016-01-01

    Childhood and early adolescence experiences, specifically those that provide an adulthood enriched with warm and safe memories, are consistently stated in literature as powerful emotional regulators. In contrast, individuals who scarcely recall positive experiences may begin to believe that others see the self as inferior, inadequate and unattractive. In order to cope with a perceived loss of social desirability and achieve other's acceptance, individuals may become submissive, and women, particularly, may resort to the presentation of a perfect body image. Both mechanisms are defensive responses suggested to be associated with mental health difficulties, particularly disordered eating behaviors. The present study aimed at exploring the association between early memories of warmth and safeness with peers and eating psychopathology. Also, a path analysis was conducted to investigate the mediator role of submissiveness and perfectionistic self-presentation focused on body image on this association, in a sample of 342 female students. Results revealed that the absence of early positive memories with peers holds a significant effect over eating psychopathology's severity, and also that this effect is mediated through submissiveness and body image-related perfectionistic self-presentation. This model accounted for 13%, 19% and 51% of submissiveness, perfectionistic self-presentation of body image and eating psychopathology's variances, respectively, and showed excellent model fit. PMID:27425603

  2. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects.

    Science.gov (United States)

    Sylwester, Andrew W; Mitchell, Bridget L; Edgar, John B; Taormina, Cara; Pelte, Christian; Ruchti, Franziska; Sleath, Paul R; Grabstein, Kenneth H; Hosken, Nancy A; Kern, Florian; Nelson, Jay A; Picker, Louis J

    2005-09-01

    Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4(+) and/or CD8(+) T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average approximately 10% of both the CD4(+) and CD8(+) memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8(+) T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans. PMID:16147978

  3. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis.

    Science.gov (United States)

    Cheuk, Stanley; Wikén, Maria; Blomqvist, Lennart; Nylén, Susanne; Talme, Toomas; Ståhle, Mona; Eidsmo, Liv

    2014-04-01

    Psoriasis is a common and chronic inflammatory skin disease in which T cells play a key role. Effective treatment heals the skin without scarring, but typically psoriasis recurs in previously affected areas. A pathogenic memory within the skin has been proposed, but the nature of such site-specific disease memory is unknown. Tissue-resident memory T (TRM) cells have been ascribed a role in immunity after resolved viral skin infections. Because of their localization in the epidermal compartment of the skin, TRM may contribute to tissue pathology during psoriasis. In this study, we investigated whether resolved psoriasis lesions contain TRM cells with the ability to maintain and potentially drive recurrent disease. Three common and effective therapies, narrowband-UVB treatment and long-term biologic treatment systemically inhibiting TNF-α or IL-12/23 signaling were studied. Epidermal T cells were highly activated in psoriasis and a high proportion of CD8 T cells expressed TRM markers. In resolved psoriasis, a population of cutaneous lymphocyte-associated Ag, CCR6, CD103, and IL-23R expressing epidermal CD8 T cells was highly enriched. Epidermal CD8 T cells expressing the TRM marker CD103 responded to ex vivo stimulation with IL-17A production and epidermal CD4 T cells responded with IL-22 production after as long as 6 y of TNF-α inhibition. Our data suggest that epidermal TRM cells are retained in resolved psoriasis and that these cells are capable of producing cytokines with a critical role in psoriasis pathogenesis. We provide a potential mechanism for a site-specific T cell-driven disease memory in psoriasis. PMID:24610014

  4. Thermally responsive polymer systems for self-healing, reversible adhesion and shape memory applications

    Science.gov (United States)

    Luo, Xiaofan

    Responsive polymers are "smart" materials that are capable of performing prescribed, dynamic functions under an applied stimulus. In this dissertation, we explore several novel design strategies to develop thermally responsive polymers and polymer composites for self-healing, reversible adhesion and shape memory applications. In the first case described in Chapters 2 and 3, a thermally triggered self-healing material was prepared by blending a high-temperature epoxy resin with a thermoplastic polymer, poly(epsilon-caprolactone) (PCL). The initially miscible system undergoes polymerization induced phase separation (PIPS) during the curing of epoxy and yields a variety of compositionally dependent morphologies. At a particular PCL loading, the cured blend displays a "bricks-and-mortar" morphology in which epoxy exists as interconnected spheres ("bricks") within a continuous PCL matrix ("mortar"). A heat induced "bleeding" phenomenon was observed in the form of spontaneous wetting of all free surfaces by the molten PCL, and is attributed to the volumetric thermal expansion of PCL above its melting point in excess of epoxy brick expansion, which we term differential expansive bleeding (DEB). This DEB is capable of healing damage such as cracks. In controlled self-healing experiments, heating of a cracked specimen led to PCL bleeding from the bulk that yields a liquid layer bridging the crack gap. Upon cooling, a "scar" composed of PCL crystals was formed at the site of the crack, restoring a significant portion of mechanical strength. We further utilized DEB to enable strong and thermally-reversible adhesion of the material to itself and to metallic substrates, without any requirement for macroscopic softening or flow. After that, Chapters 4--6 present a novel composite strategy for the design and fabrication of shape memory polymer composites. The basic approach involves physically combining two or more functional components into an interpenetrating fiber

  5. Evaluation of EBV transformation of human memory B-cells isolated by FACS and MACS techniques.

    Science.gov (United States)

    Sadreddini, Sanam; Jadidi-Niaragh, Farhad; Younesi, Vahid; Pourlak, Tala; Afkham, Amir; Shokri, Fazel; Yousefi, Mehdi

    2016-07-01

    Several studies have been performed to develop effective neutralizing monoclonal antibodies. The Epstein-Barr virus (EBV) can efficiently immortalize B-cells to establish lymphoblastoid cell lines (LCL) and so it has been used extensively for transformation of B-cells to produce and secrete immunoglobulin. The present study addressed the effect of TLR7/8 agonist (R848), feeder cells layer and fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) cell separation methods on the transformation efficiency of antibody-producing memory B-cells. For these studies, the antigen used for analyses of antibody formation was the tetanus neurotoxin (TeNT) derived from Clostridium tetani. The results here showed that employing an HFFF.PI6 feeder cell layer, R848 agonist and FACS-mediated purification of memory B-cells led to increased transformation efficiency. Altogether, the effects of the R848 and the feeder cells provided an efficient method for EBV transformation of human B-cells. Moreover, there was an advantage in using FACS sorting of B-cells over the MACS method in the context of EBV transformation and immortalization of precursors of antigen-specific B-cells. PMID:27043044

  6. Multi-Bit Nano-Electromechanical Nonvolatile Memory Cells (Zigzag T Cells) for the Suppression of Bit-to-Bit Interference.

    Science.gov (United States)

    Choi, Woo Young; Han, Jae Hwan; Cha, Tae Min

    2016-05-01

    Multi-bit nano-electromechanical (NEM) nonvolatile memory cells such as T cells were proposed for higher memory density. However, they suffered from bit-to-bit interference (BI). In order to suppress BI without sacrificing cell size, this paper proposes zigzag T cell structures. The BI suppression of the proposed zigzag T cell is verified by finite-element modeling (FEM). Based on the FEM results, the design of zigzag T cells is optimized. PMID:27483893

  7. Defect of CD8+ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

    Institute of Scientific and Technical Information of China (English)

    Zhenmin Ye; Shulin Xu; Terence Moyana; Jicheng Yang; Jim Xiang

    2008-01-01

    IL-12 priming plays an important role in stimulation of CD8+ effector T cells and development of CD8+ memory T (Tm) cells. However, the functional alteration of CD8+ Tm cells developed in the absence of IL-12 priming is elusive.In this study, we investigated the capacity of secondary expansion of CD8+ Tm cells developed from transgenic OT I CD8+ T cells. The latter cells were in vitro and in vivo stimulated by ovalbumin (OVA)-puised dendritic cells [DCOVA and (IL-12-/-)DCOVA] derived from wild-type C57BL/6 and IL-12 gene knockout mice, respectively. We demonstrated that IL-12 priming is important not only in CD8+ T cell clonal expansion, but also in generation of CD8+ Tm cells with the capacity of secondary expansion upon antigen re-encounter. However, IL-12 signaling is not involved in CD8+ Tm cell survival and recall responses. Therefore, this study provides useful information for vaccine design and development.

  8. Dissecting the T Cell Response: Proliferation Assays vs. Cytokine Signatures by ELISPOT

    Directory of Open Access Journals (Sweden)

    Magdalena Tary-Lehmann

    2012-05-01

    Full Text Available Chronic allograft rejection is in part mediated by host T cells that recognize allogeneic antigens on transplanted tissue. One factor that determines the outcome of a T cell response is clonal size, while another is the effector quality. Studies of alloimmune predictors of transplant graft survival have most commonly focused on only one measure of the alloimmune response. Because differing qualities and frequencies of the allospecific T cell response may provide distinctly different information we analyzed the relationship between frequency of soluble antigen and allo-antigen specific memory IFN-g secreting CD4 and CD8 T cells, their ability to secrete IL-2, and their proliferative capacity, while accounting for cognate and bystander proliferation. The results show proliferative responses primarily reflect on IL-2 production by antigen-specific T cells, and that proliferating cells in such assays entail a considerable fraction of bystander cells. On the other hand, proliferation (and IL-2 production did not reflect on the frequency of IFN-γ producing memory cells, a finding particularly accentuated in the CD8 T cell compartment. These data provide rationale for considering both frequency and effector function of pre-transplant T cell reactivity when analyzing immune predictors of graft rejection.

  9. Ag-dependent (in silico) approach implies a deterministic kinetics for homeostatic memory cell turnover

    CERN Document Server

    de Castro, Alexandre; Herai, Roberto

    2011-01-01

    Verhulst-like mathematical modeling has been used to investigate several complex biological issues, such as immune memory equilibrium and cell-mediated immunity in mammals. The regulation mechanisms of both these processes are still not sufficiently understood. In a recent paper, Choo et al. [J. Immunol., v. 185, pp. 3436-44, 2010], used an Ag-independent approach to quantitatively analyze memory cell turnover from some empirical data, and concluded that immune homeostasis behaves stochastically, rather than deterministically. In the paper here presented, we use an in silico Ag-dependent approach to simulate the process of antigenic mutation and study its implications for memory dynamics. Our results have suggested a deterministic kinetics for homeostatic equilibrium, what contradicts the Choo et al. findings. Accordingly, our calculations are an indication that a more extensive empirical protocol for studying the homeostatic turnover should be considered.

  10. Quantitative Analysis of Memristance Defined Exponential Model for Multi-bits Titanium Dioxide Memristor Memory Cell

    Directory of Open Access Journals (Sweden)

    DAOUD, A. A. D.

    2016-05-01

    Full Text Available The ability to store multiple bits in a single memristor based memory cell is a key feature for high-capacity memory packages. Studying multi-bit memristor circuits requires high accuracy in modelling the memristance change. A memristor model based on a novel definition of memristance is proposed. A design of a single memristor memory cell using the proposed model for the platinum electrodes titanium dioxide memristor is illustrated. A specific voltage pulse is used with varying its parameters (amplitude or pulse width to store different number of states in a single memristor. New state variation parameters associated with the utilized model are provided and their effects on write and read processes of memristive multi-states are analysed. PSPICE simulations are also held, and they show a good agreement with the data obtained from the analysis.

  11. Measurement and Prediction of the Thermomechanical Response of Shape Memory Alloy Hybrid Composite Beams

    Science.gov (United States)

    Davis, Brian; Turner, Travis L.; Seelecke, Stefan

    2005-01-01

    Previous work at NASA Langley Research Center (LaRC) involved fabrication and testing of composite beams with embedded, pre-strained shape memory alloy (SMA) ribbons within the beam structures. That study also provided comparison of experimental results with numerical predictions from a research code making use of a new thermoelastic model for shape memory alloy hybrid composite (SMAHC) structures. The previous work showed qualitative validation of the numerical model. However, deficiencies in the experimental-numerical correlation were noted and hypotheses for the discrepancies were given for further investigation. The goal of this work is to refine the experimental measurement and numerical modeling approaches in order to better understand the discrepancies, improve the correlation between prediction and measurement, and provide rigorous quantitative validation of the numerical analysis/design tool. The experimental investigation is refined by a more thorough test procedure and incorporation of higher fidelity measurements such as infrared thermography and projection moire interferometry. The numerical results are produced by a recently commercialized version of the constitutive model as implemented in ABAQUS and are refined by incorporation of additional measured parameters such as geometric imperfection. Thermal buckling, post-buckling, and random responses to thermal and inertial (base acceleration) loads are studied. The results demonstrate the effectiveness of SMAHC structures in controlling static and dynamic responses by adaptive stiffening. Excellent agreement is achieved between the predicted and measured results of the static and dynamic thermomechanical response, thereby providing quantitative validation of the numerical tool.

  12. Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex molecules

    OpenAIRE

    Markiewicz, Mary A.; Girao, Cristina; Opferman, Joseph T.; Sun, Jiling; Hu, Qinghui; Agulnik, Alexander A.; Bishop, Colin E.; Thompson, Craig B.; Ashton-Rickardt, Philip G.

    1998-01-01

    How memory T cells are maintained in vivo is poorly understood. To address this problem, a male-specific peptide (H-Y) was identified and used to activate female anti-H-Y T cells in vitro. Anti-H-Y T cells survived in vivo for at least 70 days in the absence of antigen. This persistence was not because of the intrinsic ability of memory T cells to survive in vivo. Instead, the survival and function of adoptively transferred memory cells was found to require transporter of antigen protein 1-de...

  13. Responses of Cells to Flow in Vitro

    Directory of Open Access Journals (Sweden)

    Shigehiro Hashimoto

    2013-06-01

    Full Text Available The response of cells to a flow has been studied in vitro. The response of cells was examined in two types of flow channels: a circumnutating flow in a donut-shaped open channel in a culture dish, and a one-way flow in a parallelepiped rhombus flow channel. Variation was made on the material of the parallelepiped channel to study on adhesion of cells to the plates: glass and polydimethylsiloxane. Behavior of cells on the plate was observed under a flow of a medium with an inverted phase-contrast-microscope. The shear stress on the plate is calculated with an estimated parabolic distribution of the velocity between the parallel plates. The adhesion of cells was evaluated with the cumulated shear, which is a product of the shear stress and the exposure time. The experimental results show that cells are responsive to the flow, which governs orientation, exfoliation, and differentiation. The response depends on the kinds of cells: endothelial cells orient along the stream line, although myocytes orient perpendicular to the stream line. The adhesion depends on the combination between scaffold and cell: myocytes are more adhesive to glass than cartilage cells, and fibroblasts are more adhesive to oxygenated polydimethylsiloxane than glass.

  14. A novel antibody discovery platform identifies anti-influenza A broadly neutralizing antibodies from human memory B cells.

    Science.gov (United States)

    Xiao, Xiaodong; Chen, Yan; Varkey, Reena; Kallewaard, Nicole; Koksal, Adem C; Zhu, Qing; Wu, Herren; Chowdhury, Partha S; Dall'Acqua, William F

    2016-07-01

    Monoclonal antibody isolation directly from circulating human B cells is a powerful tool to delineate humoral responses to pathological conditions and discover antibody therapeutics. We have developed a platform aimed at improving the efficiencies of B cell selection and V gene recovery. Here, memory B cells are activated and amplified using Epstein-Barr virus infection, co-cultured with CHO-muCD40L cells, and then assessed by functional screenings. An in vitro transcription and translation (IVTT) approach was used to analyze variable (V) genes recovered from each B cell sample and identify the relevant heavy/light chain pair(s). We achieved efficient amplification and activation of memory B cells, and eliminated the need to: 1) seed B cells at clonal level (≤1 cell/well) or perform limited dilution cloning; 2) immortalize B cells; or 3) assemble V genes into an IgG expression vector to confirm the relevant heavy/light chain pairing. Cross-reactive antibodies targeting a conserved epitope on influenza A hemagglutinin were successfully isolated from a healthy donor. In-depth analysis of the isolated antibodies suggested their potential uses as anti-influenza A antibody therapeutics and uncovered a distinct affinity maturation pathway. Importantly, our results showed that cognate heavy/light chain pairings contributed to both the expression level and binding abilities of our newly isolated VH1-69 family, influenza A neutralizing antibodies, contrasting with previous observations that light chains do not significantly contribute to the function of this group of antibodies. Our results further suggest the potential use of the IVTT as a powerful antibody developability assessment tool. PMID:27049174

  15. Cutting Edge: Resident Memory CD8 T Cells Express High-Affinity TCRs.

    Science.gov (United States)

    Frost, Elizabeth L; Kersh, Anna E; Evavold, Brian D; Lukacher, Aron E

    2015-10-15

    Tissue-resident memory T (TRM) cells serve as vanguards of antimicrobial host defense in nonlymphoid tissues, particularly at barrier epithelia and in organs with nonrenewable cell types (e.g., brain). In this study, we asked whether an augmented ability to sense Ag complemented their role as early alarms of pathogen invasion. Using mouse polyomavirus, we show that brain-resident mouse polyomavirus-specific CD8 T cells, unlike memory cells in the spleen, progressively increase binding to MHC class I tetramers and CD8 coreceptor expression. Using the two-dimensional micropipette adhesion-frequency assay, we show that TRM cells in brain, as well as in kidney, express TCRs with up to 20-fold higher affinity than do splenic memory T cells, whereas effector cells express TCRs of similar high affinity in all organs. Together, these data demonstrate that TRM cells retain high TCR affinity, which endows them with the high Ag sensitivity needed for front-line defense against infectious agents. PMID:26371252

  16. Specific cytotoxic T-cell immune responses against autoantigens recognized by chronic lymphocytic leukaemia cells.

    Science.gov (United States)

    Zaleska, Joanna; Skorka, Katarzyna; Zajac, Malgorzata; Karczmarczyk, Agnieszka; Karp, Marta; Tomczak, Waldemar; Hus, Marek; Wlasiuk, Paulina; Giannopoulos, Krzysztof

    2016-08-01

    Mounting evidence suggests that autoreactivity and inflammatory processes are involved in the pathogenesis of chronic lymphocytic leukaemia (CLL). Cytoskeletal proteins, including non-muscle myosin heavy chain IIA (MYHIIA), vimentin (VIM) and cofilin-1 (CFL1), exposed on the surface of apoptotic cells have been identified as autoantigens that are recognized by the specific B-cell receptors of the CLL cells. In 212 CLL patients analysed with quantitative reverse transcriptase-polymerase chain reaction we found CFL1 overexpression and low expression of MYH9 in comparison with healthy volunteers. We detected specific cytotoxic immune responses for peptides derived from MYHIIA in 66·7%, VIM in 87·5% and CFL1 in 62·5% CLL patients in an Enzyme-Linked ImmunoSpot assay. Low frequencies of autoreactive peptide-specific T cells were detected against MYHIIA, VIM and CFL1 in CLL patients ex vivo; most of the detected cells had an effector-memory phenotype. Our findings support the existence of cytotoxic immune responses against three autoantigens that have been identified as targets of CLL clonotypic B-cell receptors. The presence of autoreactive CD8(+) T cells against MYHIIA, VIM and CFL1 in CLL patients indicates the involvement of antigen-specific autoreactive T cells in the pathogenesis of CLL.

  17. Determinants of public T cell responses

    Institute of Scientific and Technical Information of China (English)

    Hanjie Li; Congting Ye; Guoli Ji; Jiahuai Han

    2012-01-01

    Historically,sharing T cell receptors (TCRs) between individuals has been speculated to be impossible,considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual.However,public T cell response,in which multiple individuals share identical TCRs in responding to a same antigenic epitope,has been extensively observed in a variety of immune responses across many species.Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens,leading to favorable biological outcomes.However,the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens.It could be a great benefit for human health if public T cell responses can be manipulated.Therefore,the mechanistic insight of public TCR generation is important to know.Recently,high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires,which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals.Here,we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

  18. Association of lymph-node antigens with lower Gag-specific central-memory and higher Env-specific effector-memory CD8(+) T-cell frequencies in a macaque AIDS model.

    Science.gov (United States)

    Ishii, Hiroshi; Matsuoka, Saori; Nomura, Takushi; Nakamura, Midori; Shiino, Teiichiro; Sato, Yuko; Iwata-Yoshikawa, Naoko; Hasegawa, Hideki; Mizuta, Kazuta; Sakawaki, Hiromi; Miura, Tomoyuki; Koyanagi, Yoshio; Naruse, Taeko K; Kimura, Akinori; Matano, Tetsuro

    2016-01-01

    Virus-specific CD8(+) T cells exert strong suppressive pressure on human/simian immunodeficiency virus (HIV/SIV) replication. These responses have been intensively examined in peripheral blood mononuclear cells (PBMCs) but not fully analyzed in lymph nodes (LNs), where interaction between CD8(+) T cells and HIV/SIV-infected cells occurs. Here, we investigated target antigen specificity of CD8(+) T cells in LNs in a macaque AIDS model. Analysis of virus antigen-specific CD8(+) T-cell responses in the inguinal LNs obtained from twenty rhesus macaques in the chronic phase of SIV infection showed an inverse correlation between viral loads and frequencies of CD8(+) T cells with CD28(+) CD95(+) central memory phenotype targeting the N-terminal half of SIV core antigen (Gag-N). In contrast, analysis of LNs but not PBMCs revealed a positive correlation between viral loads and frequencies of CD8(+) T cells with CD28(-)CD95(+) effector memory phenotype targeting the N-terminal half of SIV envelope (Env-N), soluble antigen. Indeed, LNs with detectable SIV capsid p27 antigen in the germinal center exhibited significantly lower Gag-N-specific CD28(+) CD95(+) CD8(+) T-cell and higher Env-N-specific CD28(-)CD95(+) CD8(+) T-cell responses than those without detectable p27. These results imply that core and envelope antigen-specific CD8(+) T cells show different patterns of interactions with HIV/SIV-infected cells. PMID:27452272

  19. Allergen-Experienced Group 2 Innate Lymphoid Cells Acquire Memory-like Properties and Enhance Allergic Lung Inflammation.

