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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.

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

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    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-specific memory B-cell responses to enterotoxigenic Escherichia coli infection in Bangladeshi adults.

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    Mohammad Murshid Alam

    2014-04-01

    Full Text Available BACKGROUND: Multiple infections with diverse enterotoxigenic E. coli (ETEC strains lead to broad spectrum protection against ETEC diarrhea. However, the precise mechanism of protection against ETEC infection is still unknown. Therefore, memory B cell responses and affinity maturation of antibodies to the specific ETEC antigens might be important to understand the mechanism of protection. METHODOLOGY: In this study, we investigated the heat labile toxin B subunit (LTB and colonization factor antigens (CFA/I and CS6 specific IgA and IgG memory B cell responses in Bangladeshi adults (n = 52 who were infected with ETEC. We also investigated the avidity of IgA and IgG antibodies that developed after infection to these antigens. PRINCIPAL FINDINGS: Patients infected with ETEC expressing LT or LT+heat stable toxin (ST and CFA/I group or CS6 colonization factors developed LTB, CFA/I or CS6 specific memory B cell responses at day 30 after infection. Similarly, these patients developed high avidity IgA and IgG antibodies to LTB, CFA/I or CS6 at day 7 that remained significantly elevated at day 30 when compared to the avidity of these specific antibodies at the acute stage of infection (day 2. The memory B cell responses, antibody avidity and other immune responses to CFA/I not only developed in patients infected with ETEC expressing CFA/I but also in those infected with ETEC expressing CFA/I cross-reacting epitopes. We also detected a significant positive correlation of LTB, CFA/I and CS6 specific memory B cell responses with the corresponding increase in antibody avidity. CONCLUSION: This study demonstrates that natural infection with ETEC induces memory B cells and high avidity antibodies to LTB and colonization factor CFA/I and CS6 antigens that could mediate anamnestic responses on re-exposure to ETEC and may help in understanding the requirements to design an effective vaccination strategies.

  6. Plasmacytoid DCs regulate recall responses by rapid induction of IL-10 in memory T cells.

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    Kvale, Espen O; Fløisand, Yngvar; Lund-Johansen, Fridtjof; Rollag, Halvor; Farkas, Lorant; Ghanekar, Smita; Brandtzaeg, Per; Jahnsen, Frode L; Olweus, Johanna

    2007-04-15

    Dendritic cells (DCs) are believed to regulate T cell-mediated immunity primarily by directing differentiation of naive T cells. Here, we show that a large fraction of CD4(+) memory cells produce IL-10 within the first hours after interaction with plasmacytoid DCs (PDCs). In contrast, CD11c(+) DCs induce IFN-gamma and little IL-10. IL-10-secreting T cells isolated after 36 hours of culture with PDCs suppressed antigen-induced T-cell proliferation by an IL-10-dependent mechanism, but were distinct from natural and type 1 regulatory T cells. They proliferated strongly and continued to secrete IL-10 during expansion with PDCs, and after restimulation with immature monocyte-derived DCs or CD11c(+) DCs. The IL-10-producing T cells acquired the ability to secrete high levels of IFN-gamma after isolation and subsequent coculture with PDCs or CD11c(+) DCs. Compared to CD11c(+) DCs, PDCs were superior in their ability to selectively expand T cells that produced cytokines on repeated antigenic challenge. The DC-dependent differences in cytokine profiles were observed with viral recall antigen or staphylococcal enterotoxin B and were independent of extracellular type I interferon or IL-10. Our results show that DCs can regulate memory responses and that PDCs rapidly induce regulatory cytokines in effector T cells that can suppress bystander activity.

  7. 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.

  8. 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

    2015-09-16

    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.

  9. Baseline levels of influenza-specific CD4 memory T-cells affect T-cell responses to influenza vaccines.

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    Xiao-Song He

    Full Text Available BACKGROUND: Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens. METHODOLOGY/PRINCIPAL FINDINGS: During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-gamma(+ cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-gamma(+ CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56(dim NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56(dim NK and DC

  10. Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response.

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    Blom, Kim; Braun, Monika; Ivarsson, Martin A; Gonzalez, Veronica D; Falconer, Karolin; Moll, Markus; Ljunggren, Hans-Gustaf; Michaëlsson, Jakob; Sandberg, Johan K

    2013-03-01

    The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2- and HLA-B7-restricted YFV epitope-specific effector cells predominantly displayed a CD45RA(-)CCR7(-)PD-1(+)CD27(high) phenotype, which transitioned into a CD45RA(+)CCR7(-)PD-1(-)CD27(low) memory population phenotype. The functional profile of the YFV-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3(+) T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory.

  11. Control of memory B cell responses by extrinsic and intrinsic mechanisms.

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    Wienands, Jürgen; Engels, Niklas

    2016-10-01

    Following primary activation, B lymphocytes generate a long-lived memory compartment to harness the organism for future reinfections by the same pathogen species. Only recently the composition and signaling signature of the scarce memory B cell pool could be explored in more detail. This review highlights current concepts of how B cells preserve their antigen experience at the cellular and molecular level.

  12. Real Time Multiplicative Memory Amplification Mediated by Whole-Cell Scaling of Synaptic Response in Key Neurons

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    Reuveni, Iris; Ghosh, Sourav; Barkai, Edi

    2017-01-01

    Intense spiking response of a memory-pattern is believed to play a crucial role both in normal learning and pathology, where it can create biased behavior. We recently proposed a novel model for memory amplification where the simultaneous two-fold increase of all excitatory (AMPAR-mediated) and inhibitory (GABAAR-mediated) synapses in a sub-group of cells that constitutes a memory-pattern selectively amplifies this memory. Here we confirm the cellular basis of this model by validating its major predictions in four sets of experiments, and demonstrate its induction via a whole-cell transduction mechanism. Subsequently, using theory and simulations, we show that this whole-cell two-fold increase of all inhibitory and excitatory synapses functions as an instantaneous and multiplicative amplifier of the neurons’ spiking. The amplification mechanism acts through multiplication of the net synaptic current, where it scales both the average and the standard deviation of the current. In the excitation-inhibition balance regime, this scaling creates a linear multiplicative amplifier of the cell’s spiking response. Moreover, the direct scaling of the synaptic input enables the amplification of the spiking response to be synchronized with rapid changes in synaptic input, and to be independent of previous spiking activity. These traits enable instantaneous real-time amplification during brief elevations of excitatory synaptic input. Furthermore, the multiplicative nature of the amplifier ensures that the net effect of the amplification is large mainly when the synaptic input is mostly excitatory. When induced on all cells that comprise a memory-pattern, these whole-cell modifications enable a substantial instantaneous amplification of the memory-pattern when the memory is activated. The amplification mechanism is induced by CaMKII dependent phosphorylation that doubles the conductance of all GABAA and AMPA receptors in a subset of neurons. This whole-cell transduction

  13. 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.

  14. 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.

  15. Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice

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    Contreras, Amanda; Sen, Siddhartha; Tatar, Andrew J.; Mahvi, David A.; Meyers, Justin V.; Srinand, Prakrithi; Suresh, Marulasiddappa

    2016-01-01

    Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy. PMID:27011014

  16. Polyfunctional cytokine responses by central memory CD4*T cells in response to bovine tuberculosis

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    CD4 T cells are crucial in immunity to tuberculosis (TB). Polyfunctional CD4 T cells simultaneously produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) and play relevant roles in several chronic infections, including human TB. Mycobacterium bovis in...

  17. Polyfunctional cytokine responses by central memory CD4+T cells in response to bovine tuberculosis

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    CD4 T cells are crucial in immunity to tuberculosis (TB). Polyfunctional CD4 T cells simultaneously produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) and play relevant roles in several chronic infections, including human TB and HIV. Mycobacterium ...

  18. Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells

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    Kauffman, Robert C.; Bhuiyan, Taufiqur R.; Nakajima, Rie; Mayo-Smith, Leslie M.; Rashu, Rasheduzzaman; Hoq, Mohammad Rubel; Chowdhury, Fahima; Khan, Ashraful Islam; Rahman, Atiqur; Bhaumik, Siddhartha K.; Harris, Levelle; O'Neal, Justin T.; Trost, Jessica F.; Alam, Nur Haq; Jasinskas, Algis; Dotsey, Emmanuel; Kelly, Meagan; Charles, Richelle C.; Xu, Peng; Kováč, Pavol; Calderwood, Stephen B.; Ryan, Edward T.; Felgner, Phillip L.; Qadri, Firdausi

    2016-01-01

    ABSTRACT We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli heat-labile toxin. LPS-specific MAbs uniformly targeted the O-specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera. PMID:27999163

  19. Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells

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    Robert C. Kauffman

    2016-12-01

    Full Text Available We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT or lipopolysaccharide (LPS. Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli heat-labile toxin. LPS-specific MAbs uniformly targeted the O-specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera.