    Science.gov (United States)

    Martinez-Gonzalez, Itziar; Mathä, Laura; Steer, Catherine A; Ghaedi, Maryam; Poon, Grace F T; Takei, Fumio

    2016-07-19

    Group 2 innate lymphoid cells (ILC2s) in the lung are stimulated by inhaled allergens. ILC2s do not directly recognize allergens but they are stimulated by cytokines including interleukin (IL)-33 released by damaged epithelium. In response to allergens, lung ILC2s produce T helper 2 cell type cytokines inducing T cell-independent allergic lung inflammation. Here we examined the fate of lung ILC2s upon allergen challenges. ILC2s proliferated and secreted cytokines upon initial stimulation with allergen or IL-33, and this phase was followed by a contraction phase as cytokine production ceased. Some ILC2s persisted long after the resolution of the inflammation as allergen-experienced ILC2s and responded to unrelated allergens more potently than naive ILC2s, mediating severe allergic inflammation. The allergen-experienced ILC2s exhibited a gene expression profile similar to that of memorycells. The memory-like properties of allergen-experienced ILC2s may explain why asthma patients are often sensitized to multiple allergens. PMID:27421705

  20. The effect of background music on episodic memory and autonomic responses: listening to emotionally touching music enhances facial memory capacity.

    Science.gov (United States)

    Proverbio, Alice Mado; Mado Proverbio, C A Alice; Lozano Nasi, Valentina; Alessandra Arcari, Laura; De Benedetto, Francesco; Guardamagna, Matteo; Gazzola, Martina; Zani, Alberto

    2015-10-15

    The aim of this study was to investigate how background auditory processing can affect other perceptual and cognitive processes as a function of stimulus content, style and emotional nature. Previous studies have offered contrasting evidence, and it has been recently shown that listening to music negatively affected concurrent mental processing in the elderly but not in young adults. To further investigate this matter, the effect of listening to music vs. listening to the sound of rain or silence was examined by administering an old/new face memory task (involving 448 unknown faces) to a group of 54 non-musician university students. Heart rate and diastolic and systolic blood pressure were measured during an explicit face study session that was followed by a memory test. The results indicated that more efficient and faster recall of faces occurred under conditions of silence or when participants were listening to emotionally touching music. Whereas auditory background (e.g., rain or joyful music) interfered with memory encoding, listening to emotionally touching music improved memory and significantly increased heart rate. It is hypothesized that touching music is able to modify the visual perception of faces by binding facial properties with auditory and emotionally charged information (music), which may therefore result in deeper memory encoding.

  1. The effect of background music on episodic memory and autonomic responses: listening to emotionally touching music enhances facial memory capacity.

    Science.gov (United States)

    Proverbio, Alice Mado; Mado Proverbio, C A Alice; Lozano Nasi, Valentina; Alessandra Arcari, Laura; De Benedetto, Francesco; Guardamagna, Matteo; Gazzola, Martina; Zani, Alberto

    2015-01-01

    The aim of this study was to investigate how background auditory processing can affect other perceptual and cognitive processes as a function of stimulus content, style and emotional nature. Previous studies have offered contrasting evidence, and it has been recently shown that listening to music negatively affected concurrent mental processing in the elderly but not in young adults. To further investigate this matter, the effect of listening to music vs. listening to the sound of rain or silence was examined by administering an old/new face memory task (involving 448 unknown faces) to a group of 54 non-musician university students. Heart rate and diastolic and systolic blood pressure were measured during an explicit face study session that was followed by a memory test. The results indicated that more efficient and faster recall of faces occurred under conditions of silence or when participants were listening to emotionally touching music. Whereas auditory background (e.g., rain or joyful music) interfered with memory encoding, listening to emotionally touching music improved memory and significantly increased heart rate. It is hypothesized that touching music is able to modify the visual perception of faces by binding facial properties with auditory and emotionally charged information (music), which may therefore result in deeper memory encoding. PMID:26469712

  2. Inhibition of interleukin-1β-mediated interleukin-1 receptor-associated kinase 4 phosphorylation by zinc leads to repression of memory T helper type 17 response in humans.

    Science.gov (United States)

    Lee, Hyunju; Kim, Bonah; Choi, Yeon Ho; Hwang, Yuri; Kim, Dong Hyun; Cho, Sunjung; Hong, Sung Jun; Lee, Won-Woo

    2015-12-01

    Zinc is an essential trace element that plays pivotal roles in multiple facets of the immune system. Besides its catalytic and structural roles, zinc also functions as an intracellular signalling molecule, and changes in zinc levels can cause both direct and indirect modulation of immune responses. Further, cytoplasmic levels of bioavailable zinc in immune cells are largely influenced by many extracellular stimuli. Here we provide evidence that zinc represses memory T helper type 17 responses in humans by inhibiting interleukin-1β (IL-1β)-mediated signal. In vitro zinc treatment of CD4(+) T cells in the presence of activated monocytes inhibited interferon-γ-producing cells and IL-17-producing cells, but not IL-4-producing cells. Of note, production of IL-17(+) cells from memory CD4(+) T cells, which is significantly up-regulated by lipopolysaccharide-stimulated monocytes, was preferentially repressed by zinc. Increased cytoplasmic zinc in T cells suppressed IL-1β signalling through repression of phosphorylation of IL-1 receptor-associated kinase 4 (IRAK4), so leading to an inhibitory effect on T helper type 17 responses facilitated by monocyte-derived IL-1β in humans. These findings suggest that extracellular zinc bioavailability may affect memory CD4(+) T-cell responses by modulating the zinc-mediated signalling pathway.

  3. Long-memory effects in linear-response models of Earth's temperature and implications for future global warming

    CERN Document Server

    Rypdal, Martin

    2013-01-01

    A linearized energy-balance model for global temperature is formulated, featuring a scale-free long-range memory (LRM) response and stochastic forcing representing the influence on the ocean heat reservoir from atmospheric weather systems. The model is parametrized by an effective response strength, the stochastic forcing strength, and the memory exponent. The instrumental global surface temperature record and the deterministic component of the forcing are used to estimate these parameters by means of the maximum-likelihood method. The residual obtained by subtracting the deterministic solution from the observed record is analyzed as a noise process and shown to be consistent with a long-memory time-series model and inconsistent with a short-memory model. By decomposing the forcing record in contributions from solar, volcanic, and anthropogenic activity one can estimate the contribution of each to 20'th century global warming. The LRM model is applied with a reconstruction of the forcing for the last millenni...

  4. Resistive switching behavior of reduced graphene oxide memory cells for low power nonvolatile device application

    Science.gov (United States)

    Pradhan, Sangram K.; Xiao, Bo; Mishra, Saswat; Killam, Alex; Pradhan, Aswini K.

    2016-05-01

    Graphene Oxide (GO) based low cost flexible electronics and memory cell have recently attracted more attention for the fabrication of emerging electronic devices. As a suitable candidate for resistive random access memory technology, reduced graphene oxide (RGO) can be widely used for non-volatile switching memory applications because of its large surface area, excellent scalability, retention, and endurance properties. We demonstrated that the fabricated metal/RGO/metal memory device exhibited excellent switching characteristics, with on/off ratio of two orders of magnitude and operated threshold switching voltage of less than 1 V. The studies on different cell diameter, thickness, scan voltages and period of time corroborate the reliability of the device as resistive random access memory. The microscopic origin of switching operation is governed by the establishment of conducting filaments due to the interface amorphous layer rupturing and the movement of oxygen in the GO layer. This interesting experimental finding indicates that device made up of thermally reduced GO shows more reliability for its use in next generation electronics devices.

  5. Ultra Low Voltage Class AB Switched Current Memory Cells Based on Floating Gate Transistors

    DEFF Research Database (Denmark)

    Mucha, Igor

    1999-01-01

    A proposal for a class AB switched current memory cell, suitable for ultra-low-voltage applications is presented. The proposal employs transistors with floating gates, allowing to build analog building blocks for ultralow supply voltage operation also in CMOS processes with high threshold voltages...

  6. Nanostructure-property relations for phase-change random access memory (PCRAM) line cells

    NARCIS (Netherlands)

    Kooi, B. J.; Oosthoek, J. L. M.; Verheijen, M. A.; Kaiser, M.; Jedema, F. J.; Gravesteijn, D. J.

    2012-01-01

    Phase-change random access memory (PCRAM) cells have been studied extensively using electrical characterization and rather limited by detailed structure characterization. The combination of these two characterization techniques has hardly been exploited and it is the focus of the present work. Parti

  7. Expression of the Memory Marker CD45RO on Helper T Cells in Macaques

    NARCIS (Netherlands)

    Valentine, Michael; Song, Kejing; Maresh, Grace A.; Mack, Heather; Huaman, Maria Cecilia; Polacino, Patricia; Ho, On; Cristillo, Anthony; Chung, Hye Kyung; Hu, Shiu-Lok; Pincus, Seth H.

    2013-01-01

    Background: In humans it has been reported that a major site of the latent reservoir of HIV is within CD4+ T cells expressing the memory marker CD45RO, defined by the mAb UCHL1. There are conflicting reports regarding the expression of this antigen in macaques, the most relevant animal species for s

  8. T-cell response in human leishmaniasis

    DEFF Research Database (Denmark)

    Kharazmi, A; Kemp, K; Ismail, A;

    1999-01-01

    In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered...... from cutaneous leishmaniasis (CL) responded by IFN-gamma production following stimulation with Leishmania antigens whereas cells from patients recovered from visceral leishmaniasis (VL) showed a mixed pattern of IFN-gamma and IL-4 responses. The cells producing these cytokines were predominantly CD4......+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans....

  9. Transforming growth factor-beta inhibits human antigen-specific CD4(+) T cell proliferation without modulating the cytokine response

    NARCIS (Netherlands)

    Tiemessen, MM; Kunzmann, S; Schmidt-Weber, CB; Garssen, J; Bruijnzeel-Koomen, CAFM; Knol, EF; Van Hoffen, E

    2003-01-01

    Transforming growth factor (TGF)-beta has been demonstrated to play a key role in the regulation of the immune response, mainly by its suppressive function towards cells of the immune system. In humans, the effect of TGF-beta on antigen-specific established memory T cells has not been investigated y

  10. Distinct roles of Cdc42 in thymopoiesis and effector and memory T cell differentiation.

    Directory of Open Access Journals (Sweden)

    Fukun Guo

    Full Text Available Cdc42 of the Rho GTPase family has been implicated in cell actin organization, proliferation, survival, and migration but its physiological role is likely cell-type specific. By a T cell-specific deletion of Cdc42 in mouse, we have recently shown that Cdc42 maintains naïve T cell homeostasis through promoting cell survival and suppressing T cell activation. Here we have further investigated the involvement of Cdc42 in multiple stages of T cell differentiation. We found that in Cdc42(-/- thymus, positive selection of CD4(+CD8(+ double-positive thymocytes was defective, CD4(+ and CD8(+ single-positive thymocytes were impaired in migration and showed an increase in cell apoptosis triggered by anti-CD3/-CD28 antibodies, and thymocytes were hyporesponsive to anti-CD3/-CD28-induced cell proliferation and hyperresponsive to anti-CD3/-CD28-stimulated MAP kinase activation. At the periphery, Cdc42-deficient naive T cells displayed an impaired actin polymerization and TCR clustering during the formation of mature immunological synapse, and showed an enhanced differentiation to Th1 and CD8(+ effector and memory cells in vitro and in vivo. Finally, Cdc42(-/- mice exhibited exacerbated liver damage in an induced autoimmune disease model. Collectively, these data establish that Cdc42 is critically involved in thymopoiesis and plays a restrictive role in effector and memory T cell differentiation and autoimmunity.

  11. Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers.

    Science.gov (United States)

    Budeus, Bettina; Schweigle de Reynoso, Stefanie; Przekopowitz, Martina; Hoffmann, Daniel; Seifert, Marc; Küppers, Ralf

    2015-09-22

    Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM(+) and IgG(+) memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM(+)(IgD(+)) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells--including IgM(+)IgD(+)CD27(+) B cells--are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM(+)(IgD(+)) and class-switched memory B cells. PMID:26324941

  12. Memory lineage relationships in HTLV-1-specific CD8+ cytotoxic T cells

    Science.gov (United States)

    Johnson-Nauroth, Julie M.; Graber, Jerome; Yao, Karen; Jacobson, Steve; Calabresi, Peter A.

    2016-01-01

    Cytotoxic memory T cells play a critical role in combating viral infections; however, in some diseases they may contribute to tissue damage. In HAM/TSP, HTLV-1 Tax 11–19+ cells proliferate spontaneously in vitro and can be tracked using the Tax 11–19 MHC Class I tetramer. Immediately ex vivo, these cells were a mix of CD45RA−/CCR7− TEM and CD45RA+/CCR7− TDiff memory CTL. The subsequent proliferating Tax 11–19 tetramer+ population expressed low levels of IL-7Rα, failed to respond to IL-7 and IL-15, and did not develop a TCM phenotype. Thus, chronic exposure to viral antigen may result in a sustained pool of TEM cells that home to the CNS and mediate the spinal cord pathology seen in this disease. PMID:16740321

  13. DNA damage response in adult stem cells.

    Science.gov (United States)

    Insinga, Alessandra; Cicalese, Angelo; Pelicci, Pier Giuseppe

    2014-04-01

    This review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span of stem cells suggests that they may respond differently to DNA damage than their downstream progeny and, indeed, studies have begun to elucidate the unique stem cell response mechanisms to DNA damage. Because the DNA damage responses in stem cells and progenitor cells are distinctly different, stem and progenitor cells should be considered as two different entities from this point of view. Hematopoietic and mammary stem cells display a unique DNA-damage response, which involves active inhibition of apoptosis, entry into the cell-cycle, symmetric division, partial DNA repair and maintenance of self-renewal. Each of these biological events depends on the up-regulation of the cell-cycle inhibitor p21. Moreover, inhibition of apoptosis and symmetric stem cell division are the consequence of the down-regulation of the tumor suppressor p53, as a direct result of p21 up-regulation. A deeper understanding of these processes is required before these findings can be translated into human anti-aging and anti-cancer therapies. One needs to clarify and dissect the pathways that control p21 regulation in normal and cancer stem cells and define (a) how p21 blocks p53 functions in stem cells and (b) how p21 promotes DNA repair in stem cells. Is this effect dependent on p21s ability to inhibit p53? Such molecular knowledge may pave the way to methods for maintaining short-term tissue reconstitution while retaining long-term cellular and genomic integrity.

  14. From sensorimotor learning to memory cells in prefrontal and temporal association cortex: a neurocomputational study of disembodiment.

    Science.gov (United States)

    Pulvermüller, Friedemann; Garagnani, Max

    2014-08-01

    Memory cells, the ultimate neurobiological substrates of working memory, remain active for several seconds and are most commonly found in prefrontal cortex and higher multisensory areas. However, if correlated activity in "embodied" sensorimotor systems underlies the formation of memory traces, why should memory cells emerge in areas distant from their antecedent activations in sensorimotor areas, thus leading to "disembodiment" (movement away from sensorimotor systems) of memory mechanisms? We modelled the formation of memory circuits in six-area neurocomputational architectures, implementing motor and sensory primary, secondary and higher association areas in frontotemporal cortices along with known between-area neuroanatomical connections. Sensorimotor learning driven by Hebbian neuroplasticity led to formation of cell assemblies distributed across the different areas of the network. These action-perception circuits (APCs) ignited fully when stimulated, thus providing a neural basis for long-term memory (LTM) of sensorimotor information linked by learning. Subsequent to ignition, activity vanished rapidly from APC neurons in sensorimotor areas but persisted in those in multimodal prefrontal and temporal areas. Such persistent activity provides a mechanism for working memory for actions, perceptions and symbols, including short-term phonological and semantic storage. Cell assembly ignition and "disembodied" working memory retreat of activity to multimodal areas are documented in the neurocomputational models' activity dynamics, at the level of single cells, circuits, and cortical areas. Memory disembodiment is explained neuromechanistically by APC formation and structural neuroanatomical features of the model networks, especially the central role of multimodal prefrontal and temporal cortices in bridging between sensory and motor areas. These simulations answer the "where" question of cortical working memory in terms of distributed APCs and their inner structure

  15. Photo-Responsive Shape-Memory and Shape-Changing Liquid-Crystal Polymer Networks

    Directory of Open Access Journals (Sweden)

    Danish Iqbal

    2013-01-01

    Full Text Available “Surrounding matters” is a phrase that has become more significant in recent times when discussing polymeric materials. Although regular polymers do respond to external stimuli like softening of material at higher temperatures, that response is gradual and linear in nature. Smart polymers (SPs or stimuli-responsive polymers (SRPs behave differently to those external stimuli, as their behavior is more rapid and nonlinear in nature and even a small magnitude of external stimulus can cause noticeable changes in their shape, size, color or conductivity. Of these SRPs, two types of SPs with the ability to actively change can be differentiated: shape-memory polymers and shape-changing polymers. The uniqueness of these materials lies not only in the fast macroscopic changes occurring in their structure but also in that some of these shape changes are reversible. This paper presents a brief review of current progress in the area of light activated shape-memory polymers and shape-changing polymers and their possible field of applications.

  16. Memory CD8+ T cell differentiation in viral infection: A cell for all seasons

    Institute of Scientific and Technical Information of China (English)

    Henry Radziewicz; Luke Uebelhoer; Bertram Bengsch; Arash Grakoui

    2007-01-01

    Chronic viral infections such as hepatitis B virus (HBV),hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specific CD8+ T cells play an important role in the course and outcome of these viral infections and it is hypothesized that altered or impaired differentiation of virusspecific CD8+ T cells contributes to the development of persistence and/or disease progression. A deeper understanding of the mechanisms responsible for functional differentiation of CD8+ T cells is essential for the generation of successful therapies aiming to strengthen the adaptive component of the immune system.

  17. Growth and self-assembly of BaTiO{sub 3} nanocubes for resistive switching memory cells

    Energy Technology Data Exchange (ETDEWEB)

    Chu, Dewei, E-mail: D.Chu@unsw.edu.au [School of Materials Science and Engineering, University of New South Wales, Sydney, 2052 NSW (Australia); Lin, Xi; Younis, Adnan [School of Materials Science and Engineering, University of New South Wales, Sydney, 2052 NSW (Australia); Li, Chang Ming [Chongqing Key Lab for Advanced Materials and Clean Energies of Techonologies Dean, Institute for Clean Energy and Advanced Materials, Southwest University, Chongqing (China); Dang, Feng [Research Center for Materials Back Casting Technology (MBT Center), Nagoya University, Nagoya 464-8603 (Japan); Li, Sean [School of Materials Science and Engineering, University of New South Wales, Sydney, 2052 NSW (Australia)

    2014-06-01

    In this work, the self-assembled BaTiO{sub 3} nanocubes based resistive switching memory capacitors are fabricated with hydrothermal and drop-coating approaches. The device exhibits excellent bipolar resistance switching characteristics with ON/OFF ratio of 58–70, better reliability and stability over various polycrystalline BaTiO{sub 3} nanostructures. It is believed that the inter cube junctions is responsible for such a switching behaviour and it can be described by the filament model. The effect of film thickness on switching ratio (ON/OFF) was also investigated in details. - Graphical abstract: This work describes a novel resistive switching memory cell based on self-assembled BaTiO{sub 3} nanocubes. - Highlights: • BaTiO{sub 3} nanocubes were prepared by one step facile hydrothermal method. • Self-assembled BaTiO{sub 3} nanocubes thin films were obtained by drop-coating approach. • The BaTiO{sub 3} nanocubes show excellent resistive switching properties for memory applications.

  18. Multilevel Cell Storage and Resistance Variability in Resistive Random Access Memory

    Science.gov (United States)

    Pantelis, D. I.; Karakizis, P. N.; Dragatogiannis, D. A.; Charitidis, C. A.

    2016-06-01

    Multilevel per cell (MLC) storage in resistive random access memory (ReRAM) is attractive in achieving high-density and low-cost memory and will be required in future. In this chapter, MLC storage and resistance variability and reliability of multilevel in ReRAM are discussed. Different MLC operation schemes with their physical mechanisms and a comprehensive analysis of resistance variability have been provided. Various factors that can induce variability and their effect on the resistance margin between the multiple resistance levels are assessed. The reliability characteristics and the impact on MLC storage have also been assessed.

  19. Interaction effect of response medium and working memory capacity on creative idea generation.

    Science.gov (United States)

    Hao, Ning; Yuan, Huan; Cheng, Rui; Wang, Qing; Runco, Mark A

    2015-01-01

    This study aimed to examine the interaction effect of response medium (i.e., write down ideas and orally report ideas) and working memory capacity (WMC) on creative idea generation. Participants (N = 90) with higher or lower WMC were asked to solve Alternative Uses Task (AUT) problems in the condition of writing down or speaking out ideas. The results showed that fluency of AUT performance was higher in the writing than in the speaking condition. Additionally, participants with higher WMC performed better on AUT fluency than those with lower WMC in the writing condition, while they showed no difference in the speaking condition. Moreover, level of cognitive demand fully mediated the effect of response medium on AUT fluency. Theoretically, these findings indicated the importance of WMC in creative idea generation, which supported the controlled-attention theory of creativity. Practical implications and future directions were discussed.

  20. Interaction effect of response medium and working memory capacity on creative idea generation

    Directory of Open Access Journals (Sweden)

    Ning eHao

    2015-10-01

    Full Text Available This study aimed to examine the interaction effect of response medium (i.e., write down ideas and orally report ideas and working memory capacity (WMC on creative idea generation. Participants (N = 90 with higher or lower WMC were asked to solve Alternative Uses Task (AUT problems in the condition of writing down or speaking out ideas. The results showed that fluency of AUT performance was higher in the writing than in the speaking condition. Additionally, participants with higher WMC performed better on AUT fluency than those with lower WMC in the writing condition, while they showed no difference in the speaking condition. Moreover, level of cognitive demand fully mediated the effect of response medium on AUT fluency. Theoretically, these findings indicated the importance of WMC in creative idea generation, which supported the controlled-attention theory of creativity. Practical implications and future directions were discussed.

  1. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics

    Science.gov (United States)

    Crompton, Joseph G.; Sukumar, Madhusudhanan; Roychoudhuri, Rahul; Clever, David; Gros, Alena; Eil, Robert; Tran, Eric; Hanada, Ken-ichi; Yu, Zhiya; Palmer, Douglas C.; Kerkar, Sid P.; Michalek, Ryan D.; Upham, Trevor; Leonardi, Anthony; Aquavella, Nicholas; Wang, Ena; Marincola, Francesco M.; Gattinoni, Luca; Muranski, Pawel; Sundrud, Mark S.; Klebanoff, Christopher A.; Rosenberg, Steven A.; Fearon, Douglas T.; Restifo, Nicholas P.

    2015-01-01

    Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can result in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy might be limited by poor persistence of TIL after adoptive-transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in viral-specific murine models, but whether this approach may enhance features of memory (e.g. long-term persistence) in TIL which are characteristically exhausted and senescent is not established. Here we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments anti-tumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of anti-tumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. PMID:25432172

  2. Antigen-specific B cells reactivate an effective cytotoxic T cell response against phagocytosed Salmonella through cross-presentation.

    Directory of Open Access Journals (Sweden)

    Jelle de Wit

    Full Text Available BACKGROUND: The eradication of facultative intracellular bacterial pathogens, like Salmonella typhi, requires the concerted action of both the humoral immune response and the cytotoxic CD8(+ T cell response. Dendritic cells (DCs are considered to orchestrate the cytotoxic CD8(+ T cell response via cross-presentation of bacterial antigens onto MHC class I molecules. Cross-presentation of Salmonella by DCs however, is accompanied by the induction of apoptosis in the DCs. Besides antibody production, B cells are required to clear Salmonella infection for other unknown reasons. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that Salmonella-specific B cells that phagocytose Salmonella upon BCR-ligation reactivate human memory CD8(+ T cells via cross-presentation yielding a Salmonella-specific cytotoxic T cell response. The reactivation of CD8(+ T cells is dependent on CD4(+ T cell help. Unlike the DCs, B cell-mediated cross-presentation of Salmonella does not coincide with apoptosis. CONCLUSIONS/SIGNIFICANCE: B cells form a new player in the activation of the cytotoxic effector arm of the immune response and the generation of effective adaptive immunity in Salmonella infection.

  3. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35.

    Science.gov (United States)

    Huang, Chiung-Hui; Loo, Evelyn Xiu-Ling; Kuo, I-Chun; Soh, Gim Hooi; Goh, Denise Li-Meng; Lee, Bee Wah; Chua, Kaw Yan

    2011-07-01

    CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-α, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Rα(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC-motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation.

  4. CD161 Expression Defines a Th1/Th17 Polyfunctional Subset of Resident Memory T Lymphocytes in Bronchoalveolar Cells.

    Directory of Open Access Journals (Sweden)

    Yolanda Gonzalez

    Full Text Available Alveolar resident memory T cells (T(RM comprise a currently uncharacterized mixture of cell subpopulations. The CD3(+CD161(+ T cell subpopulation resides in the liver, intestine and skin, but it has the capacity for tissue migration; however, the presence of resident CD3(+CD161(+ T cells in the bronchoalveolar space under normal conditions has not been reported. Bronchoalveolar cells (BACs from healthy volunteers were evaluated and found that 8.6% (range 2.5%-21% of these cells were CD3(+ T lymphocytes. Within the CD3(+ population, 4.6% of the cells (2.1-11.3 expressed CD161 on the cell surface, and 74.2% of the CD161(+CD3(+ T cells expressed CD45RO. The number of CD3(+CD161(+ T cells was significantly lower in the bronchoalveolar space than in the blood (4.6% of BACs vs 8.4% of peripheral blood mononuclear cells (PBMCs; P<0.05. We also found that 2.17% of CD4(+ T lymphocytes and 1.52% of CD8(+ T lymphocytes expressed CD161. Twenty-two percent of the alveolar CD3(+CD161(+ T lymphocytes produced cytokines upon stimulation by PMA plus ionomycin, and significantly more interferon gamma (IFN-γ was produced compared with other cytokines (P = 0.05. Most alveolar CD3(+CD161(+ T cells produced interleukin-17 (IL-17 and IFN-γ simultaneously, and the percentage of these cells was significantly higher than the percentage of CD3(+CD161- T cells. Moreover, the percentage of alveolar CD3(+CD161(+ T lymphocytes that produced IFN-γ/IL-17 was significantly higher than those in the peripheral blood (p<0.05. In conclusion, Th1/Th17-CD3(+CD161(+ TRM could contribute to compartment-specific immune responses in the lung.

  5. Endothelial Cell Response to Fusobacterium nucleatum.

    Science.gov (United States)

    Mendes, Reila Tainá; Nguyen, Daniel; Stephens, Danielle; Pamuk, Ferda; Fernandes, Daniel; Van Dyke, Thomas E; Kantarci, Alpdogan

    2016-07-01

    Vascular response is an essential aspect of an effective immune response to periodontal disease pathogens, as new blood vessel formation contributes to wound healing and inflammation. Gaining a greater understanding of the factors that affect vascular response may then contribute to future breakthroughs in dental medicine. In this study, we have characterized the endothelial cell response to the common bacterium Fusobacterium nucleatum, an important bridging species that facilitates the activity of late colonizers of the dental biofilm. Endothelial cells were infected with Fusobacterium nucleatum (strain 25586) for periods of 4, 12, 24, or 48 h. Cell proliferation and tube formation were analyzed, and expression of adhesion molecules (CD31 and CD34) and vascular endothelial growth factor (VEGF) receptors 1 and 2 was measured by fluorescence-activated cell sorter (FACS) analysis. Data indicate that F. nucleatum impaired endothelial cell proliferation and tube formation. The findings suggest that the modified endothelial cell response acts as a mechanism promoting the pathogenic progression of periodontal diseases and may potentially suggest the involvement of periodontopathogens in systemic diseases associated with periodontal inflammation. PMID:27185790

  6. Reduced Number of Transitional and Naive B Cells in Addition to Decreased BAFF Levels in Response to the T Cell Independent Immunogen Pneumovax®23.

    Science.gov (United States)

    Roth, Alena; Glaesener, Stephanie; Schütz, Katharina; Meyer-Bahlburg, Almut

    2016-01-01

    Protective immunity against T cell independent (TI) antigens such as Streptococcus pneumoniae is characterized by antibody production of B cells induced by the combined activation of T cell independent type 1 and type 2 antigens in the absence of direct T cell help. In mice, the main players in TI immune responses have been well defined as marginal zone (MZ) B cells and B-1 cells. However, the existence of human equivalents to these B cell subsets and the nature of the human B cell compartment involved in the immune reaction remain elusive. We therefore analyzed the effect of a TI antigen on the B cell compartment through immunization of healthy individuals with the pneumococcal polysaccharide (PnPS)-based vaccine Pneumovax®23, and subsequent characterization of B cell subpopulations. Our data demonstrates a transient decrease of transitional and naïve B cells, with a concomitant increase of IgA+ but not IgM+ or IgG+ memory B cells and a predominant generation of PnPS-specific IgA+ producing plasma cells. No alterations could be detected in T cells, or proposed human B-1 and MZ B cell equivalents. Consistent with the idea of a TI immune response, antigen-specific memory responses could not be observed. Finally, BAFF, which is supposed to drive class switching to IgA, was unexpectedly found to be decreased in serum in response to Pneumovax®23. Our results demonstrate that a characteristic TI response induced by Pneumovax®23 is associated with distinct phenotypical and functional changes within the B cell compartment. Those modulations occur in the absence of any modulations of T cells and without the development of a specific memory response.

  7. Osteogenic Capacity of Human Adipose-Derived Stem Cells is Preserved Following Triggering of Shape Memory Scaffolds.

    Science.gov (United States)

    Tseng, Ling-Fang; Wang, Jing; Baker, Richard M; Wang, Guirong; Mather, Patrick T; Henderson, James H

    2016-08-01

    Recent advances in shape memory polymers have enabled the study of programmable, shape-changing, cytocompatible tissue engineering scaffolds. For treatment of bone defects, scaffolds with shape memory functionality have been studied for their potential for minimally invasive delivery, conformal fitting to defect margins, and defect stabilization. However, the extent to which the osteogenic differentiation capacity of stem cells resident in shape memory scaffolds is preserved following programmed shape change has not yet been determined. As a result, the feasibility of shape memory polymer scaffolds being employed in stem cell-based treatment strategies remains unclear. To test the hypothesis that stem cell osteogenic differentiation can be preserved during and following triggering of programmed architectural changes in shape memory polymer scaffolds, human adipose-derived stem cells were seeded in shape memory polymer foam scaffolds or in shape memory polymer fibrous scaffolds programmed to expand or contract, respectively, when warmed to body temperature. Osteogenic differentiation in shape-changing and control scaffolds was compared using mineral deposition, protein production, and gene expression assays. For both shape-changing and control scaffolds, qualitatively and quantitatively comparable amounts of mineral deposition were observed; comparable levels of alkaline phosphatase activity were measured; and no significant differences in the expression of genetic markers of osteogenesis were detected. These findings support the feasibility of employing shape memory in scaffolds for stem cell-based therapies for bone repair.

  8. T-cell response to allergens.

    Science.gov (United States)

    Ozdemir, Cevdet; Akdis, Mübeccel; Akdis, Cezmi A

    2010-01-01

    Anaphylaxis is a life-threatening IgE-dependent type 1 hypersensitivity reaction in which multiple organ systems are involved. The existence of allergen exposure and specific IgE are the major contributors to this systemic reaction. The decision of the immune system to respond to allergens is highly dependent on factors including the type and load of allergen, behavior and type of antigen-presenting cells, innate immune response stimulating substances in the same micromilieu, the tissue of exposure, interactions between T and B lymphocytes, costimulators, and genetic propensity known as atopy. Antigen-presenting cells introduce processed allergens to T-helper lymphocytes, where a decision of developing different types of T-cell immunity is given under the influence of several cytokines, chemokines, costimulatory signals and regulatory T cells. Among Th2-type cytokines, interleukin (IL)-4 and IL-13 are responsible for class switching in B cells, which results in production of allergen-specific IgE antibodies that bind to specific receptors on mast cells and basophils. After re-exposure to the sensitized allergen, this phase is followed by activation of IgE Fc receptors on mast cells and basophils resulting in biogenic mediator releases responsible for the symptoms and signs of anaphylaxis. Since the discovery of regulatory T cells, the concepts of immune regulation have substantially changed during the last decade. Peripheral T-cell tolerance is a key immunologic mechanism in healthy immune response to self antigens and non-infectious non-self antigens. Both naturally occurring CD4+CD25+ regulatory T (Treg) cells and inducible populations of allergen-specific, IL-10-secreting Treg type 1 cells inhibit allergen-specific effector cells and have been shown to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses. On the other hand, Th17 cells are characterized by their IL-17 (or IL-17A), IL-17F, IL-6

  9. During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion

    NARCIS (Netherlands)

    Hendriks, Jenny; Xiao, Yanling; Rossen, John W A; van der Sluijs, Koenraad F; Sugamura, Kazuo; Ishii, Naoto; Borst, Jannie

    2005-01-01

    Independent studies have shown that CD27, 4-1BB, and OX40 can all promote survival of activated CD8+ T cells. We have therefore compared their impact on CD8+ memory T cell formation and responsiveness within one, physiologically relevant model system. Recombinant mice, selectively lacking input of o

  10. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade A and B viruses.

    Directory of Open Access Journals (Sweden)

    Hugo Mouquet

    Full Text Available Understanding the antibody response to HIV-1 in humans that show broad neutralizing serologic activity is a crucial step in trying to reproduce such responses by vaccination. Investigating antibodies with cross clade reactivity is particularly important as these antibodies may target conserved epitopes on the HIV envelope gp160 protein. To this end we have used a clade B YU-2 gp140 trimeric antigen and single-cell antibody cloning methods to obtain 189 new anti-gp140 antibodies representing 51 independent B cell clones from the IgG memory B cells of 3 patients infected with HIV-1 clade A or B viruses and exhibiting broad neutralizing serologic activity. Our results support previous findings showing a diverse antibody response to HIV gp140 envelope protein, characterized by differentially expanded B-cell clones producing highly hypermutated antibodies with heterogenous gp140-specificity and neutralizing activity. In addition to their high-affinity binding to the HIV spike, the vast majority of the new anti-gp140 antibodies are also polyreactive. Although none of the new antibodies are as broad or potent as VRC01 or PG9, two clonally-related antibodies isolated from a clade A HIV-1 infected donor, directed against the gp120 variable loop 3, rank in the top 5% of the neutralizers identified in our large collection of 185 unique gp140-specific antibodies in terms of breadth and potency.

  11. Thermo-mechanical Response and Damping Behavior of Shape Memory Alloy-MAX Phase Composites

    Science.gov (United States)

    Kothalkar, Ankush Dilip; Benitez, Rogelio; Hu, Liangfa; Radovic, Miladin; Karaman, Ibrahim

    2014-05-01

    NiTi/Ti3SiC2 interpenetrating composites that combine two unique material systems—a shape memory alloy (SMA) and a MAX phase—demonstrating two different pseudoelastic mechanisms, were processed using spark plasma sintering. The goal of mixing these two material systems was to enhance the damping behavior and thermo-mechanical response of the composite by combining two pseudoelastic mechanisms, i.e., reversible stress-induced martensitic transformation in SMA and reversible incipient kink band formation in MAX phase. Equal volume fractions of equiatomic NiTi and Ti3SiC2 were used. Microstructural characterization was conducted using scanning electron microscopy to study the distribution of NiTi, Ti3SiC2, and remnant porosity in the composite. Thermo-mechanical testing in the form of thermal cycles under constant stress levels was performed in order to characterize shape memory behavior and thereby introducing residual stresses in the composites. Evolution of two-way shape memory effect was studied and related to the presence of residual stresses in the composites. Damping behavior, implying the energy dissipation per loading-unloading cycle under increasing compressive stresses, of pure NiTi, pure Ti3SiC2, as-sintered, and thermo-mechanically cycled (TC) NiTi/Ti3SiC2 composites, was investigated and compared to the literature data. In this study, the highest energy dissipation was observed for the TC composite followed by the as-sintered (AS) composite, pure NiTi, and pure Ti3SiC2 when compared at the same applied stress levels. Both the AS and TC composites showed higher damping up to 200 MPa stress than any of the metal—MAX phase composites reported in the literature to date. The ability to enhance the performance of the composite by controlling the thermo-mechanical loading paths was further discussed.

  12. Accessory signals in T-T cell interactions between antigen- and alloantigen-specific, human memory T cells generated in vitro

    DEFF Research Database (Denmark)

    Odum, N; Ryder, L P; Georgsen, J;

    1990-01-01

    The potential of activated HLA class II-positive T cells as antigen-/alloantigen-presenting cells remains controversial. In our model system we use in vitro-primed, HLA class II-specific T cells of the memory T-cell phenotype, CD4+, CD29+ (4B4+), and CD45RO+ (UCHL-1). We have previously shown...... that alloactivated, HLA class II-positive T cells (Ta) are unable to stimulate proliferative responses in naive and primed allospecific T cells when 'back-stimulation' is avoided. The explanation of this feature of Ta is unknown, but it is due neither to suppression nor to insufficient HLA class II expression....... Accordingly, we investigated the possibility that Ta have a deficient expression of accessory signals critical for the induction of proliferative T-cell responses. We found that (1) non-mitogenic concentrations of phorbol myristate acetate (PMA) in combination with either rIL-4, a CD28-reactive MoAb (Kolt-2...

  13. Learning and memory in Rhodnius prolixus: habituation and aversive operant conditioning of the proboscis extension response.

    Science.gov (United States)

    Vinauger, Clément; Lallement, Hélène; Lazzari, Claudio R

    2013-03-01

    It has been largely accepted that the cognitive abilities of disease vector insects may have drastic consequences on parasite transmission. However, despite the research effort that has been invested in the study of learning and memory in haematophagous insects, hitherto few conclusive results have been obtained. Adapting procedures largely validated in Drosophila, honeybees and butterflies, we demonstrate here that the proboscis extension response (PER) of the haematophagous insect Rhodnius prolixus can be modulated by non-associative (habituation) and associative (aversive conditioning) learning forms. Thermal stimuli were used as both unconditional stimulus (appetitive temperatures) and negative reinforcement (thermal shock). In the first part of this work, the PER was habituated and dishabituated to thermal stimuli, demonstrating the true central processing of information and discarding motor fatigue or sensory adaptation. Habituation was revealed to be modulated by the spatial context. In the second part, bugs that were submitted to aversive operant conditioning stopped responding with PER to thermal stimulation more quickly than by habituation. They were able to use their training experience when tested up to 72 h later. Our work constitutes the first demonstration of PER habituation and conditioning in a blood-sucking insect and provides reproducible experimental tools for the study of the mechanisms underlying learning and memory in disease vectors. PMID:23408803

  14. Epigenetic Control of Smooth Muscle Cell Identity and Lineage Memory.

    Science.gov (United States)

    Gomez, Delphine; Swiatlowska, Pamela; Owens, Gary K

    2015-12-01

    Vascular smooth muscle cells (SMCs), like all cells, acquire a cell-specific epigenetic signature during development that includes acquisition of a unique repertoire of histone and DNA modifications. These changes are postulated to induce an open chromatin state (referred to as euchromatin) on the repertoire of genes that are expressed in differentiated SMC, including SMC-selective marker genes like Acta2 and Myh11, as well as housekeeping genes expressed by most cell types. In contrast, genes that are silenced in differentiated SMC acquire modifications associated with a closed chromatin state (ie, heterochromatin) and transcriptional silencing. Herein, we review mechanisms that regulate epigenetic control of the differentiated state of SMC. In addition, we identify some of the major limitations in the field and future challenges, including development of innovative new tools and approaches, for performing single-cell epigenetic assays and locus-selective editing of the epigenome that will allow direct studies of the functional role of specific epigenetic controls during development, injury repair, and disease, including major cardiovascular diseases, such as atherosclerosis, hypertension, and microvascular disease, associated with diabetes mellitus.

  15. Item response theory analyses of the Cambridge Face Memory Test (CFMT).

    Science.gov (United States)

    Cho, Sun-Joo; Wilmer, Jeremy; Herzmann, Grit; McGugin, Rankin Williams; Fiset, Daniel; Van Gulick, Ana E; Ryan, Kaitlin F; Gauthier, Isabel

    2015-06-01

    We evaluated the psychometric properties of the Cambridge Face Memory Test (CFMT; Duchaine & Nakayama, 2006). First, we assessed the dimensionality of the test with a bifactor exploratory factor analysis (EFA). This EFA analysis revealed a general factor and 3 specific factors clustered by targets of CFMT. However, the 3 specific factors appeared to be minor factors that can be ignored. Second, we fit a unidimensional item response model. This item response model showed that the CFMT items could discriminate individuals at different ability levels and covered a wide range of the ability continuum. We found the CFMT to be particularly precise for a wide range of ability levels. Third, we implemented item response theory (IRT) differential item functioning (DIF) analyses for each gender group and 2 age groups (age ≤ 20 vs. age > 21). This DIF analysis suggested little evidence of consequential differential functioning on the CFMT for these groups, supporting the use of the test to compare older to younger, or male to female, individuals. Fourth, we tested for a gender difference on the latent facial recognition ability with an explanatory item response model. We found a significant but small gender difference on the latent ability for face recognition, which was higher for women than men by 0.184, at age mean 23.2, controlling for linear and quadratic age effects. Finally, we discuss the practical considerations of the use of total scores versus IRT scale scores in applications of the CFMT.