  20. Fast Response, Open-Celled Porous, Shape Memory Effect Actuators with Integrated Attachments

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    Jardine, Andrew Peter (Inventor)

    2015-01-01

    This invention relates to the exploitation of porous foam articles exhibiting the Shape Memory Effect as actuators. Each foam article is composed of a plurality of geometric shapes, such that some geometric shapes can fit snugly into or around rigid mating connectors that attach the Shape Memory foam article intimately into the load path between a static structure and a moveable structure. The foam is open-celled, composed of a plurality of interconnected struts whose mean diameter can vary from approximately 50 to 500 microns. Gases and fluids flowing through the foam transfer heat rapidly with the struts, providing rapid Shape Memory Effect transformations. Embodiments of porous foam articles as torsional actuators and approximately planar structures are disposed. Simple, integral connection systems exploiting the ability to supply large loads to a structure, and that can also supply hot and cold gases and fluids to effect rapid actuation are also disposed.

  1. Specificity and dynamics of effector and memory CD8 T cell responses in human tick-borne encephalitis virus infection.

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    Kim Blom

    2015-01-01

    Full Text Available Tick-borne encephalitis virus (TBEV is transferred to humans by ticks. The virus causes tick-borne encephalitis (TBE with symptoms such as meningitis and meningoencephalitis. About one third of the patients suffer from long-lasting sequelae after clearance of the infection. Studies of the immune response during TBEV-infection are essential to the understanding of host responses to TBEV-infection and for the development of therapeutics. Here, we studied in detail the primary CD8 T cell response to TBEV in patients with acute TBE. Peripheral blood CD8 T cells mounted a considerable response to TBEV-infection as assessed by Ki67 and CD38 co-expression. These activated cells showed a CD45RA-CCR7-CD127- phenotype at day 7 after hospitalization, phenotypically defining them as effector cells. An immunodominant HLA-A2-restricted TBEV epitope was identified and utilized to study the characteristics and temporal dynamics of the antigen-specific response. The functional profile of TBEV-specific CD8 T cells was dominated by variants of mono-functional cells as the effector response matured. Antigen-specific CD8 T cells predominantly displayed a distinct Eomes+Ki67+T-bet+ effector phenotype at the peak of the response, which transitioned to an Eomes-Ki67-T-bet+ phenotype as the infection resolved and memory was established. These transcription factors thus characterize and discriminate stages of the antigen-specific T cell response during acute TBEV-infection. Altogether, CD8 T cells responded strongly to acute TBEV infection and passed through an effector phase, prior to gradual differentiation into memory cells with distinct transcription factor expression-patterns throughout the different phases.

  2. Distinct kinetics of memory B-cell and plasma-cell responses in peripheral blood following a blood-stage Plasmodium chabaudi infection in mice.

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    Eunice W Nduati

    Full Text Available B cell and plasma cell responses take place in lymphoid organs, but because of the inaccessibility of these organs, analyses of human responses are largely performed using peripheral blood mononuclear cells (PBMC. To determine whether PBMC are a useful source of memory B cells and plasma cells in malaria, and whether they reflect Plasmodium-specific B cell responses in spleen or bone marrow, we have investigated these components of the humoral response in PBMC using a model of Plasmodium chabaudi blood-stage infections in C57BL/6 mice. We detected memory B cells, defined as isotype-switched IgD(- IgM(- CD19(+ B cells, and low numbers of Plasmodium chabaudi Merozoite Surface Protein-1 (MSP1-specific memory B cells, in PBMC at all time points sampled for up to 90 days following primary or secondary infection. By contrast, we only detected CD138(+ plasma cells and MSP1-specific antibody-secreting cells within a narrow time frame following primary (days 10 to 25 or secondary (day 10 infection. CD138(+ plasma cells in PBMC at these times expressed CD19, B220 and MHC class II, suggesting that they were not dislodged bone-marrow long-lived plasma cells, but newly differentiated migratory plasmablasts migrating to the bone marrow; thus reflective of an ongoing or developing immune response. Our data indicates that PBMC can be a useful source for malaria-specific memory B cells and plasma cells, but extrapolation of the results to human malaria infections suggests that timing of sampling, particularly for plasma cells, may be critical. Studies should therefore include multiple sampling points, and at times of infection/immunisation when the B-cell phenotypes of interest are likely to be found in peripheral blood.

  3. 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.