  16. Polylactide-based polyurethane shape memory nanocomposites (Fe3O4/PLAUs) with fast magnetic responsiveness

    Science.gov (United States)

    Gu, Shu-Ying; Jin, Sheng-Peng; Gao, Xie-Feng; Mu, Jian

    2016-05-01

    Polylactide-based polyurethane shape memory nanocomposites (Fe3O4/PLAUs) with fast magnetic responsiveness are presented. For the purpose of fast response and homogeneous dispersion of magnetic nanoparticles, oleic acid was used to improve the dispersibility of Fe3O4 nanoparticles in a polymer matrix. A homogeneous distribution of Fe3O4 nanoparticles in the polymer matrix was obtained for nanocomposites with low Fe3O4 loading content. A small agglomeration was observed for nanocomposites with 6 wt% and 9 wt% loading content, leading to a small decline in the mechanical properties. PLAU and its nanocomposites have glass transition around 52 °C, which can be used as the triggering temperature. PLAU and its nanocomposites have shape fixity ratios above 99%, shape recovery ratios above 82% for the first cycle and shape recovery ratios above 91% for the second cycle. PLAU and its nanocomposites also exhibit a fast water bath or magnetic responsiveness. The magnetic recovery time decreases with an increase in the loading content of Fe3O4 nanoparticles due to an improvement in heating performance for increased weight percentage of fillers. The nanocomposites have fast responses in an alternating magnetic field and have potential application in biomedical areas such as intravascular stent.

  17. Nonlinear cell response to strong electric fields

    Science.gov (United States)

    Bardos, D. C.; Thompson, C. J.; Yang, Y. S.; Joyner, K. H.

    2000-07-01

    The response of living cells to externally applied electric fields is of widespread interest. In particular, the intensification of electric fields across cell membranes is believed to be responsible, through membrane rupture and reversible membrane breakdown processes, for certain types of tissue damage in electrical trauma cases which cannot be attributed to Joule heating. Large elongated cells such as skeletal muscle fibres are particularly vulnerable to such damage. Previous theoretical studies of field intensification across cell membranes in such cells have assumed the membrane current to be linear in the applied field (Ohmic membrane conductivity) and were limited to sinusoidal applied fields. In this paper, we investigate a simple model of a long cylindrical cell, corresponding to nerve or skeletal muscle cells. Employing the electroquasistatic approximation, a system of coupled first-order differential equations for the membrane electric field is derived which incorporates arbitrary time dependence in the external field and nonlinear membrane response (non-Ohmic conductivity). The behaviour of this model is investigated for a variety of applied fields in both the linear and highly nonlinear regimes. We find that peak membrane fields predicted by the nonlinear model are approximately twice as intense, for low-frequency electrical trauma conditions, as those of the linear theory.

  18. Quantitative separation of the influence of copper (II) chloride mass migration on the chemo-responsive shape memory effect in polyurethane shape memory polymer

    Science.gov (United States)

    Lu, Haibao; Lu, Chunrui; Huang, Wei Min; Leng, Jinsong

    2016-10-01

    Chemo-responsive shape memory effect in polyurethane shape memory polymer (SMP) composite triggered by mass migration of copper (II) chloride (CuCl2) has been experimentally demonstrated. In this study, we present a comprehensive study on quantitative separation of the effect of CuCl2 particle mass migration on the chemo-responsive shape recovery behavior of polyurethane SMP composites with different concentrations of CuCl2 particles. It is found that the SMP is featured with a critical release rate of the mechanical energy storage associated with the shape recovery behavior due to mass migration of the CuCl2 particle. A sequence of molecular interactions among CuCl2 particles, polyurethane macromolecules and water molecules, i.e., assembly of the CuCl2 particle with polyurethane macromolecules, and then disassembly and dissolution of the CuCl2 particle in water, results in an acceleration of water-induced shape recovery of polyurethane SMP. This study focuses on the quantitative separation of the influence of mass migration on the chemo-responsive shape recovery behavior of polyurethane SMP in response to water. It is expected to promote and achieve the actuation of chemo-responsive SMPs in a fully controllable manner.

  19. Thermodynamics-based models for the magneto-mechanical response of magnetic shape memory alloys

    Science.gov (United States)

    LaMaster, Douglas H.

    Magnetic shape memory alloys (MSMAs) are a relatively new class of smart material that exhibit large recoverable strain (up to 10%) [1] and fast response time (higher than 1 kilohertz) [2]. MSMAs are comprised of martensitic variants arranged as tetragonal unit cells with one short side, denoted by c, and two longer sides, denoted by a. With single crystal MSMAs, these variants align with one of the three Cartesian directions, and the volume fraction of variants with short side aligned in the i-direction is given by ξi. The boundary between two variants, called the twin boundary, moves as one variant volume fraction grows at the expense of the other. Under an applied compressive stress in the i-direction, variants will reorient into the ξi configuration to align the short side of the unit cell with the compressive stress. Each variant has an internal magnetization vector of length Msat that is approximately [3] aligned with the short length of the unit cell in the absence of an external applied magnetic field. This internal magnetization vector tends to align with an externally applied field to minimize the energy in the MSMA. The magnetization vector may align with the external field by: 1) changing internal magnetic domains, 2) rotating magneti- zation vectors away from the easy axis, or 3) variant reorientation . The fraction of the magnetic domains in the ξi variant with easy-axis in the i-direction is denoted by αi, and the domain fraction of the ξi variants with easy axis in the direction opposite to the i-direction is given by (1 - αi). Under an applied field in the i-direction, the αi domain will grow at the expense of the (1 - αi) domain, and vice versa for an applied field in the -i-direction. When the volume fraction αi reaches either 1 or 0, this domain wall motion ceases and the domains are said to be saturated. After domains in ξi have saturated, increasing the magnetic field further may rotate the magnetization vectors in other variants

  20. Mechanical memory and dosing influence stem cell fate

    Science.gov (United States)

    Yang, Chun; Tibbitt, Mark W.; Basta, Lena; Anseth, Kristi S.

    2014-06-01

    We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young’s modulus E ~ 2 kPa) depended on previous culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). In addition, mechanical dosing of hMSCs cultured on initially stiff (E ~ 10 kPa) and then soft (E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible or—above a threshold mechanical dose—irreversible activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs towards osteogenic differentiation. We conclude that stem cells possess mechanical memory—with YAP/TAZ acting as an intracellular mechanical rheostat—that stores information from past physical environments and influences the cells’ fate.

  1. Heterogeneity of memory marginal zone B cells in the rat

    NARCIS (Netherlands)

    Hendricks, Jacobus

    2015-01-01

    The spleen is an important organ of the immune system. Like other lymphoid organs, the spleen is compartmentalized. Different compartments harbor different populations of lymphocytes, subpopulation of the white blood cells. One of these compartments in the spleen is the so-called marginal zone. Most

  2. Radiosensitivity of CD45RO+ memory and CD45RO- naive T cells in culture

    International Nuclear Information System (INIS)

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4+ helper and CD8+ killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO+ memory and CD45RO- naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO+ cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity. 27 refs., 7 figs., 1 tab

  3. The effect of liking on the memorial response to advertising: the case of small cars

    Directory of Open Access Journals (Sweden)

    Sergio Brasini

    2013-05-01

    Full Text Available In marketing literature there is actually very poor evidence of how ad liking works to build its impact on memorial response to ad pressure. This study investigates the problem of the existence of carryover effects of ad liking on recall, by modelling the dynamic patterns of recall, ad pressure and liking by means of the specification of an augmented Koyck-type model and provides a methodology for assessing ad likeability ex post effectiveness on recall variables. The analysis is carried out for the Italian market of small automobiles. Main empirical findings highlight that carryover effects of ad liking can be detected, even if systematically. For practitioners the most important implication is that likeability may play a key role in building consumer attention.

  4. T-cell responses in malaria

    DEFF Research Database (Denmark)

    Hviid, L; Jakobsen, P H; Abu-Zeid, Y A;

    1992-01-01

    Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria...... vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information, and...... discusses factors affecting the responses of T cells to malaria antigens....

  5. Radiation response of human hematopoietic cells

    International Nuclear Information System (INIS)

    The radiosensitivity and capacity to accumulate and repair sub-lethal damage has been studied in hematopoietic cell lines of human origin and in stem cells derived from blood and bone narrow of normal human donors. The results were analysed in terms of the linear quadratic and multitarget models. For the cell lines intrinsic radiosensitivity varied widely with D/sub o/'s ranging from 0.53 to 1.39 Gy. Five of the cell lines showed same capacity to accumulate sub-lethal damage and in three of these survival was enhanced by dose fractionation or reduction of dose rate. Among the cell lines of leukemic origin, several did not conform in one or more respects with the highly radiosensitive and repair deficient model associated with hematopoietic cells. There was no apparent correlation between radiation response and the phenotype (myeloid, lymphoid or undifferentiated) of the cell lines studied. Variability of radiation response and in some cases an unpredicted degree of radioresistance and capacity to repair sub-lethal damage has now been demonstrated for both cultured and primary explants of human leukemic cells. These observations have implications for the design of Total Body Irradiation protocols for use prior to bone narrow transplant

  6. Regulatory T cells in cutaneous immune responses.

    OpenAIRE

    Honda, Tetsuya; MIYACHI, YOSHIKI; Kabashima, Kenji

    2011-01-01

    Regulatory T cells (Treg) are a subset of T cells with strong immunosuppressive activity. In the skin, it has recently been revealed that Treg play important roles not only in the maintenance of skin homeostasis but also in the regulation of the immune responses, such as contact hypersensitivity and atopic dermatitis. Furthermore, the skin plays important roles in the induction of Treg in the periphery. In this review, we will provide an overview of the mechanism of Treg-mediated immunosuppre...

  7. Activated human CD4+CD45RO+ memory T-cells indirectly inhibit NLRP3 inflammasome activation through downregulation of P2X7R signalling.

    Directory of Open Access Journals (Sweden)

    Vanessa Beynon

    Full Text Available Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.

  8. Neisseria gonorrhoeae triggers the PGE2/IL-23 pathway and promotes IL-17 production by human memory T cells.

    Science.gov (United States)

    Stefanelli, Paola; Teloni, Raffaela; Carannante, Anna; Mariotti, Sabrina; Nisini, Roberto; Gagliardi, Maria Cristina

    2012-10-01

    PGE2 is a potent modulator of the T helper (Th)17 immune response that plays a critical role in the host defense against bacterial, fungal and viral infections. We recently showed high serum levels of interleukin (IL)-17 in patients with gonococcal infection and we hypothesized that Neisseria gonorrhoeae could exploit a PGE2 mediated mechanism to promote IL-17 production. Here we show that N. gonorrhoeae induces human dendritic cell (DC) maturation, secretion of prostaglandin E2 and proinflammatory cytokines, including the pro-Th17 cytokine IL-23. Blocking PGE2 endogenous synthesis selectively reduces IL-23 production by DC in response to gonococcal stimulation, confirming recent data on PGE2/IL-23 crosstalk. N. gonorrhoeae stimulated DC induce a robust IL-17 production by memory CD4(+) T cells and this function correlates with PGE2 production. Our findings delineate a previously unknown role for PGE2 in the immune response to N. gonorrhoeae, suggesting its contribute via Th17 cell expansion. PMID:22542425

  9. Temperature dependence of SET switching characteristics in phase-change memory cells

    Science.gov (United States)

    He, Qiang; Li, Zhen; Liu, Chang; Meng, Xiang-ru; Peng, Ju-hong; Lai, Zhi-bo; Miao, Xiang-shui

    2016-09-01

    The temperature dependence of crystallization kinetics of phase-change materials raises a series of reliability issues, while phase-change memory cells work at high temperature or thermal-disturbance condition. These issues hinder the development of ultrahigh-density storage devices. We investigate the evolution of SET switching characteristics of phase-change memory cells at high operating temperature. We show that the high temperature strongly impacts the SET state resistance. As a result, SET failure has been observed with elevated ambient temperature. Our SPICE simulations indicate that transient amorphization behavior during a complete SET pulse period is considered as the potential mechanism of SET failure. By modifying the SET pulse intensity and width linearly, we successfully reduce the SET failure in the experiments. The results illustrate that the demonstrated linear properties may optimize SET pulse performance.

  10. Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge.

    Science.gov (United States)

    Krishnamurty, Akshay T; Thouvenel, Christopher D; Portugal, Silvia; Keitany, Gladys J; Kim, Karen S; Holder, Anthony; Crompton, Peter D; Rawlings, David J; Pepper, Marion

    2016-08-16

    Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M(+) (IgM(+)) and IgG(+) MBC subsets and an unmutated IgD(+) MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM(+) MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM(+) MBCs also gave rise to T cell-dependent IgM(+) and IgG(+)B220(+)CD138(+) plasmablasts or T cell-independent B220(-)CD138(+) IgM(+) plasma cells. Thus, even in competition with IgG(+) MBCs, IgM(+) MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies. PMID:27473412

  11. Subsisting H1N1 influenza memory responses are insufficient to protect from pandemic H1N1 influenza challenge in C57BL/6 mice

    OpenAIRE

    Sage, Leo K.; Fox, Julie M.; Tompkins, Stephen M.; Tripp, Ralph A.

    2013-01-01

    The 2009 swine-origin pandemic H1N1 (pH1N1) influenza virus transmitted and caused disease in many individuals immune to pre-2009 H1N1 influenza virus. Whilst extensive studies on antibody-mediated pH1N1 cross-reactivity have been described, few studies have focused on influenza-specific memory T-cells. To address this, the immune response in pre-2009 H1N1 influenza-immune mice was evaluated after pH1N1 challenge and disease pathogenesis was determined. The results show that despite homology ...

  12. Response-time evidence for mixed memory states in a sequential-presentation change-detection task.

    Science.gov (United States)

    Nosofsky, Robert M; Donkin, Chris

    2016-02-01

    Response-time (RT) and choice-probability data were obtained in a rapid visual sequential-presentation change-detection task in which memory set size, study-test lag, and objective change probabilities were manipulated. False "change" judgments increased dramatically with increasing lag, consistent with the idea that study items with long lags were ejected from a discrete-slots buffer. Error RTs were nearly invariant with set size and lag, consistent with the idea that the errors were produced by a stimulus-independent guessing process. The patterns of error and RT data could not be explained in terms of encoding limitations, but were consistent with the hypothesis that long retention lags produced a zero-stimulus-information state that required guessing. Formal modeling of the change-detection RT and error data pointed toward a hybrid model of visual working memory. The hybrid model assumed mixed states involving a combination of memory and guessing, but with higher memory resolution for items with shorter retention lags. The work raises new questions concerning the nature of the memory representations that are produced across the closely related tasks of change detection and visual memory search.

  13. Serine protease inhibitor-6 differentially affects the survival of effector and memory alloreactive CD8-T cells.

    Science.gov (United States)

    Azzi, J; Ohori, S; Ting, C; Uehara, M; Abdoli, R; Smith, B D; Safa, K; Solhjou, Z; Lukyanchykov, P; Patel, J; McGrath, M; Abdi, R

    2015-01-01

    The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.

  14. Mast cells as regulators of T cell responses

    Directory of Open Access Journals (Sweden)

    Silvia eBulfone-Paus

    2015-08-01

    Full Text Available Mast cells are recognized to participate in the regulation of innate and adaptive immune responses. Owing to their strategic location at the host-environment interface they control tissue homeostasis and are key cells for starting early host defence against intruders. Upon degranulation induced, e.g. by immunoglobulin E (IgE and allergen-mediated engagement of the high-affinity IgE receptor, complement or certain neuropeptide receptors, mast cells release a wide variety of preformed and newly synthesized products including proteases, lipid mediators, and many cytokines, chemokines, and growth factors. Interestingly, increasing evidence suggests a regulatory role for mast cells in inflammatory diseases via the regulation of T cell activities. Furthermore, rather than only serving as effector cells, mast cells are now recognized to induce T cell activation, recruitment, proliferation and cytokine secretion in an antigen-dependent manner and to impact on regulatory T cells. This review synthesizes recent developments in mast cell-T cell interactions, discusses their biological and clinical relevance, and explores recent controversies in this field of mast cell research.

  15. Realisation of all 16 Boolean logic functions in a single magnetoresistance memory cell

    Science.gov (United States)

    Gao, Shuang; Yang, Guang; Cui, Bin; Wang, Shouguo; Zeng, Fei; Song, Cheng; Pan, Feng

    2016-06-01

    Stateful logic circuits based on next-generation nonvolatile memories, such as magnetoresistance random access memory (MRAM), promise to break the long-standing von Neumann bottleneck in state-of-the-art data processing devices. For the successful commercialisation of stateful logic circuits, a critical step is realizing the best use of a single memory cell to perform logic functions. In this work, we propose a method for implementing all 16 Boolean logic functions in a single MRAM cell, namely a magnetoresistance (MR) unit. Based on our experimental results, we conclude that this method is applicable to any MR unit with a double-hump-like hysteresis loop, especially pseudo-spin-valve magnetic tunnel junctions with a high MR ratio. Moreover, after simply reversing the correspondence between voltage signals and output logic values, this method could also be applicable to any MR unit with a double-pit-like hysteresis loop. These results may provide a helpful solution for the final commercialisation of MRAM-based stateful logic circuits in the near future.Stateful logic circuits based on next-generation nonvolatile memories, such as magnetoresistance random access memory (MRAM), promise to break the long-standing von Neumann bottleneck in state-of-the-art data processing devices. For the successful commercialisation of stateful logic circuits, a critical step is realizing the best use of a single memory cell to perform logic functions. In this work, we propose a method for implementing all 16 Boolean logic functions in a single MRAM cell, namely a magnetoresistance (MR) unit. Based on our experimental results, we conclude that this method is applicable to any MR unit with a double-hump-like hysteresis loop, especially pseudo-spin-valve magnetic tunnel junctions with a high MR ratio. Moreover, after simply reversing the correspondence between voltage signals and output logic values, this method could also be applicable to any MR unit with a double-pit-like hysteresis

  16. The Incidental Influence of Memories of Past Eating Occasions on Consumers’ Emotional Responses to Food and Food-Related Behaviors

    Science.gov (United States)

    Piqueras-Fiszman, Betina; Jaeger, Sara R.

    2016-01-01

    Our memories of past eating experiences are influential in shaping food preferences and consumption behavior, and the emotions that people associate to these memories are linked to their attitudes toward foods and their everyday food-related behaviors. This work studies the impact that food-related memories have on peoples’ emotional state and how this state is projected in a subsequent evaluation of images pertaining to food and food-related behaviors. Focus is placed on guilt and shame emotions. Through an online survey, three memories were investigated (a positive meal, a routine evening meal, and an overeating occasion) among UK consumers (N = 710). Participants primed with the overeating memory evaluated images related to junk food as conveying more feelings of guilt and shame than did participants primed with the memory of a positive meal. Moreover, this effect was moderated by participants’ dietary restraint status. Participants classified as having a high dietary restraint had stronger associations with the emotions guilt and shame than participants classified as low in dietary restraint. In contrast, a memory of a positive meal did not lead to positive valuations of any of the food-related images shown. Overall, the findings from the present study illustrate the partial impact that personal food memories have on consumers’ emotional response toward food-related issues, which in turn has the potential to affect future behavior. This study therefore contributes to the literature about cognitive effects on food attitudes and behavior. Furthermore, the results suggest that the empirical approach may be tapping into possibly unconscious emotions toward foods and food-related behavior. PMID:27445911

  17. The Incidental Influence of Memories of Past Eating Occasions on Consumers’ Emotional Responses to Food and Food-Related Behaviors

    Science.gov (United States)

    Piqueras-Fiszman, Betina; Jaeger, Sara R.

    2016-01-01

    Our memories of past eating experiences are influential in shaping food preferences and consumption behavior, and the emotions that people associate to these memories are linked to their attitudes toward foods and their everyday food-related behaviors. This work studies the impact that food-related memories have on peoples’ emotional state and how this state is projected in a subsequent evaluation of images pertaining to food and food-related behaviors. Focus is placed on guilt and shame emotions. Through an online survey, three memories were investigated (a positive meal, a routine evening meal, and an overeating occasion) among UK consumers (N = 710). Participants primed with the overeating memory evaluated images related to junk food as conveying more feelings of guilt and shame than did participants primed with the memory of a positive meal. Moreover, this effect was moderated by participants’ dietary restraint status. Participants classified as having a high dietary restraint had stronger associations with the emotions guilt and shame than participants classified as low in dietary restraint. In contrast, a memory of a positive meal did not lead to positive valuations of any of the food-related images shown. Overall, the findings from the present study illustrate the partial impact that personal food memories have on consumers’ emotional response toward food-related issues, which in turn has the potential to affect future behavior. This study therefore contributes to the literature about cognitive effects on food attitudes and behavior. Furthermore, the results suggest that the empirical approach may be tapping into possibly unconscious emotions toward foods and food-related behavior.

  18. The Incidental Influence of Memories of Past Eating Occasions on Consumers' Emotional Responses to Food and Food-Related Behaviors.

    Science.gov (United States)

    Piqueras-Fiszman, Betina; Jaeger, Sara R

    2016-01-01

    Our memories of past eating experiences are influential in shaping food preferences and consumption behavior, and the emotions that people associate to these memories are linked to their attitudes toward foods and their everyday food-related behaviors. This work studies the impact that food-related memories have on peoples' emotional state and how this state is projected in a subsequent evaluation of images pertaining to food and food-related behaviors. Focus is placed on guilt and shame emotions. Through an online survey, three memories were investigated (a positive meal, a routine evening meal, and an overeating occasion) among UK consumers (N = 710). Participants primed with the overeating memory evaluated images related to junk food as conveying more feelings of guilt and shame than did participants primed with the memory of a positive meal. Moreover, this effect was moderated by participants' dietary restraint status. Participants classified as having a high dietary restraint had stronger associations with the emotions guilt and shame than participants classified as low in dietary restraint. In contrast, a memory of a positive meal did not lead to positive valuations of any of the food-related images shown. Overall, the findings from the present study illustrate the partial impact that personal food memories have on consumers' emotional response toward food-related issues, which in turn has the potential to affect future behavior. This study therefore contributes to the literature about cognitive effects on food attitudes and behavior. Furthermore, the results suggest that the empirical approach may be tapping into possibly unconscious emotions toward foods and food-related behavior. PMID:27445911

  19. CD4+ T-cell priming as biomarker to study immune response to preventive vaccines

    Directory of Open Access Journals (Sweden)

    Annalisa eCiabattini

    2013-12-01

    Full Text Available T-cell priming is a critical event in the initiation of the immune response to vaccination since it deeply influences both the magnitude and the quality of the immune response induced. CD4+ T-cell priming, required for the induction of high-affinity antibodies and immune memory, represents a key target for improving and modulating vaccine immunogenicity. A major challenge in the study of in vivo T-cell priming is due to the low frequency of antigen-specific T cells. This review discusses the current knowledge on antigen-specific CD4+ T-cell priming in the context of vaccination, as well as the most advanced tools for the characterization of the in vivo T-cell priming and the opportunities offered by the application of systems biology.

  20. A model of episodic memory: mental time travel along encoded trajectories using grid cells.

    Science.gov (United States)

    Hasselmo, Michael E

    2009-11-01

    The definition of episodic memory includes the concept of mental time travel: the ability to re-experience a previously experienced trajectory through continuous dimensions of space and time, and to recall specific events or stimuli along this trajectory. Lesions of the hippocampus and entorhinal cortex impair human episodic memory function and impair rat performance in tasks that could be solved by retrieval of trajectories. Recent physiological data suggests a novel model for encoding and retrieval of trajectories, and for associating specific stimuli with specific positions along the trajectory. During encoding in the model, external input drives the activity of head direction cells. Entorhinal grid cells integrate the head direction input to update an internal representation of location, and drive hippocampal place cells. Trajectories are encoded by Hebbian modification of excitatory synaptic connections between hippocampal place cells and head direction cells driven by external action. Associations are also formed between hippocampal cells and sensory stimuli. During retrieval, a sensory input cue activates hippocampal cells that drive head direction activity via previously modified synapses. Persistent spiking of head direction cells maintains the direction and speed of the action, updating the activity of entorhinal grid cells that thereby further update place cell activity. Additional cells, termed arc length cells, provide coding of trajectory segments based on the one-dimensional arc length from the context of prior actions or states, overcoming ambiguity where the overlap of trajectory segments causes multiple head directions to be associated with one place. These mechanisms allow retrieval of complex, self-crossing trajectories as continuous curves through space and time. PMID:19615456

  1. Persistence of T-cell immune response induced by two acellular pertussis vaccines in children five years after primary vaccination.

    Science.gov (United States)

    Palazzo, Raffaella; Carollo, Maria; Bianco, Manuela; Fedele, Giorgio; Schiavoni, Ilaria; Pandolfi, Elisabetta; Villani, Alberto; Tozzi, Alberto E; Mascart, Françoise; Ausiello, Clara M

    2016-01-01

    The resurgence of pertussis suggests the need for greater efforts to understand the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of T memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac® vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa® (Infanrix) (Glaxo-SmithKline Biologicals). We evaluated magnitude and duration of T-cell responses to pertussis toxin (PT) by measuring T-cell proliferation, cytokines (IL-2 and IFNγ) production and memory subsets in two groups of children 5 years after primary vaccination. Some of the enrolled children received only primary vaccination, while others had the pre-school boost dose. Positive T-cell responses to PT were detected in 36% of children. Percentage of responsive children, T-cell proliferation and CD4IL-2+ cells were significantly higher in the children primed with Hexavac than in those who received Infanrix vaccine. No major effects of the boost on PT-specific proliferation were observed. Overall, our data documented a persistence of T-cell memory against PT in a minor fraction of children 5 years after primary vaccination. The different responses induced by Hexavac and Infanrix vaccine could rely on differences in PT inactivation process or excipients/adjuvants formulations.

  2. The human intestinal B-cell response.

    Science.gov (United States)

    Spencer, J; Sollid, L M

    2016-09-01

    The intestinal immune system is chronically challenged by a huge plethora of antigens derived from the lumen. B-cell responses in organized gut-associated lymphoid tissues and regional lymph nodes that are driven chronically by gut antigens generate the largest population of antibody-producing cells in the body: the gut lamina propria plasma cells. Although animal studies have provided insights into mechanisms that underpin this dynamic process, some very fundamental differences in this system appear to exist between species. Importantly, this prevents extrapolation from mice to humans to inform translational research questions. Therefore, in this review we will describe the structures and mechanisms involved in the propagation, dissemination, and regulation of this immense plasma cell population in man. Uniquely, we will seek our evidence exclusively from studies of human cells and tissues. PMID:27461177

  3. Dynamic Memory Cells Using MoS2 Field-Effect Transistors Demonstrating Femtoampere Leakage Currents.

    Science.gov (United States)

    Kshirsagar, Chaitanya U; Xu, Weichao; Su, Yang; Robbins, Matthew C; Kim, Chris H; Koester, Steven J

    2016-09-27

    Two-dimensional semiconductors such as transition-metal dichalcogenides (TMDs) are of tremendous interest for scaled logic and memory applications. One of the most promising TMDs for scaled transistors is molybdenum disulfide (MoS2), and several recent reports have shown excellent performance and scalability for MoS2 MOSFETs. An often overlooked feature of MoS2 is that its wide band gap (1.8 eV in monolayer) and high effective masses should lead to extremely low off-state leakage currents. These features could be extremely important for dynamic memory applications where the refresh rate is the primary factor affecting the power consumption. Theoretical predictions suggest that leakage currents in the 10(-18) to 10(-15) A/μm range could be possible, even in scaled transistor geometries. Here, we demonstrate the operation of one- and two-transistor dynamic memory circuits using MoS2 MOSFETs. We characterize the retention times in these circuits and show that the two-transistor memory cell reveals MoS2 MOSFETs leakage currents as low as 1.7 × 10(-15) A/μm, a value that is below the noise floor of conventional DC measurements. These results have important implications for the future use of MoS2 MOSFETs in low-power circuit applications.

  4. Carving Executive Control at Its Joints: Working Memory Capacity Predicts Stimulus-Stimulus, but Not Stimulus-Response, Conflict

    Science.gov (United States)

    Meier, Matt E.; Kane, Michael J.

    2015-01-01

    Three experiments examined the relation between working memory capacity (WMC) and 2 different forms of cognitive conflict: stimulus-stimulus (S-S) and stimulus-response (S-R) interference. Our goal was to test whether WMC's relation to conflict-task performance is mediated by stimulus-identification processes (captured by S-S conflict),…

  5. Mechanisms of regulating cell topology in proliferating epithelia: impact of division plane, mechanical forces, and cell memory.

    Directory of Open Access Journals (Sweden)

    Yingzi Li

    Full Text Available Regulation of cell growth and cell division has a fundamental role in tissue formation, organ development, and cancer progression. Remarkable similarities in the topological distributions were found in a variety of proliferating epithelia in both animals and plants. At the same time, there are species with significantly varied frequency of hexagonal cells. Moreover, local topology has been shown to be disturbed on the boundary between proliferating and quiescent cells, where cells have fewer sides than natural proliferating epithelia. The mechanisms of regulating these topological changes remain poorly understood. In this study, we use a mechanical model to examine the effects of orientation of division plane, differential proliferation, and mechanical forces on animal epithelial cells. We find that regardless of orientation of division plane, our model can reproduce the commonly observed topological distributions of cells in natural proliferating animal epithelia with the consideration of cell rearrangements. In addition, with different schemes of division plane, we are able to generate different frequency of hexagonal cells, which is consistent with experimental observations. In proliferating cells interfacing quiescent cells, our results show that differential proliferation alone is insufficient to reproduce the local changes in cell topology. Rather, increased tension on the boundary, in conjunction with differential proliferation, can reproduce the observed topological changes. We conclude that both division plane orientation and mechanical forces play important roles in cell topology in animal proliferating epithelia. Moreover, cell memory is also essential for generating specific topological distributions.

  6. Mechanisms of regulating cell topology in proliferating epithelia: impact of division plane, mechanical forces, and cell memory.

    Science.gov (United States)

    Li, Yingzi; Naveed, Hammad; Kachalo, Sema; Xu, Lisa X; Liang, Jie

    2012-01-01

    Regulation of cell growth and cell division has a fundamental role in tissue formation, organ development, and cancer progression. Remarkable similarities in the topological distributions were found in a variety of proliferating epithelia in both animals and plants. At the same time, there are species with significantly varied frequency of hexagonal cells. Moreover, local topology has been shown to be disturbed on the boundary between proliferating and quiescent cells, where cells have fewer sides than natural proliferating epithelia. The mechanisms of regulating these topological changes remain poorly understood. In this study, we use a mechanical model to examine the effects of orientation of division plane, differential proliferation, and mechanical forces on animal epithelial cells. We find that regardless of orientation of division plane, our model can reproduce the commonly observed topological distributions of cells in natural proliferating animal epithelia with the consideration of cell rearrangements. In addition, with different schemes of division plane, we are able to generate different frequency of hexagonal cells, which is consistent with experimental observations. In proliferating cells interfacing quiescent cells, our results show that differential proliferation alone is insufficient to reproduce the local changes in cell topology. Rather, increased tension on the boundary, in conjunction with differential proliferation, can reproduce the observed topological changes. We conclude that both division plane orientation and mechanical forces play important roles in cell topology in animal proliferating epithelia. Moreover, cell memory is also essential for generating specific topological distributions.

  7. Accessing complexity: the dynamics of virus-specific T cell responses

    DEFF Research Database (Denmark)

    Doherty, P C; Christensen, Jan Pravsgaard

    2000-01-01

    The cellular dynamics of the immune system are complex and difficult to measure. Access to this problematic area has been greatly enhanced by the recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) for the direct staining of freshly isolated, antigen......-specific CD8(+ )T cells. Analysis to date with both naturally acquired and experimentally induced infections has established that the numbers of virus-specific CD8(+) T cells present during both the acute and memory phases of the host response are more than tenfold in excess of previously suspected values....... The levels are such that the virus-specific CD8(+) set is readily detected in the human peripheral blood lymphocyte compartment, particularly during persistent infections. Experimentally, it is now possible to measure the extent of cycling for tetramer (+)CD8(+) T cells during the acute and memory...

  8. Atypical radiation response of SCID cells

    Science.gov (United States)

    Chawapun, Nisa

    Murine SCID (severe combined immune deficiency) cells are well known for their defect in DNA double-strand break repair and in variable(diversity)joining [V(D)J] recombination due to a mutation in a catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). As a consequence, scid cells are hypersensitive to ionizing radiation. The present study showed that asynchronous populations of scid cells were about two-fold more sensitive than Balb/c with respect to cell killing and the defect in scid cells was corrected by complementation with human chromosome 8. Analysis of the survival of synchronized populations as a function of the cell cycle revealed that while scid cells were hypersensitive in all cell cycle phases compared to wild-type cells, this hypersensitivity is even more pronounced in G1 phase. The hypersensitivity reduced as the cells progressed into S phase suggested that homologous recombination repair plays a role. The results imply that there are at least two pathways for the repair of DSB DNA, consistent with a model previously proposed by others. The scid cells were also more sensitive to UVC light (254 nm) killing as compared to wild type cells by clonogenic survival. Using a host cell reactivation (HCR) assay to study the nucleotide excision repair (NER) which is the major repair pathway for UV-photoproducts, the results showed that NER in scid cells was not as efficient as CB- 17. This suggests that DNA-PK is involved in NER as well as non-homologous end-joining (NHEJ) DSB repair which is responsible for ionizing radiation sensitivity in scid cells. Repair in scid cells was not totally absent as shown by low dose rate sparing of cell killing after exposure to 137Cs γ-rays at dose rate of 0.6 cGy/h, 1.36 cGy/h, 6 cGy/h as compared to high dose rate at 171 cGy/min, although this phenomenon could be explained partly by proliferation. However, for radiation induced transformation, no significant dose rate effect was seen. A plot of transformation

  9. Basophils Initiate IL-4 Production during a Memory T-dependent Response

    OpenAIRE

    Khodoun, Marat V.; Orekhova, Tatyana; Potter, Crystal; Morris, Suzanne; Finkelman, Fred D.

    2004-01-01

    Experiments were performed to characterize and identify the cellular sources of the secondary interleukin (IL)-4 response to a T cell–dependent antigen. Mice were primed by immunization with goat anti–mouse immunoglobulin (Ig)D antibody (GaMD), which stimulates naive CD4+ T cells to secrete IL-4 in 3–4 d. When challenged with goat serum 14 d after immunization, GaMD-primed mice generated an IL-4 response that exceeded the primary response by ∼100-fold, started in

  10. Single Cell Element of Chalcogenide Random Access Memory Fabricated with the Focused Ion Beam Method

    Institute of Scientific and Technical Information of China (English)

    LIU Bo; SONG Zhi-Tang; FENG Song-Lin; CHEN Bomy

    2004-01-01

    A single cell element of chalcogenide random access memory was fabricated by using the focused ion beam method. The contact size between the Ge2Sb2 Te5 phase change film and the top electrode film is about 600nm (diameter) and the contact area is calculated to be 0.28pm2. The thickness of the phase change film is 83nm.The current-voltage characteristics of the cell element are studied using the home-made current-voltage tester in our laboratory. The minimum threshold current of about 0.6mA is obtained.

  11. Increased B cell and cytotoxic NK cell proportions and increased T cell responsiveness in blood of natalizumab-treated multiple sclerosis patients.

    Directory of Open Access Journals (Sweden)

    Johan Mellergård

    Full Text Available BACKGROUND: Changes in the blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks. METHODS: A broad panel of markers for lymphocyte populations, including states of activation and co-stimulation, as well as functional T cell responses to recall antigens and mitogens, were assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment. RESULTS: Absolute numbers of all major lymphocyte populations increased after treatment, most markedly for NK and B cells. The fraction of both memory and presumed regulatory B cell subsets increased, as did CD3(-CD56(dim cytotoxic NK cells, whereas CD3(-CD56(bright regulatory NK cells decreased. The increase in cell numbers was further associated with a restored T cell responsiveness to recall antigens and mitogens in functional assays. CONCLUSIONS: Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK and B cells. This finding supports reduction of lymphocyte extravasation as a main mode of action, although the differential effects on subpopulation composition suggests that cell-signalling may also be affected. The systemic increase in T cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses may become correspondingly decreased.

  12. Altered distribution of peripheral blood memory B cells in humans chronically infected with Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Esteban R Fernández

    Full Text Available Numerous abnormalities of the peripheral blood T cell compartment have been reported in human chronic Trypanosoma cruzi infection and related to prolonged antigenic stimulation by persisting parasites. Herein, we measured circulating lymphocytes of various phenotypes based on the differential expression of CD19, CD4, CD27, CD10, IgD, IgM, IgG and CD138 in a total of 48 T. cruzi-infected individuals and 24 healthy controls. Infected individuals had decreased frequencies of CD19+CD27+ cells, which positively correlated with the frequencies of CD4+CD27+ cells. The contraction of CD19+CD27+ cells was comprised of IgG+IgD-, IgM+IgD- and isotype switched IgM-IgD- memory B cells, CD19+CD10+CD27+ B cell precursors and terminally differentiated CD19+CD27+CD138+ plasma cells. Conversely, infected individuals had increased proportions of CD19+IgG+CD27-IgD- memory and CD19+IgM+CD27-IgD+ transitional/naïve B cells. These observations prompted us to assess soluble CD27, a molecule generated by the cleavage of membrane-bound CD27 and used to monitor systemic immune activation. Elevated levels of serum soluble CD27 were observed in infected individuals with Chagas cardiomyopathy, indicating its potentiality as an immunological marker for disease progression in endemic areas. In conclusion, our results demonstrate that chronic T. cruzi infection alters the distribution of various peripheral blood B cell subsets, probably related to the CD4+ T cell deregulation process provoked by the parasite in humans.

  13. Altered distribution of peripheral blood memory B cells in humans chronically infected with Trypanosoma cruzi.

    Science.gov (United States)

    Fernández, Esteban R; Olivera, Gabriela C; Quebrada Palacio, Luz P; González, Mariela N; Hernandez-Vasquez, Yolanda; Sirena, Natalia María; Morán, María L; Ledesma Patiño, Oscar S; Postan, Miriam

    2014-01-01

    Numerous abnormalities of the peripheral blood T cell compartment have been reported in human chronic Trypanosoma cruzi infection and related to prolonged antigenic stimulation by persisting parasites. Herein, we measured circulating lymphocytes of various phenotypes based on the differential expression of CD19, CD4, CD27, CD10, IgD, IgM, IgG and CD138 in a total of 48 T. cruzi-infected individuals and 24 healthy controls. Infected individuals had decreased frequencies of CD19+CD27+ cells, which positively correlated with the frequencies of CD4+CD27+ cells. The contraction of CD19+CD27+ cells was comprised of IgG+IgD-, IgM+IgD- and isotype switched IgM-IgD- memory B cells, CD19+CD10+CD27+ B cell precursors and terminally differentiated CD19+CD27+CD138+ plasma cells. Conversely, infected individuals had increased proportions of CD19+IgG+CD27-IgD- memory and CD19+IgM+CD27-IgD+ transitional/naïve B cells. These observations prompted us to assess soluble CD27, a molecule generated by the cleavage of membrane-bound CD27 and used to monitor systemic immune activation. Elevated levels of serum soluble CD27 were observed in infected individuals with Chagas cardiomyopathy, indicating its potentiality as an immunological marker for disease progression in endemic areas. In conclusion, our results demonstrate that chronic T. cruzi infection alters the distribution of various peripheral blood B cell subsets, probably related to the CD4+ T cell deregulation process provoked by the parasite in humans.

  14. Nature of traps responsible for the memory effect in silicon nitride

    Science.gov (United States)

    Gritsenko, V. A.; Perevalov, T. V.; Orlov, O. M.; Krasnikov, G. Ya.

    2016-08-01

    Nature of traps responsible for the memory effect in Si3N4 still remains the subject matter of much discussion. Based on our quantum chemical simulation results, Si-Si bonds can be identified as traps for electrons and holes with localization energies falling within the ranges of Wt e = 1.2 - 1.7 eV and Wt h = 0.9 - 1.4 eV . Within the multiphonon trap ionization model, our experimental data on Si3N4 conductivity have allowed us to evaluate the thermal ionization energies of electron and hole traps in Si3N4 as Wt e = Wt h = 1.4 eV . The same value of 1.4 eV was obtained as half the Stokes shift of the 2.4 eV green photoluminescence line observed in Si3N4 films under excitation with 5.2 eV. Thus, the data obtained in the present study strongly suggest that Si-Si bonds are responsible for localization of electrons and holes in Si3N4.

  15. Induction of Plasmodium falciparum-specific CD4+ T cells and memory B cells in Gabonese children vaccinated with RTS,S/AS01(E and RTS,S/AS02(D.

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    Selidji T Agnandji

    Full Text Available UNLABELLED: The recombinant circumsporozoite protein (CS based vaccine, RTS,S, confers protection against Plasmodium falciparum infection in controlled challenge trials and in field studies. The RTS,S recombinant antigen has been formulated with two adjuvant systems, AS01 and AS02, which have both been shown to induce strong specific antibody responses and CD4 T cell responses in adults. As infants and young children are particularly susceptible to malaria infection and constitute the main target population for a malaria vaccine, we have evaluated the induction of adaptive immune responses in young children living in malaria endemic regions following vaccination with RTS,S/AS01(E and RTS,S/AS02(D. Our data show that a CS-specific memory B cell response is induced one month after the second and third vaccine dose and that CS-specific antibodies and memory B cells persist up to 12 months after the last vaccine injection. Both formulations also induced low but significant amounts of CS-specific IL-2(+ CD4(+ T cells one month after the second and third vaccine dose, upon short-term in vitro stimulation of whole blood cells with peptides covering the entire CS derived sequence in RTS,S. These results provide evidence that both RTS,S/AS01(E and RTS,S/AS02(D induced adaptive immune responses including antibodies, circulating memory B cells and CD4(+ T cells directed against P. falciparum CS protein. TRIAL REGISTRATION: ClinicalTrials.gov NCT00307021.

  16. Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: role of epigenetic adaptation.