  4. 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

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

    Science.gov (United States)

    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

  6. Stress disrupts response memory retrieval.

    Science.gov (United States)

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

    2013-08-01

    Stress effects on memory are well-known. Most studies, however, focused on the impact of stress on hippocampus-dependent 'declarative' memory processes. Less is known about whether stress influences also striatum-based memory processes, such as stimulus-response (S-R) memory. First evidence from rodent experiments shows that glucocorticoid stress hormones may enhance the consolidation of S-R memories. Whether stress affects also S-R memory retrieval remains largely elusive. Therefore, we tested in the present experiment in humans the effect of stress on the retrieval of S-R memories. Healthy men and women were trained to locate three objects in an S-R version of a virtual eight-arm radial maze. One week later, participants underwent a stressor or a control condition before their memory of the S-R task was tested. Our results showed that participants (n=43) who were exposed to the stressor before retention testing made significantly more errors in this test trial, suggesting that stress impaired S-R memory retrieval. Moreover, high cortisol concentrations were associated with reduced S-R memory. These findings indicate that stress may affect memory retrieval processes in humans beyond hippocampal 'declarative' memory.

  7. Triggering DTH and CTL Activity by fd Filamentous Bacteriophages: Role of CD4+ T Cells in Memory Responses

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    Giovanna Del Pozzo

    2010-01-01

    Full Text Available The ability of fd bacteriophage particles to trigger different arms of the immune system has been previously shown by us with particular emphasis on the ability of phages to raise CTL responses in vitro and in vivo. Here we show that fd virions in the absence of adjuvants are able to evoke a DTH reaction mediated by antigen specific CD8+ T cells. In addition, we analyzed the induction of CTL responses in mice depleted of CD4+ T cells, and we observed that short-term secondary CTL responses were induced in the absence of CD4+ T cells while induction of long-term memory CTLs required the presence of CD4+ T lymphocytes. These results examine the cellular mechanism at the basis of fd efficiency and provide new elements to further validate the use of fd particles for eliciting and monitoring antigen-specific CTLs.

  8. Characterization of effector and memory T cell subsets in the immune response to bovine tuberculosis in cattle.

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    Mayara F Maggioli

    Full Text Available Cultured IFN-γ ELISPOT assays are primarily a measure of central memory T cell (Tcm responses with humans; however, this important subset of lymphocytes is poorly characterized in cattle. Vaccine-elicited cultured IFN-γ ELISPOT responses correlate with protection against bovine tuberculosis in cattle. However, whether this assay measures cattle Tcm responses or not is uncertain. The objective of the present study was to characterize the relative contribution of Tcm (CCR7+, CD62Lhi, CD45RO+, T effector memory (Tem, defined as: CCR7-, CD62Llow/int, CD45RO+, and T effector cells (CCR7-, CD62L-/low, CD45RO-, in the immune response to Mycobacterium bovis. Peripheral blood mononuclear cells (PBMC from infected cattle were stimulated with a cocktail of M. bovis purified protein derivative, rTb10.4 and rAg85A for 13 days with periodic addition of fresh media and rIL-2. On day 13, cultured PBMC were re-stimulated with medium alone, rESAT-6:CFP10 or PPDb with fresh autologous adherent cells for antigen presentation. Cultured cells (13 days or fresh PBMCs (ex vivo response from the same calves were analyzed for IFN-γ production, proliferation, and CD4, CD45RO, CD62L, CD44, and CCR7 expression via flow cytometry after overnight stimulation. In response to mycobacterial antigens, ~75% of CD4+ IFN-γ+ cells in long-term cultures expressed a Tcm phenotype while less than 10% of the ex vivo response consisted of Tcm cells. Upon re-exposure to antigen, long-term cultured cells were highly proliferative, a distinctive characteristic of Tcm, and the predominant phenotype within the long-term cultures switched from Tcm to Tem. These findings suggest that proliferative responses of Tcm cells to some extent occurs simultaneously with reversion to effector phenotypes (mostly Tem. The present study characterizes Tcm cells of cattle and their participation in the response to M. bovis infection.

  9. Cross-reactive memory CD8(+) T cells alter the immune response to heterologous secondary dengue virus infections in mice in a sequence-specific manner.

    Science.gov (United States)

    Beaumier, Coreen M; Mathew, Anuja; Bashyam, Hema S; Rothman, Alan L

    2008-02-15

    Dengue virus is the causative agent of dengue fever and the more-severe dengue hemorrhagic fever (DHF). Human studies suggest that the increased risk of DHF during secondary infection is due to immunopathology partially mediated by cross-reactive memory T cells from the primary infection. To model T cell responses to sequential infections, we immunized mice with different sequences of dengue virus serotypes and measured the frequency of peptide-specific T cells after infection. The acute response after heterologous secondary infections was enhanced compared with the acute or memory response after primary infection. Also, the hierarchy of epitope-specific responses was influenced by the specific sequence of infection. Adoptive-transfer experiments showed that memory T cells responded preferentially to the secondary infection. These findings demonstrate that cross-reactive T cells from a primary infection alter the immune response during a heterologous secondary infection.