    Science.gov (United States)

    Sharples, Adam P; Polydorou, Ioanna; Hughes, David C; Owens, Daniel J; Hughes, Thomas M; Stewart, Claire E

    2016-06-01

    received an early plus late lifespan dose of TNF-α exhibited reduced morphological (myotube number) and biochemical (creatine kinase activity) differentiation vs. control cells that underwent the same number of proliferative divisions but only a later life encounter with TNF-α. This suggested that muscle cells had a morphological memory of the acute early lifespan TNF-α encounter. Importantly, methylation of myoD CpG islands were increased in the early TNF-α cells, 30 population doublings later, suggesting that even after an acute encounter with TNF-α, the cells have the capability of retaining elevated methylation for at least 30 cellular divisions. Despite these fascinating findings, there were no further increases in myoD methylation or changes in its gene expression when these cells were exposed to a later TNF-α dose suggesting that this was not directly responsible for the decline in differentiation observed. In conclusion, data suggest that elevated myoD methylation is retained throughout muscle cells proliferative lifespan as result of early life TNF-α treatment and has implications for the epigenetic control of muscle loss. PMID:26349924

  17. Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: role of epigenetic adaptation.

    Science.gov (United States)

    Sharples, Adam P; Polydorou, Ioanna; Hughes, David C; Owens, Daniel J; Hughes, Thomas M; Stewart, Claire E

    2016-06-01

    received an early plus late lifespan dose of TNF-α exhibited reduced morphological (myotube number) and biochemical (creatine kinase activity) differentiation vs. control cells that underwent the same number of proliferative divisions but only a later life encounter with TNF-α. This suggested that muscle cells had a morphological memory of the acute early lifespan TNF-α encounter. Importantly, methylation of myoD CpG islands were increased in the early TNF-α cells, 30 population doublings later, suggesting that even after an acute encounter with TNF-α, the cells have the capability of retaining elevated methylation for at least 30 cellular divisions. Despite these fascinating findings, there were no further increases in myoD methylation or changes in its gene expression when these cells were exposed to a later TNF-α dose suggesting that this was not directly responsible for the decline in differentiation observed. In conclusion, data suggest that elevated myoD methylation is retained throughout muscle cells proliferative lifespan as result of early life TNF-α treatment and has implications for the epigenetic control of muscle loss.

  18. High Oestradiol Replacement Reverses Response Memory Bias in Ovariectomised Female Rats Regardless of Dopamine Levels in the Dorsal Striatum.

    Science.gov (United States)

    Hussain, D; Cossette, M-P; Brake, W G

    2016-05-01

    Oestrogens influence memory system bias in female rats such that high levels of oestrogen are associated with place (or spatial) memory use, and low oestrogen levels with response (or habitual) memory use. Moreover, striatal-dependent response memory is sensitive to dopamine transmission in the dorsal striatum, and oestrogens have been shown to affect dopamine release in that brain area. In the present study, the effects of oestrogens and dopamine transmission on multiple memory system bias were explored in ovariectomised rats receiving low or high 17β-oestradiol replacement under saline, autoreceptor-activating doses of the dopamine D2 receptor agonist, apomorphine (50 and 80 μg/kg), or amphetamine (0.5 mg/kg) administration. Furthermore, dorsal striatal dopamine release was measured after administration of the same drug conditions using in vivo microdialysis. As expected, high oestradiol rats predominantly used place memory, whereas the opposite pattern was observed in low oestradiol rats. However, the high apomorphine dose statistically significantly altered memory bias in high oestradiol rats from predominant place to predominant response memory, with a similar trend in the low apomorphine dose and the amphetamine group. There was no effect of drugs on memory bias in low oestradiol rats. Rats with high oestradiol replacement receiving amphetamine exhibited greater dorsal striatal dopamine release than low oestradiol replacement rats, and this difference was amplified in the right hemisphere. Furthermore, a logistic regression analysis revealed that oestradiol, but not dorsal striatal dopamine levels, significantly predicted response memory bias. These findings provide further evidence that oestradiol modulates memory system bias, and also that memory bias is changed by systemic apomorphine administration. However, although oestradiol affects dopamine transmission in the dorsal striatum in a lateralised manner, this does not predict memory system bias. PMID

  19. Sizing of SRAM Cell with Voltage Biasing Techniques for Reliability Enhancement of Memory and PUF Functions

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    Chip-Hong Chang

    2016-08-01

    Full Text Available Static Random Access Memory (SRAM has recently been developed into a physical unclonable function (PUF for generating chip-unique signatures for hardware cryptography. The most compelling issue in designing a good SRAM-based PUF (SPUF is that while maximizing the mismatches between the transistors in the cross-coupled inverters improves the quality of the SPUF, this ironically also gives rise to increased memory read/write failures. For this reason, the memory cells of existing SPUFs cannot be reused as storage elements, which increases the overheads of cryptographic system where long signatures and high-density storage are both required. This paper presents a novel design methodology for dual-mode SRAM cell optimization. The design conflicts are resolved by using word-line voltage modulation, dynamic voltage scaling, negative bit-line and adaptive body bias techniques to compensate for reliability degradation due to transistor downsizing. The augmented circuit-level techniques expand the design space to achieve a good solution to fulfill several otherwise contradicting key design qualities for both modes of operation, as evinced by our statistical analysis and simulation results based on complementary metal–oxide–semiconductor (CMOS 45 nm bulk Predictive Technology Model.

  20. miRNA profiling of naive, effector and memory CD8 T cells.

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    Haoquan Wu

    Full Text Available microRNAs have recently emerged as master regulators of gene expression during development and cell differentiation. Although profound changes in gene expression also occur during antigen-induced T cell differentiation, the role of miRNAs in the process is not known. We compared the miRNA expression profiles between antigen-specific naïve, effector and memory CD8+ T cells using 3 different methods--small RNA cloning, miRNA microarray analysis and real-time PCR. Although many miRNAs were expressed in all the T cell subsets, the frequency of 7 miRNAs (miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b and let-7f alone accounted for approximately 60% of all miRNAs, and their expression was several fold higher than the other expressed miRNAs. Global downregulation of miRNAs (including 6/7 dominantly expressed miRNAs was observed in effector T cells compared to naïve cells and the miRNA expression levels tended to come back up in memory T cells. However, a few miRNAs, notably miR-21 were higher in effector and memory T cells compared to naïve T cells. These results suggest that concomitant with profound changes in gene expression, miRNA profile also changes dynamically during T cell differentiation. Sequence analysis of the cloned mature miRNAs revealed an extensive degree of end polymorphism. While 3'end polymorphisms dominated, heterogeneity at both ends, resembling drosha/dicer processing shift was also seen in miR-142, suggesting a possible novel mechanism to generate new miRNA and/or to diversify miRNA target selection. Overall, our results suggest that dynamic changes in the expression of miRNAs may be important for the regulation of gene expression during antigen-induced T cell differentiation. Our study also suggests possible novel mechanisms for miRNA biogenesis and function.

  1. Geometrically pinned magnetic domain wall for multi-bit per cell storage memory

    Science.gov (United States)

    Bahri, M. Al; Sbiaa, R.

    2016-06-01

    Spintronic devices currently rely on magnetic switching or controlled motion of domain walls (DWs) by an external magnetic field or a spin-polarized current. Controlling the position of DW is essential for defining the state/information in a magnetic memory. During the process of nanowire fabrication, creating an off-set of two parts of the device could help to pin DW at a precise position. Micromagnetic simulation conducted on in-plane magnetic anisotropy materials shows the effectiveness of the proposed design for pinning DW at the nanoconstriction region. The critical current for moving DW from one state to the other is strongly dependent on nanoconstricted region (width and length) and the magnetic properties of the material. The DW speed which is essential for fast writing of the data could reach values in the range of hundreds m/s. Furthermore, evidence of multi-bit per cell memory is demonstrated via a magnetic nanowire with more than one constriction.

  2. Zinc-oxide charge trapping memory cell with ultra-thin chromium-oxide trapping layer

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    Nazek El-Atab

    2013-11-01

    Full Text Available A functional zinc-oxide based SONOS memory cell with ultra-thin chromium oxide trapping layer was fabricated. A 5 nm CrO2 layer is deposited between Atomic Layer Deposition (ALD steps. A threshold voltage (Vt shift of 2.6V was achieved with a 10V programming voltage. Also for a 2V Vt shift, the memory with CrO2 layer has a low programming voltage of 7.2V. Moreover, the deep trapping levels in CrO2 layer allows for additional scaling of the tunnel oxide due to an increase in the retention time. In addition, the structure was simulated using Physics Based TCAD. The results of the simulation fit very well with the experimental results providing an understanding of the charge trapping and tunneling physics.

  3. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naïve) and CD45RO+ (memory) subsets in HIV-1-infected subjects.

    Science.gov (United States)

    Veiga, Ana Paula Rocha; Casseb, Jorge; Duarte, Alberto J S

    2006-11-30

    HIV disease leads to defects in cell-mediated immunity, impairing the immune response to new and recall antigens. We studied 55 HIV 1-infected patients who received of recombinant DNA hepatitis B vaccine and 20 controls. The overall hepatitis B virus (HBV) seroconversion rate was 59%. The median CD4+ T cell count among responders was 452 cell/mm(3), higher than non-responders (359 cells/mm(3)). The HIV plasmaviral loads were higher in non-responders. We concluded that total T CD4 cell count, memory T CD4+ cells and lower plasma viral load among HIV-1-infected subjects treated with HAART could be used to predict the immune response to vaccination with hepatitis B vaccine. Thus, considering cost benefits, HVB vaccination should be preferentially provided to HIV-infected patients with T CD4 cells count over 450 cells/mm(3), preferentially whose under HIV replication controlled. PMID:16884833

  4. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies.

    Science.gov (United States)

    Sabatino, Marianna; Hu, Jinhui; Sommariva, Michele; Gautam, Sanjivan; Fellowes, Vicki; Hocker, James D; Dougherty, Sean; Qin, Haiying; Klebanoff, Christopher A; Fry, Terry J; Gress, Ronald E; Kochenderfer, James N; Stroncek, David F; Ji, Yun; Gattinoni, Luca

    2016-07-28

    Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naive precursors. CD8(+)CD62L(+)CD45RA(+) naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions enabled the generation of CD19-CAR-modified CD8(+) TSCM that were phenotypically, functionally, and transcriptomically equivalent to their naturally occurring counterpart. Compared with CD8(+) T cells generated with clinical protocols currently under investigation, CD19-CAR-modified CD8(+) TSCM exhibited enhanced metabolic fitness and mediated robust, long-lasting antitumor responses against systemic acute lymphoblastic leukemia xenografts. This clinical-grade platform provides the basis for a phase 1 trial evaluating the activity of CD19-CAR-modified CD8(+) TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation. PMID:27226436

  5. Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication.

    Science.gov (United States)

    Chaoul, Nada; Fayolle, Catherine; Desrues, Belinda; Oberkampf, Marine; Tang, Alexandre; Ladant, Daniel; Leclerc, Claude

    2015-08-15

    The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell-mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines.

  6. Striatal intrinsic reinforcement signals during recognition memory: relationship to response bias and dysregulation in schizophrenia.

    Science.gov (United States)

    Wolf, Daniel H; Gerraty, Raphaelt; Satterthwaite, Theodore D; Loughead, James; Campellone, Timothy; Elliott, Mark A; Turetsky, Bruce I; Gur, Ruben C; Gur, Raquel E

    2011-01-01

    Ventral striatum (VS) is a critical brain region for reinforcement learning and motivation, and VS hypofunction is implicated in psychiatric disorders including schizophrenia. Providing rewards or performance feedback has been shown to activate VS. Intrinsically motivated subjects performing challenging cognitive tasks are likely to engage reinforcement circuitry even in the absence of external feedback or incentives. However, such intrinsic reinforcement responses have received little attention, have not been examined in relation to behavioral performance, and have not been evaluated for impairment in neuropsychiatric disorders such as schizophrenia. Here we used fMRI to examine a challenging "old" vs. "new" visual recognition task in healthy subjects and patients with schizophrenia. Targets were unique fractal stimuli previously presented as salient distractors in a visual oddball task, producing incidental memory encoding. Based on the prediction error theory of reinforcement learning, we hypothesized that correct target recognition would activate VS in controls, and that this activation would be greater in subjects with lower expectation of responding correctly as indexed by a more conservative response bias. We also predicted these effects would be reduced in patients with schizophrenia. Consistent with these predictions, controls activated VS and other reinforcement processing regions during correct recognition, with greater VS activation in those with a more conservative response bias. Patients did not show either effect, with significant group differences suggesting hyporesponsivity in patients to internally generated feedback. These findings highlight the importance of accounting for intrinsic motivation and reward when studying cognitive tasks, and add to growing evidence of reward circuit dysfunction in schizophrenia that may impact cognition and function.

  7. Striatal intrinsic reinforcement signals during recognition memory: relationship to response bias and dysregulation in schizophrenia

    Directory of Open Access Journals (Sweden)

    Daniel H Wolf

    2011-12-01

    Full Text Available Ventral striatum (VS is a critical brain region for reinforcement learning and motivation, and VS hypofunction is implicated in psychiatric disorders including schizophrenia. Providing rewards or performance feedback has been shown to activate VS. Intrinisically motivated subjects performing challenging cognitive tasks are likely to engage reinforcement circuitry even in the absence of external feedback or incentives. However, such intrinsic reinforcement responses have received little attention, have not been examined in relation to behavioral performance, and have not been evaluated for impairment in neuropsychiatric disorders such as schizophrenia. Here we used fMRI to examine a challenging 'old' vs. 'new' visual recognition task in healthy subjects and patients with schizophrenia. Targets were unique fractal stimuli previously presented as salient distractors in a visual oddball task, producing incidental memory encoding. Based on the prediction error theory of reinforcement learning, we hypothesized that correct target recognition would activate VS in controls, and that this activation would be greater in subjects with lower expectation of responding correctly as indexed by a more conservative response bias. We also predicted these effects would be reduced in patients with schizophrenia. Consistent with these predictions, controls activated VS and other reinforcement processing regions during correct recognition, with greater VS activation in those with a more conservative response bias. Patients did not show either effect, with significant group differences suggesting hyporesponsivity in patients to internally-generated feedback. These findings highlight the importance of accounting for intrinsic motivation and reward when studying cognitive tasks, and add to growing evidence of reward circuit dysfunction in schizophrenia that may impact cognition and function.

  8. Neural stem cell apoptosis after low-methylmercury exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits.

    Science.gov (United States)

    Sokolowski, Katie; Obiorah, Maryann; Robinson, Kelsey; McCandlish, Elizabeth; Buckley, Brian; DiCicco-Bloom, Emanuel

    2013-12-01

    The developing brain is particularly sensitive to exposures to environmental contaminants. In contrast to the adult, the developing brain contains large numbers of dividing neuronal precursors, suggesting that they may be vulnerable targets. The postnatal day 7 (P7) rat hippocampus has populations of both mature neurons in the CA1-3 region as well as neural stem cells (NSC) in the dentate gyrus (DG) hilus, which actively produce new neurons that migrate to the granule cell layer (GCL). Using this well-characterized NSC population, we examined the impact of low levels of methylmercury (MeHg) on proliferation, neurogenesis, and subsequent adolescent learning and memory behavior. Assessing a range of exposures, we found that a single subcutaneous injection of 0.6 µg/g MeHg in P7 rats induced caspase activation in proliferating NSC of the hilus and GCL. This acute NSC death had lasting impact on the DG at P21, reducing cell numbers in the hilus by 22% and the GCL by 27%, as well as reductions in neural precursor proliferation by 25%. In contrast, non-proliferative CA1-3 pyramidal neuron cell number was unchanged. Furthermore, animals exposed to P7 MeHg exhibited an adolescent spatial memory deficit as assessed by Morris water maze. These results suggest that environmentally relevant levels of MeHg exposure may decrease NSC populations and, despite ongoing neurogenesis, the brain may not restore the hippocampal cell deficits, which may contribute to hippocampal-dependent memory deficits during adolescence.

  9. Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy

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    Campbell James J

    2006-07-01

    Full Text Available Abstract Background Circulating memory T cells can be divided into tissue-specific subsets, which traffic through distinct tissue compartments during physiologic immune surveillance, based on their expression of adhesion molecules and chemokine receptors. We reasoned that a bias (either enrichment or depletion of CSF T cell expression of known organ-specific trafficking determinants might suggest that homing of T cells to the subarachnoid space could be governed by a CNS-specific adhesion molecule or chemokine receptor. Results The expression of cutaneous leukocyte antigen (CLA and CC-chemokine receptor 4 (CCR4; associated with skin-homing as well as the expression of integrin α4β7 and CCR9 (associated with gut-homing was analyzed on CD4+ memory T cells in CSF from individuals with non-inflammatory neurological diseases using flow cytometry. CSF contained similar proportions of CD4+ memory T cells expressing CLA, CCR4, integrin α4β7 and CCR9 as paired blood samples. Conclusion The results extend our previous findings that antigen-experienced CD4+ memory T cells traffic through the CSF in proportion to their abundance in the peripheral circulation. Furthermore, the ready access of skin- and gut-homing CD4+ memory T cells to the CNS compartment via CSF has implications for the mechanisms of action of immunotherapeutic strategies, such as oral tolerance or therapeutic immunization, where immunogens are administered using an oral or subcutaneous route.

  10. Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells

    Science.gov (United States)

    Church, Sarah E; Jensen, Shawn M; Antony, Paul A; Restifo, Nicholas P; Fox, Bernard A

    2014-01-01

    Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4+ T cells enhance CD8+ T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4+ transgenic T cells-CD4+ T cells and pmel-CD8+ T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8+ T cells with tumor-specific cytokine expression. When combined with CD4+ T cells, transfer of total (naïve and effector) or effector CD8+ T cells were highly effective, suggesting CD4+ T cells can help mediate therapeutic effects by maintaining function of activated CD8+ T cells. In addition, CD4+ T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8+ T cells recovered from mice treated with both CD8+ and CD4+ T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4+ T cells help reduce CD8+ T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4+ and CD8+ T cells for treatment of patients with cancer. PMID:24114780

  11. Galvanic vestibular stimulation impairs cell proliferation and neurogenesis in the rat hippocampus but not spatial memory.

    Science.gov (United States)

    Zheng, Yiwen; Geddes, Lisa; Sato, Go; Stiles, Lucy; Darlington, Cynthia L; Smith, Paul F

    2014-05-01

    Galvanic vestibular stimulation (GVS) is a method of activating the peripheral vestibular system using direct current that is widely employed in clinical neurological testing. Since movement is recognized to stimulate hippocampal neurogenesis and movement is impossible without activation of the vestibular system, we speculated that activating the vestibular system in rats while minimizing movement, by delivering GVS under anesthesia, would affect hippocampal cell proliferation and neurogenesis, and spatial memory. Compared with the sham control group, the number of cells incorporating the DNA replication marker, bromodeoxyuridine (BrdU), was significantly reduced in the bilateral hippocampi in both the cathode left-anode right and cathode right-anode left stimulation groups (P ≤ 0.0001). The majority of the BrdU(+ve) cells co-expressed Ki-67, a marker for the S phase of the cell cycle, suggesting that these BrdU(+ve) cells were still in the cell cycle; however, there was no significant difference in the degree of co-labeling between the two stimulation groups. Single labeling for doublecortin (DCX), a marker of immature neurons, showed that while there was no significant difference between the different groups in the number of DCX(+ve) cells in the right dentate gryus, in the left dentate gyrus there was a significant decrease in the cathode left-anode right group compared with the sham controls (P ≤ 0.03). Nonetheless, when animals were tested in place recognition, object exploration and Morris water maze tasks, there were no significant differences between the GVS groups and the sham controls. These results suggest that GVS can have striking effects on cell proliferation and possibly neurogenesis in the hippocampus, without affecting spatial memory. PMID:24449222

  12. Galvanic vestibular stimulation impairs cell proliferation and neurogenesis in the rat hippocampus but not spatial memory.

    Science.gov (United States)

    Zheng, Yiwen; Geddes, Lisa; Sato, Go; Stiles, Lucy; Darlington, Cynthia L; Smith, Paul F

    2014-05-01

    Galvanic vestibular stimulation (GVS) is a method of activating the peripheral vestibular system using direct current that is widely employed in clinical neurological testing. Since movement is recognized to stimulate hippocampal neurogenesis and movement is impossible without activation of the vestibular system, we speculated that activating the vestibular system in rats while minimizing movement, by delivering GVS under anesthesia, would affect hippocampal cell proliferation and neurogenesis, and spatial memory. Compared with the sham control group, the number of cells incorporating the DNA replication marker, bromodeoxyuridine (BrdU), was significantly reduced in the bilateral hippocampi in both the cathode left-anode right and cathode right-anode left stimulation groups (P ≤ 0.0001). The majority of the BrdU(+ve) cells co-expressed Ki-67, a marker for the S phase of the cell cycle, suggesting that these BrdU(+ve) cells were still in the cell cycle; however, there was no significant difference in the degree of co-labeling between the two stimulation groups. Single labeling for doublecortin (DCX), a marker of immature neurons, showed that while there was no significant difference between the different groups in the number of DCX(+ve) cells in the right dentate gryus, in the left dentate gyrus there was a significant decrease in the cathode left-anode right group compared with the sham controls (P ≤ 0.03). Nonetheless, when animals were tested in place recognition, object exploration and Morris water maze tasks, there were no significant differences between the GVS groups and the sham controls. These results suggest that GVS can have striking effects on cell proliferation and possibly neurogenesis in the hippocampus, without affecting spatial memory.

  13. Metabolic Responses of Bacterial Cells to Immobilization

    Directory of Open Access Journals (Sweden)

    Joanna Żur

    2016-07-01

    Full Text Available In recent years immobilized cells have commonly been used for various biotechnological applications, e.g., antibiotic production, soil bioremediation, biodegradation and biotransformation of xenobiotics in wastewater treatment plants. Although the literature data on the physiological changes and behaviour of cells in the immobilized state remain fragmentary, it is well documented that in natural settings microorganisms are mainly found in association with surfaces, which results in biofilm formation. Biofilms are characterized by genetic and physiological heterogeneity and the occurrence of altered microenvironments within the matrix. Microbial cells in communities display a variety of metabolic differences as compared to their free-living counterparts. Immobilization of bacteria can occur either as a natural phenomenon or as an artificial process. The majority of changes observed in immobilized cells result from protection provided by the supports. Knowledge about the main physiological responses occurring in immobilized cells may contribute to improving the efficiency of immobilization techniques. This paper reviews the main metabolic changes exhibited by immobilized bacterial cells, including growth rate, biodegradation capabilities, biocatalytic efficiency and plasmid stability.

  14. Metabolic Responses of Bacterial Cells to Immobilization.

    Science.gov (United States)

    Żur, Joanna; Wojcieszyńska, Danuta; Guzik, Urszula

    2016-01-01

    In recent years immobilized cells have commonly been used for various biotechnological applications, e.g., antibiotic production, soil bioremediation, biodegradation and biotransformation of xenobiotics in wastewater treatment plants. Although the literature data on the physiological changes and behaviour of cells in the immobilized state remain fragmentary, it is well documented that in natural settings microorganisms are mainly found in association with surfaces, which results in biofilm formation. Biofilms are characterized by genetic and physiological heterogeneity and the occurrence of altered microenvironments within the matrix. Microbial cells in communities display a variety of metabolic differences as compared to their free-living counterparts. Immobilization of bacteria can occur either as a natural phenomenon or as an artificial process. The majority of changes observed in immobilized cells result from protection provided by the supports. Knowledge about the main physiological responses occurring in immobilized cells may contribute to improving the efficiency of immobilization techniques. This paper reviews the main metabolic changes exhibited by immobilized bacterial cells, including growth rate, biodegradation capabilities, biocatalytic efficiency and plasmid stability. PMID:27455220

  15. Differentiation and Response Bias in Episodic Memory: Evidence from Reaction Time Distributions

    Science.gov (United States)

    Criss, Amy H.

    2010-01-01

    In differentiation models, the processes of encoding and retrieval produce an increase in the distribution of memory strength for targets and a decrease in the distribution of memory strength for foils as the amount of encoding increases. This produces an increase in the hit rate and decrease in the false-alarm rate for a strongly encoded compared…

  16. The Distribution of Subjective Memory Strength: List Strength and Response Bias

    Science.gov (United States)

    Criss, Amy H.

    2009-01-01

    Models of recognition memory assume that memory decisions are based partially on the subjective strength of the test item. Models agree that the subjective strength of targets increases with additional time for encoding however the origin of the subjective strength of foils remains disputed. Under the fixed strength assumption the distribution of…

  17. Zoledronic acid enhances Vδ2 T-lymphocyte antitumor response to human glioma cell lines.

    Science.gov (United States)

    Cimini, E; Piacentini, P; Sacchi, A; Gioia, C; Leone, S; Lauro, G M; Martini, F; Agrati, C

    2011-01-01

    Glioblastoma multiforme (GBM), the most frequent and aggressive primary brain tumor in humans, responds modestly to treatment: most patients survive less than one year after diagnosis, despite both classical and innovative treatment approaches. A recent paper focused on γδ T-cell response in GBM patients, suggesting the application of an immunomodulating strategy based on γδ T-cells which is already in clinical trials for other tumors. Human Vγ2 T-cells recognize changes in the mevalonate metabolic pathway of transformed cells by activating cytotoxic response, and by cytokine and chemokine release. Interestingly, this activation may also be induced in vivo by drugs, such as zoledronic acid, that induce the accumulation of Vγ2 T-cell ligand Isopentenyl-pyrophosphate by blocking the farnesyl pyrophosphate synthase enzyme. The aim of our work is to confirm whether bisphosphonate treatment would make glioma cell lines more susceptible to lysis by in vitro expanded γδ T-cells, improving their antitumor activity. We expanded in vitro human Vγ2 T-cells by phosphoantigen stimulation and tested their activity against glioma cell lines. Co-culture with glioma cells induced Vγ2 T-cell differentiation in effector/memory cells, killing glioma cells by the release of perforin. Interestingly, glioma cells were directly affected by zoledronic acid; moreover, treatment increased their activating ability on Vγ2 T-cells, inducing an effective antitumor cytotoxic response. Taken together, our results show that aminobisphosphonate drugs may play a dual role against GBM, by directly affecting tumor cells, and by enhancing the antitumor response of Vγ2 T-cells. Our results confirm the practicability of this approach as a new immunotherapeutic strategy for GBM treatment.

  18. Improving Response Time of Authorization Process of Credit Card System Using Multi-Threading and Shared-Memory Pool Techniques

    Directory of Open Access Journals (Sweden)

    Siti H.A. Hamid

    2008-01-01

    Full Text Available Current credit card authorization was developed on single-threaded model whereby authentication process takes longer time to respond due to sequential process of card's risk management profile and its limitation of handling huge number of simultaneous transactions at single point of time. As a result, the performance of the authorization system was affected during peak hours. This study presented an architectural framework and prototype of credit card authorization system using multi-threading and shared memory pool techniques in order to improve the response time during authorization process. Through multi-threading technique, each worker thread will be assigned with several child threads to perform online fraud validation concurrently, depending on numbers of cryptographic elements presented in transaction message. Meanwhile, the worker threads itself performed card restriction validation based on the information stored in card's shared memory pool. This approach was implemented to reduce the idle time while waiting for slow cryptographic operation in each I/O operations that is performed through external device and to accelerate the authorization process through memory operation instead of accessing similar information from database. The implementation of these techniques, were then measured in terms of response time. The results showed that the performance of multi-threaded authentication engine was almost double of single-threaded authentication engine and the number of credit card authorization that can be processed using shared memory was ten percent higher than the number of credit card authorization that can be processed using database at single point of time.

  19. The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses

    Directory of Open Access Journals (Sweden)

    Michal Pyzik

    2011-01-01

    Full Text Available Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV. Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses.

  20. Laser Chemosensor with Rapid Responsivity and Inherent Memory Based on a Polymer of Intrinsic Microporosity

    Directory of Open Access Journals (Sweden)

    Graham A. Turnbull

    2011-02-01

    Full Text Available This work explores the use of a polymer of intrinsic microporosity (PIM-1 as the active layer within a laser sensor to detect nitroaromatic-based explosive vapors. We show successful detection of dinitrobenzene (DNB by monitoring the real-time photoluminescence. We also show that PIM-1 has an inherent memory, so that it accumulates the analyte during exposure. In addition, the optical gain and refractive index of the polymer were studied by amplified spontaneous emission and variable-angle ellipsometry, respectively. A second-order distributed feedback PIM-1 laser sensor was fabricated and found to show an increase in laser threshold of 2.5 times and a reduction of the laser slope efficiency by 4.4 times after a 5-min exposure to the DNB vapor. For pumping at 2 times threshold, the lasing action was stopped within 30 s indicating that PIM-1 has a very fast responsivity and as such has a potential sensing ability for ultra-low-concentration explosives.

  1. Memory B cells from older people express normal levels of cyclooxygenase-2 and produce higher levels of IL-6 and IL-10 upon in vitro activation.

    Science.gov (United States)

    Bancos, Simona; Phipps, Richard P

    2010-01-01

    Worldwide the elderly population is increasing. The elderly show deficiencies in immune function. B lymphocytes are essential elements of the immune system responsible for antibody production. This laboratory previously showed that activated human B cells isolated from young adults express cyclooxygenase-2 (Cox-2) and that Cox-2 is essential for optimal antibody responses. Recent data suggests that Cox-2 expression decreases with age in mouse bone tissue. There is no information regarding Cox-2 expression in B cells from older human subjects. We investigated the expression and activity of Cox-2 in naïve and memory B cells from older people. We show that B cells from older subjects show similar Cox-2 protein expression and activity, antibody production and proliferation compared to younger people. However, we found that activated memory B cells from older people produce higher levels of IL-6 and IL-10 compared to young adults. Therefore, the dysregulated cytokine production could contribute to immune senescence in the elderly.

  2. Concept of rewritable organic ferroelectric random access memory in two lateral transistors-in-one cell architecture

    International Nuclear Information System (INIS)

    We propose a concept of rewritable ferroelectric random access memory (RAM) with two lateral organic transistors-in-one cell architecture. Lateral integration of a paraelectric organic field-effect transistor (OFET), being a selection transistor, and a ferroelectric OFET as a memory transistor is realized using a paraelectric depolarizing layer (PDL) which is patterned on a ferroelectric insulator by transfer-printing. For the selection transistor, the key roles of the PDL are to reduce the dipolar strength and the surface roughness of the gate insulator, leading to the low memory on–off ratio and the high switching on–off current ratio. A new driving scheme preventing the crosstalk between adjacent memory cells is also demonstrated for the rewritable operation of the ferroelectric RAM. (paper)

  3. Concept of rewritable organic ferroelectric random access memory in two lateral transistors-in-one cell architecture

    Science.gov (United States)

    Kim, Min-Hoi; Lee, Gyu Jeong; Keum, Chang-Min; Lee, Sin-Doo

    2014-02-01

    We propose a concept of rewritable ferroelectric random access memory (RAM) with two lateral organic transistors-in-one cell architecture. Lateral integration of a paraelectric organic field-effect transistor (OFET), being a selection transistor, and a ferroelectric OFET as a memory transistor is realized using a paraelectric depolarizing layer (PDL) which is patterned on a ferroelectric insulator by transfer-printing. For the selection transistor, the key roles of the PDL are to reduce the dipolar strength and the surface roughness of the gate insulator, leading to the low memory on-off ratio and the high switching on-off current ratio. A new driving scheme preventing the crosstalk between adjacent memory cells is also demonstrated for the rewritable operation of the ferroelectric RAM.

  4. Preserved Intention Maintenance and Impaired Execution of Prospective Memory Responses in Schizophrenia: Evidence from an Event-based Prospective Memory Study.

    Science.gov (United States)

    Demeter, Gyula; Szendi, István; Domján, Nóra; Juhász, Marianna; Greminger, Nóra; Szőllősi, Ágnes; Racsmány, Mihály

    2016-01-01

    Executive system dysfunction and impaired prospective memory (PM) are widely documented in schizophrenia. However, it is not yet clarified which components of PM function are impaired in this disorder. Two plausible target components are the maintenance of delayed intentions and the execution of PM responses. Furthermore, it is debated whether the impaired performance on frequently used executive tasks is associated with deficit in PM functions. The aim of our study was twofold. First, we aimed to investigate the specific processes involved in event-based PM function, mainly focusing on difference between maintenance of intention and execution of PM responses. Second, we aimed to unfold the possible connections between executive functions, clinical symptoms, and PM performance. An event-based PM paradigm was applied with three main conditions: baseline (with no expectation of PM stimuli, and without PM stimuli), expectation condition (participants were told that PM stimuli might occur, though none actually did), and execution condition (participants were told that PM stimuli might occur, and PM stimuli did occur). This procedure allowed us to separately investigate performances associated with intention maintenance and execution of PM responses. We assessed working memory and set-shifting executive functions by memory span tasks and by the Wisconsin Card Sorting Test (WCST), respectively. Twenty patients diagnosed with schizophrenia and 20 healthy control subjects (matched according to age and education) took part in the study. It was hypothesized that patients would manifest different levels of performance in the expectation and execution conditions of the PM task. Our results confirmed that the difference between baseline performance and performance in the execution condition (execution cost) was significantly larger for participants diagnosed with schizophrenia in comparison with matched healthy control group. However, this difference was not observed in the

  5. Preserved intention maintenance and impaired execution of prospective memory responses in schizophrenia: evidence from an event-based prospective memory study

    Directory of Open Access Journals (Sweden)

    Gyula eDemeter

    2016-04-01

    Full Text Available Executive system dysfunction and impaired prospective memory (PM are widely documented in schizophrenia. However, it is not yet clarified which components of PM function are impaired in this disorder. Two plausible target components are the maintenance of delayed intentions and the execution of PM responses. Furthermore, it is debated whether the impaired performance on frequently used executive tasks is associated with deficit in PM functions. The aim of our study was twofold. First, we aimed to investigate the specific processes involved in event-based PM function, mainly focusing on difference between maintenance of intention and execution of PM responses. Second, we aimed to unfold the possible connections between executive functions, clinical symptoms, and PM performance. An event-based PM paradigm was applied with three main conditions: baseline (with no expectation of PM stimuli, and without PM stimuli, expectation condition (participants were told that PM stimuli might occur, though none actually did, and execution condition (participants were told that PM stimuli might occur, and PM stimuli did occur. This procedure allowed us to separately investigate performances associated with intention maintenance and execution of PM responses. We assessed working memory and set-shifting executive functions by memory span tasks and by the Wisconsin Card Sorting Test (WCST, respectively. Twenty patients diagnosed with schizophrenia and 20 healthy control subjects (matched according to age and education took part in the study. It was hypothesized that patients would manifest different levels of performance in the expectation and execution conditions of the PM task. Our results confirmed that the difference between baseline performance and performance in the execution condition (execution cost was significantly larger for participants diagnosed with schizophrenia in comparison with matched healthy control group. However, this difference was not

  6. Role of tantalum nitride as active top electrode in electroforming-free bipolar resistive switching behavior of cerium oxide-based memory cells

    Energy Technology Data Exchange (ETDEWEB)

    Ismail, Muhammad, E-mail: ismailmalikbzu10@gmail.com [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan); Ahmed, Ejaz; Rana, Anwar Manzoor; Talib, Ijaz; Khan, Tahira [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan); Iqbal, Khalid [Department of Radiation Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore (Pakistan); Nadeem, Muhammad Younus [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan)

    2015-05-29

    Electroforming-free cerium oxide-based bipolar resistive switching memory devices have been deposited using radio frequency magnetron sputtering technique. These devices demonstrate two types of forming-free cells: some in the low-resistance state and the others in high-resistance state. The transmission electron microscopy and X-ray diffraction analyses illustrate the formation of tantalum oxynitride layer between tantalum nitride (TaN) and cerium oxide (CeO{sub x}), which looks to be responsible for the two types of cells as well as their memory performance. Ohmic and Poole-Frenkel conduction mechanisms are found to be responsible for charge transport in the low- and high-resistance states. The current-voltage characteristics and temperature dependence of resistance suggest that resistive switching mechanism in our TaN/CeO{sub x}/Pt devices may be explained by the model of connection and disconnection of filamentary paths made of oxygen vacancies. The reliability characteristics of TaN/CeO{sub x}/Pt devices indicate better endurance and stable retention performance at relatively lower programming voltages and larger memory window (OFF/ON resistance ratio ~ 10{sup 3}) at room temperature and at 100 °C. - Highlights: • Electroforming-free TaN/CeO{sub x}/Pt memory cells have been fabricated by sputtering. • Device exhibits good endurance, long data retention and high-resistance window (~ 10{sup 3}). • Voltages for SET and RESET transitions of our device exhibit narrow distribution. • The device is forming-free due to pre-existence of abundant oxygen vacancies. • TaN top electrode play major role in uniformity of resistive switching characteristics.

  7. Role of tantalum nitride as active top electrode in electroforming-free bipolar resistive switching behavior of cerium oxide-based memory cells

    International Nuclear Information System (INIS)

    Electroforming-free cerium oxide-based bipolar resistive switching memory devices have been deposited using radio frequency magnetron sputtering technique. These devices demonstrate two types of forming-free cells: some in the low-resistance state and the others in high-resistance state. The transmission electron microscopy and X-ray diffraction analyses illustrate the formation of tantalum oxynitride layer between tantalum nitride (TaN) and cerium oxide (CeOx), which looks to be responsible for the two types of cells as well as their memory performance. Ohmic and Poole-Frenkel conduction mechanisms are found to be responsible for charge transport in the low- and high-resistance states. The current-voltage characteristics and temperature dependence of resistance suggest that resistive switching mechanism in our TaN/CeOx/Pt devices may be explained by the model of connection and disconnection of filamentary paths made of oxygen vacancies. The reliability characteristics of TaN/CeOx/Pt devices indicate better endurance and stable retention performance at relatively lower programming voltages and larger memory window (OFF/ON resistance ratio ~ 103) at room temperature and at 100 °C. - Highlights: • Electroforming-free TaN/CeOx/Pt memory cells have been fabricated by sputtering. • Device exhibits good endurance, long data retention and high-resistance window (~ 103). • Voltages for SET and RESET transitions of our device exhibit narrow distribution. • The device is forming-free due to pre-existence of abundant oxygen vacancies. • TaN top electrode play major role in uniformity of resistive switching characteristics

  8. Divisions of Identified Parvalbumin-Expressing Basket Cells during Working Memory-Guided Decision Making.

    Science.gov (United States)

    Lagler, Michael; Ozdemir, A Tugrul; Lagoun, Sabria; Malagon-Vina, Hugo; Borhegyi, Zsolt; Hauer, Romana; Jelem, Anna; Klausberger, Thomas

    2016-09-21

    Parvalbumin-expressing basket cells tightly control cortical networks and fire remarkably stereotyped during network oscillations and simple behaviors. How can these cells support multifaceted situations with different behavioral options and complex temporal sequences? We recorded from identified parvalbumin-expressing basket cells in prefrontal cortex of freely moving rats performing a multidimensional delayed cue-matching-to-place task, juxtacellularly filled recorded neurons for unequivocal histological identification, and determined their activity during temporally structured task episodes, associative working-memory, and stimulus-guided choice behavior. We show that parvalbumin-expressing basket cells do not fire homogenously, but individual cells were recruited or inhibited during different task episodes. Firing of individual basket cells was correlated with amount of presynaptic VIP (vasoactive intestinal polypeptide)-expressing GABAergic input. Together with subsets of pyramidal neurons, activity of basket cells differentiated for sequential actions and stimulus-guided choice behavior. Thus, interneurons of the same cell type can be recruited into different neuronal ensembles with distinct firing patterns to support multi-layered cognitive computations. PMID:27593181

  9. Autoreactive effector/memory CD4+ and CD8+ T cells infiltrating grafted and endogenous islets in diabetic NOD mice exhibit similar T cell receptor usage.

    Directory of Open Access Journals (Sweden)

    Ramiro Diz

    Full Text Available Islet transplantation provides a "cure" for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4(+ and CD8(+ T cells. Insight into the T cell receptor (TCR repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4(+ and CD8(+ T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8(+ T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4(+ T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8(+ T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4(+ T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4(+ and CD8(+ T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4(+ and CD8(+ T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.

  10. Multi-bits memory cell using degenerated magnetic states in a synthetic antiferromagnetic reference layer

    Science.gov (United States)

    Fukushima, Akio; Yakushiji, Kay; Konoto, Makoto; Kubota, Hitoshi; Imamura, Hiroshi; Yuasa, Shinji

    2016-02-01

    We newly developed a magnetic memory cell having multi-bit function. The memory cell composed of a perpendicularly magnetized magnetic tunnel junction (MB-pMTJ) and a synthetic antiferromagnetic reference layer. The multi-bit function is realized by combining the freedom of states of the magnetic free layer and that in the antiferromagnetically coupled reference layer. The structure of the reference layer is (FeB/Ta/[Co/Pt]3)/Ru/([Co/Pt]6); the top and the bottom layers are coupled through Ru layer where the reference layer has two degrees of freedom of a head-to-head and a bottom-to-bottom magnetic configuration. A four-state memory cell is realized by combination of both degrees of freedom. The states in the reference layer however is hardly detected by the total resistance of MB-pMTJ, because the magnetoresistance effect in the reference layer is negligibly small. That implies that the resistance values for the different states in the reference layer are degenerated. On the other hand, the two different states in the reference layer bring different stray fields to the free layer, which generate two different minor loop with different switching fields. Therefore, the magnetic states in the reference layer can be differentiated by the two-step reading, before and after applying the appropriately pulsed magnetic field which can identify the initial state in the reference layer. This method is similar to distinguishing different magnetic states in an in-plane magnetized spin-valve element. We demonstrated that four different states in the MB-pMTJ can be distinguished by the two-step read-out. The important feature of the two-step reading is a practically large operation margins (large resistance change in reading) which is equal to that of a single MTJ. Even though the two-step reading is a destructive method by which 50% of the magnetic state is changed, this MB-pMTJ is promising for high density non-volatile memory cell with a minor cost of operation speed.

  11. Memory-enriched CAR-T Cells Immunotherapy for B Cell Lymphoma

    Science.gov (United States)

    2016-04-25

    Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  12. Human T cell responses to Japanese encephalitis virus in health and disease.

    Science.gov (United States)

    Turtle, Lance; Bali, Tanushka; Buxton, Gemma; Chib, Savita; Chan, Sajesh; Soni, Mohammed; Hussain, Mohammed; Isenman, Heather; Fadnis, Prachi; Venkataswamy, Manjunatha M; Satishkumar, Vishali; Lewthwaite, Penny; Kurioka, Ayako; Krishna, Srinivasa; Shankar, M Veera; Ahmed, Riyaz; Begum, Ashia; Ravi, Vasanthapuram; Desai, Anita; Yoksan, Sutee; Fernandez, Stefan; Willberg, Christian B; Kloverpris, Henrik N; Conlon, Christopher; Klenerman, Paul; Satchidanandam, Vijaya; Solomon, Tom

    2016-06-27

    Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus. PMID:27242166

  13. The B-cell response to foot-and-mouth-disease virus in cattle following vaccination and live-virus challenge.

    Science.gov (United States)

    Grant, Clare F J; Carr, B Veronica; Singanallur, Nagendrakumar B; Morris, Jacqueline; Gubbins, Simon; Hudelet, Pascal; Ilott, Martin; Charreyre, Catherine; Vosloo, Wilna; Charleston, Bryan

    2016-09-01

    Antibodies play a pivotal role against viral infection, and maintenance of protection is dependent on plasma and memory B-cells. Understanding antigen-specific B-cell responses in cattle is essential to inform future vaccine design. We have previously defined T-cell-dependent and -independent B-cell responses in cattle, as a prelude to investigating foot-and-mouth-disease-virus (FMDV)-specific B-cell responses. In this study, we have used an FMDV O-serotype vaccination (O1-Manisa or O SKR) and live-virus challenge (FMDV O SKR) to investigate the homologous and heterologous B-cell response in cattle following both vaccination and live-virus challenge. The FMDV O-serotype vaccines were able to induce a cross-reactive plasma-cell response, specific for both O1-Manisa and O SKR, post-vaccination. Post-FMDV O SKR live-virus challenge, the heterologous O1-Manisa vaccination provided cross-protection against O SKR challenge and cross-reactive O SKR-specific plasma cells were induced. However, vaccination and live-virus challenge were not able to induce a detectable FMDV O-serotype-specific memory B-cell response in any of the cattle. The aim of new FMDV vaccines should be to induce memory responses and increased duration of immunity in cattle. PMID:27260141

  14. Altered Memory Capacities and Response to Stress in p300/CBP-Associated Factor (PCAF) Histone Acetylase Knockout Mice

    OpenAIRE

    Maurice, Tangui; Duclot, Florian; Meunier, Johann; Naert, Gaëlle; Givalois, Laurent; Meffre, Julie; Célérier, Aurélie; Jacquet, Chantal; Copois, Virginie; Mechti, Nadir; Ozato, Keiko; Gongora, Céline

    2007-01-01

    International audience Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone...

  15. Flexible conductive-bridging random-access-memory cell vertically stacked with top Ag electrode, PEO, PVK, and bottom Pt electrode

    Science.gov (United States)

    Seung, Hyun-Min; Kwon, Kyoung-Cheol; Lee, Gon-Sub; Park, Jea-Gun

    2014-10-01

    Flexible conductive-bridging random-access-memory (RAM) cells were fabricated with a cross-bar memory cell stacked with a top Ag electrode, conductive polymer (poly(n-vinylcarbazole): PVK), electrolyte (polyethylene oxide: PEO), bottom Pt electrode, and flexible substrate (polyethersulfone: PES), exhibiting the bipolar switching behavior of resistive random access memory (ReRAM). The cell also exhibited bending-fatigue-free nonvolatile memory characteristics: i.e., a set voltage of 1.0 V, a reset voltage of -1.6 V, retention time of >1 × 105 s with a memory margin of 9.2 × 105, program/erase endurance cycles of >102 with a memory margin of 8.4 × 105, and bending-fatigue-free cycles of ˜1 × 103 with a memory margin (Ion/Ioff) of 3.3 × 105.

  16. Altered pattern of Naïve and memory B cells and B1 cells in patients with chronic granulomatous disease.

    Directory of Open Access Journals (Sweden)

    Monireh Mohsenzadegan

    2014-06-01

    Full Text Available Chronic granulomatous disease (CGD is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC to study naïve (IgD+/CD27-, memory (CD27+ B and B1a (CD5+ cells. Soluble CD27 (sCD27 and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27 alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients.

  17. High Inter-Individual Diversity of Point Mutations, Insertions, and Deletions in Human Influenza Virus Nucleoprotein-Specific Memory B Cells.

    Directory of Open Access Journals (Sweden)

    Sven Reiche

    Full Text Available The diversity of virus-specific antibodies and of B cells among different individuals is unknown. Using single-cell cloning of antibody genes, we generated recombinant human monoclonal antibodies from influenza nucleoprotein-specific memory B cells in four adult humans with and without preceding influenza vaccination. We examined the diversity of the antibody repertoires and found that NP-specific B cells used numerous immunoglobulin genes. The heavy chains (HCs originated from 26 and the kappa light chains (LCs from 19 different germ line genes. Matching HC and LC chains gave rise to 43 genetically distinct antibodies that bound influenza NP. The median lengths of the CDR3 of the HC, kappa and lambda LC were 14, 9 and 11 amino acids, respectively. We identified changes at 13.6% of the amino acid positions in the V gene of the antibody heavy chain, at 8.4% in the kappa and at 10.6 % in the lambda V gene. We identified somatic insertions or deletions in 8.1% of the variable genes. We also found several small groups of clonal relatives that were highly diversified. Our findings demonstrate broadly diverse memory B cell repertoires for the influenza nucleoprotein. We found extensive variation within individuals with a high number of point mutations, insertions, and deletions, and extensive clonal diversification. Thus, structurally conserved proteins can elicit broadly diverse and highly mutated B-cell responses.

  18. Suppression of circulating IgD+CD27+ memory B cells in infants living in a malaria-endemic region of Kenya

    Directory of Open Access Journals (Sweden)

    Asito Amolo S

    2011-12-01

    Full Text Available Abstract Background Plasmodium falciparum infection leads to alterations in B cell subset distribution. During infancy, development of peripheral B cell subsets is also occurring. However, it is unknown if infants living a malaria endemic region have alterations in B cell subsets that is independent of an age effect. Methods To evaluate the impact of exposure to P. falciparum on B cell development in infants, flow cytometry was used to analyse the distribution and phenotypic characteristic of B cell subsets in infant cohorts prospectively followed at 12, 18 and 24 months from two geographically proximate regions in western Kenya with divergent malaria exposure i.e. Kisumu (malaria-endemic, n = 24 and Nandi (unstable malaria transmission, n = 21. Results There was significantly higher frequency and absolute cell numbers of CD19+ B cells in Kisumu relative to Nandi at 12(p = 0.0440, 18(p = 0.0210 and 24 months (p = 0.0493. No differences were observed between the infants from the two sites in frequencies of naïve B cells (IgD+CD27- or classical memory B cells (IgD-CD27+. However, immature transitional B cells (CD19+CD10+CD34- were higher in Kisumu relative to Nandi at all three ages. In contrast, the levels of non-class switched memory B cells (CD19+IgD+CD27+ were significantly lower overall in Kisumu relative to Nandi at significantly at 12 (p = 0.0144, 18 (p = 0.0013 and 24 months (p = 0.0129. Conclusions These data suggest that infants living in malaria endemic regions have altered B cell subset distribution. Further studies are needed to understand the functional significance of these changes and long-term impact on ability of these infants to develop antibody responses to P. falciparum and heterologous infections.

  19. Expansion of IgG+ B-cells during mitogen stimulation for memory B-cell ELISpot analysis is influenced by size and composition of the B-cell pool

    NARCIS (Netherlands)

    Scholzen, A.; Nahrendorf, W.; Langhorne, J.; Sauerwein, R.W.

    2014-01-01

    The memory B-cell (MBC) ELISpot assay is the main technique used to measure antigen-specific MBCs as a readout of humoral immune memory. This assay relies on the ability of MBCs to differentiate into antibody-secreting cells (ASC) upon polyclonal stimulation. The total number of IgG+ ASCs generated

  20. Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

    OpenAIRE

    Strange, Bryan A; Gartmann, N.; Brenninkmeyer, Jessica; Haaker, Jan; Reif, Andreas; Kalisch, Raffael; Büchel, Christian

    2014-01-01

    Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -521Cmayor queT DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextuall...

  1. Depletion of CD25+CD4+T cells (Tregs) enhances the HBV-specific CD8+ T cell response primed by DNA immunization

    Institute of Scientific and Technical Information of China (English)

    Yoshihiro Furuichi; Hirotake Tokuyama; Satoshi Ueha; Makoto Kurachi; Fuminori Moriyasu; Kazuhiro Kakimi

    2005-01-01

    AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25+CD4+ regulatory T (Treg) cells might be involved in a inhibition of CD8+T cell priming or in the modulation of the magnitude of the'peak' antiviral CD8+ T cell response primed by DNA immunization. METHODS: B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 μg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25+ cells. Induction of HBV-specific CD8+ T ceils in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-γ staining.RESULTS: DNA immunization induced HBV-specific CD8+ T cells. At the peak T cell response (d 10), 7.1±2.0% of CD8+ T cells were HBV-specific after DNA immunization, whereas 12.7±3.2% of CD8+ T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8+ T cells in the absence of CD25+ Treg cells (n = 6, P<0.05). Similarly, fewer HBVspecific memory T cells were detected in the presence of these cells (1.3±0.4%) in comparison to Treg-depleted mice (2.6±0.9%) on d 30 after DNA immunization (n = 6, P<0.01). Both IFN-γ production and the avidity of the HBV-specific CD8+ T cell response to antigen were higher in HBV-specific CD8+ T cells induced in the absence of Treg cells.CONCLUSION: CD25+ Treg cells suppress priming and/or expansion of antigen-specific CD8+ T cells during DNA immunization and the peak CD8+ T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8+ T ceil response and may affect the quality of memory T cell pools. The elimination of Treg

  2. Alteration of lymphocyte phenotype and function in sickle cell anemia: Implications for vaccine responses.

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    Balandya, Emmanuel; Reynolds, Teri; Obaro, Stephen; Makani, Julie

    2016-09-01

    Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper: CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (Treg ), skewing of CD4+ T cells towards Th2 response and loss of IgM-secreting CD27 + IgM(high) IgD(low) memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C-reactive protein and pro-inflammatory cytokines IL-6 and TNF-α, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub-Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. Am. J. Hematol. 91:938-946, 2016. © 2016 Wiley Periodicals, Inc. PMID:27237467

  3. Age related effects in children taking the computerized assessment of response bias and word memory test.

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    Courtney, John C; Dinkins, Juliet P; Allen, Lyle M; Kuroski, Katherine

    2003-06-01

    The assessment of effort is a fundamental component of test performance analysis, since effort determines whether a psychological evaluation is valid. The assessment of effort in children has proven problematic. This may be related to the variable and inconsistent nature of children's developing self-regulatory systems, and the fact that measures commonly used to assess effort were standardized on adults. If one uses effort measures designed for adults to assess children, then one must presume that the maintenance of effort in children is comparable to the same behavior in adults. However, because children's executive functioning, including their abilities to self-regulate, attend, concentrate, and to engage in various cognitive activities improve with time (Barkley, 1997, pp. 209-234), our hypothesis is that young children's effort regulation is dissimilar to that of adults, and the presumption of similarity is implausible. The purpose of this study was to determine whether age is a significant influence upon young children's performances on the Computerized Assessment of Response Bias (CARB) and Word Memory Test (WMT). Statistical analysis suggests that younger children (those under 10 years of age) tended to produce poorer performance on these instruments. Younger children's scores differed significantly from children ages 10 and older. Children 11 years and older produced CARB and WMT results similar to adult participants, suggesting a viability for adult normative comparisons with children in this age range. The current investigation concluded that children's maintenance of effort appears to be significantly related to age and reading ability level. Consequently, the use of current adult-based norms with the CARB and WMT, without regard for a child's developmental status and other contextual factors such as the child's ability to read, appears ill-advised especially with children under 11 years of age. PMID:12815513

  4. Prime-Boost Vaccination Using Chemokine-Fused gp120 DNA and HIV Envelope Peptides Activates Both Immediate and Long-Term Memory Cellular Responses in Rhesus Macaques

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    Hong Qin

    2010-01-01

    Full Text Available HIV vaccine candidates with improved immunogenicity and induction of mucosal T-cell immunity are needed. A prime-boost strategy using a novel HIV glycoprotein 120 DNA vaccine was employed to immunize rhesus macaques. The DNA vaccine encoded a chimeric gp120 protein in fusion with monocyte chemoattractant protein-3, which was hypothesized to improve the ability of antigen-presenting cells to capture viral antigen through chemokine receptor-mediated endocytosis. DNA vaccination induced virus-reactive T cells in peripheral blood, detectable by T cell proliferation, INFγ ELISPOT and sustained IL-6 production, without humoral responses. With a peptide-cocktail vaccine containing a set of conserved polypeptides of HIV-1 envelope protein, given by nasogastric administration, primed T-cell immunity was significantly boosted. Surprisingly, long-term and peptide-specific mucosal memory T-cell immunity was detected in both vaccinated macaques after one year. Therefore, data from this investigation offer proof-of-principle for potential effectiveness of the prime-boost strategy with a chemokine-fused gp120 DNA and warrant further testing in the nonhuman primate models for developing as a potential HIV vaccine candidate in humans.

  5. Novel Circuitry Configuration with Paired-Cell Erase Operation for High-Density 90-nm Embedded Resistive Random Access Memory

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    Sato, Yoshihiro; Tsunoda, Koji; Aoki, Masaki; Sugiyama, Yoshihiro

    2009-04-01

    We propose a novel circuitry configuration for high-density 90-nm embedded resistive random access memory (ReRAM). The memory cells are operated at 2 V, and a small memory cell size of 6F2 consisting of a 1.2-V standard transistor and a resistive junction (1T-1R) is designed, where F is the feature size. The unique circuitry configuration is that each pair of source-lines connects to each source-line selective gate. Therefore, erasing is done by a pair of cells in turn in the whole sector, while the reading or programming is done by a random accessing operation. We simulated the ReRAM circuit for read and write operations with SPICE. As a result, we found that 5-ns high-speed read access was obtained in the 256-word lines (WLs) × 256-bit lines (BLs) and that the SET/RESET operation was stable.

  6. The impact of B-cell perturbations on pneumococcal conjugate vaccine response in HIV-infected adults.

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    Thomas G Johannesson

    Full Text Available Untreated HIV infection results in severe perturbations of the B-cell population and hyporesponsiveness to vaccination. We studied associations between circulating B-cell subsets and antibody response to pneumococcal conjugate vaccine in treated and untreated HIV patients.Ninety-five HIV-infected adults were grouped according to antiretroviral therapy (ART and CD4+ cell count as follows: 20 ART-naïve (no prior ART, 62 ART-responders (received ART, and CD4 count >500 cells/µl, and 13 impaired responders (received ART for more than 3 years, and CD4 count <500 cells/µl. All subjects were immunized twice with double-dose 7-valent pneumococcal conjugate vaccine with or without 1 mg CPG 7909 (toll-like receptor 9 agonist at baseline and after three months. Pre-vaccination B-cell subpopulations were assessed by flow cytometry. Serum IgG concentrations for vaccine serotypes were quantified by ELISA at baseline and 3, 4, and 9 months post-vaccination. ART responders had more isotype-switched memory B cells and more marginal-zone (MZ-like B cells compared with impaired responders. Furthermore, ART-naïve patients had higher concentration of transitional B cells and plasmablasts compared with B cells of other patient groups. The concentration of MZ-like, isotype switched memory cells and plasmablasts correlated positively with post-vaccination IgG concentration at 3, 4, and 9 months. Low concentrations of isotype-switched memory B cells was the strongest independent predictor of poor pneumococcal conjugate vaccine responsiveness, emphasizing that B-cell subset disturbances are associated with poor vaccine response among HIV-infected patients.

  7. Cell Culture Assay for Human Noroviruses [response

    Energy Technology Data Exchange (ETDEWEB)

    Straub, Tim M.; Honer Zu Bentrup, Kerstin; Orosz Coghlan, Patricia; Dohnalkova, Alice; Mayer, Brooke K.; Bartholomew, Rachel A.; Valdez, Catherine O.; Bruckner-Lea, Cindy J.; Gerba, Charles P.; Abbaszadegan, Morteza A.; Nickerson, Cheryl A.

    2007-07-01

    We appreciate the comments provided by Leung et al., in response to our recently published article “In Vitro Cell Culture Infectivity Assay for Human Noroviruses” by Straub et al. (1). The specific aim of our project was to develop an in vitro cell culture infectivity assay for human noroviruses (hNoV) to enhance risk assessments when they are detected in water supplies. Reverse transcription (RT) qualitative or quantitative PCR are the primary assays for waterborne NoV monitoring. However, these assays cannot distinguish between infectious vs. non-infectious virions. When hNoV is detected in water supplies, information provided by our infectivity assay will significantly improve risk assessment models and protect human health, regardless of whether we are propagating NoV. Indeed, in vitro cell culture infectivity assays for the waterborne pathogen Cryptosporidium parvum that supplement approved fluorescent microscopy assays, do not result in amplification of the environmentally resistant hard-walled oocysts (2). However, identification of life cycle stages in cell culture provides evidence of infectious oocysts in a water supply. Nonetheless, Leung et al.’s assertion regarding the suitability of our method for the in vitro propagation of high titers of NoV is valid for the medical research community. In this case, well-characterized challenge pools of virus would be useful for developing and testing diagnostics, therapeutics, and vaccines. As further validation of our published findings, we have now optimized RT quantitative PCR to assess the level of viral production in cell culture, where we are indeed finding significant increases in viral titer. The magnitude and time course of these increases is dependent on both virus strain and multiplicity of infection. We are currently preparing a manuscript that will discuss these findings in greater detail, and the implications this may have for creating viral challenge pools

  8. Priming and competition of associated memory representations: A comparison between response times and event-related potentials following lesions to left temporal cortex

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    Vitória Piai

    2015-05-01

    These results suggest that associated concepts and words in memory prime each other (as indexed by the N400 effect, but also incur a stronger competition between them (as indicated by the RT effect, delaying response selection.

  9. T- and B-cell responses and previous exposure to hepatitis B virus in 'anti-HBc alone' patients.

    Science.gov (United States)

    Wang, Q; Sachse, P; Semmo, M; Lokhande, M; Montani, M; Dufour, J-F; Zoulim, F; Klenerman, P; Semmo, N

    2015-12-01

    A serologic response to hepatitis B virus (HBV) defined as 'anti-HBc alone' is commonly observed, but its significance remains unclear. This study aimed to define the relationship between 'anti-HBc alone' serostatus and HBV infection, including HBV-specific T- and B-cell memory responses. We enrolled 31 'anti-HBc alone' patients. Total HBV DNA and cccDNA were tested by nested polymerase chain reaction (PCR) analysis in liver samples from 22 'anti-HBc alone' patients vs controls (chronic or resolved HBV infection), followed by HBsAg/HBcAg immunohistochemical (IHC) staining. IFN-γ secretion by HBV-specific T cells was compared in individuals who were 'anti-HBc alone' (n = 27), resolved HBV (n = 21), chronic HBV (n = 24) and 12 healthy controls using enzyme-linked immunospot (ELISpot) assays. An HBsAg-IgG B-cell ELISpot assay was performed in 'anti-HBc alone' patients before and after one dose of recombinant HBsAg vaccine. The majority (23/31, 74.2%) of the 'anti-HBc alone' individuals were co-infected with HCV. Infrequent intrahepatic total HBV DNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV-specific T-cell responses were similar between 'anti-HBc alone' individuals and HBV resolvers. Circulating HBV-memory B-cell responses were detected in all 'anti-HBc alone' individuals, consistent with an HBsAg-specific memory pool. After one HBV vaccine dose, increased anti-HBs antibody levels were observed, accompanied by an expansion of HBsAg-specific memory B cells (P = 0.0226). 'Anti-HBc alone' individuals showed HBV-specific T-cell and memory B-cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection. PMID:26075501

  10. Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naive T cells into cytokine-producing mature T cells.

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    Kenshiro Tsuda

    Full Text Available T cells have been classified as belonging to the Th1 or Th2 subsets according to the production of defining cytokines such as IFN-γ and IL-4. The discovery of the Th17 lineage and regulatory T cells shifted the simple concept of the Th1/Th2 balance into a 4-way mechanistic pathway of local and systemic immunological activity. Clinically, the blockage of cytokine signals or non-specific suppression of cytokine predominance by immunosuppressants is the first-line treatment for inflammatory T cell-mediated disorders. Cyclosporine A (CsA and Tacrolimus (Tac are commonly used immunosuppressants for the treatment of autoimmune disease, psoriasis, and atopic disorders. Many studies have shown that these compounds suppress the activation of the calcium-dependent phosphatase calcineurin, thereby inhibiting T-cell activation. Although CsA and Tac are frequently utilized, their pharmacological mechanisms have not yet been fully elucidated.In the present study, we focused on the effects of CsA and Tac on cytokine secretion from purified human memory CD4(+T cells and the differentiation of naïve T cells into cytokine-producing memory T cells. CsA or Tac significantly inhibited IFN-γ, IL-4, and IL-17 production from memory T cells. These compounds also inhibited T cell differentiation into the Th1, Th2, and Th17 subsets, even when used at a low concentration. This study provided critical information regarding the