  10. Antigen-Specific lgA B Memory Cell Responses to Shigella Antigens Elicited in Volunteers Immunized with Live Attenuated Shigella flexneri 2a Oral Vaccine Candidates

    Science.gov (United States)

    2011-01-01

    cell responses to Shigella antigens elicited in volunteers immunized with live attenuated Shigella flexneri 2a oral vaccine candidates J.K. Simona,b... Shigella ;. B cell memory; Immunoglobulin lgA; Mucosal immunity Abstract We studied the induction of antigen-specific lgA memory B cells (BM) in...volunteers who received live attenuated Shigella flexneri 2a vaccines. Subjects ingested a single oral dose of 107 , 108 or 109 CFU of S. flexneri 2a with

  11. HIV-associated memory B cell perturbations.

    Science.gov (United States)

    Hu, Zhiliang; Luo, Zhenwu; Wan, Zhuang; Wu, Hao; Li, Wei; Zhang, Tong; Jiang, Wei

    2015-05-21

    Memory B-cell depletion, hyperimmunoglobulinemia, and impaired vaccine responses are the hallmark of B cell perturbations inhuman immunodeficiency virus (HIV) disease. Although B cells are not the targets for HIV infection, there is evidence for B cell, especially memory B cell dysfunction in HIV disease mediated by other cells or HIV itself. This review will focus on HIV-associated phenotypic and functional alterations in memory B cells. Additionally, we will discuss the mechanism underlying these perturbations and the effect of anti-retroviral therapy (ART) on these perturbations.

  12. The initial draining lymph node primes the bulk of the CD8 T cell response and influences memory T cell trafficking after a systemic viral infection.

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    Matthew R Olson

    Full Text Available Lymphocytic choriomeningitis virus (LCMV causes a systemic infection in mice with virus replication occurring in both peripheral tissues and secondary lymphoid organs. Because of the rapid systemic dissemination of the virus, the secondary lymphoid organs responsible for the induction of the LCMV-specific CD8 T cell response are poorly defined. We show that the mediastinal lymph node (MedLN serves as the primary draining lymph node following LCMV infection. In addition, we demonstrate that the MedLN is responsible for priming the majority of the virus-specific CD8 T cell response. Following resolution of the acute infection, the draining MedLN exhibits characteristics of a reactive lymph node including an increased presence of germinal center B cells and increased cellularity for up to 60 days post-infection. Furthermore, the reactive MedLN harbors an increased frequency of CD62L(- effector memory CD8 T cells as compared to the non-draining lymph nodes. The accumulation of LCMV-specific CD62L(- memory CD8 T cells in the MedLN is independent of residual antigen and is not a unique feature of the MedLN as footpad infection with LCMV leads to a similar increase of virus-specific CD62L(- effector memory CD8 T cells in the draining popliteal lymph node. Our results indicate that CD62L(- effector memory CD8 T cells are granted preferential access into the draining lymph nodes for an extended time following resolution of an infection.

  13. Trypanosomiasis-Induced B Cell Apoptosis Results in Loss of Protective Anti-Parasite Antibody Responses and Abolishment of Vaccine-Induced Memory Responses

    Science.gov (United States)

    Radwanska, Magdalena; Guirnalda, Patrick; De Trez, Carl; Ryffel, Bernard; Black, Samuel; Magez, Stefan

    2008-01-01

    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. PMID:18516300

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

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    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.

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

    Science.gov (United States)

    Radwanska, Magdalena; Guirnalda, Patrick; De Trez, Carl; Ryffel, Bernard; Black, Samuel; Magez, Stefan

    2008-05-30

    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.

  16. 10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV) induces memory B cell responses in healthy Kenyan toddlers.

    Science.gov (United States)

    Muema, D M; Nduati, E W; Uyoga, M; Bashraheil, M; Scott, J A G; Hammitt, L L; Urban, B C

    2015-08-01

    Memory B cells are long-lived and could contribute to persistence of humoral immunity by maintaining the plasma-cell pool or making recall responses upon re-exposure to an antigen. We determined the ability of a pneumococcal conjugate vaccine to induce anti-pneumococcal memory B cells. Frequencies of memory B cells against pneumococcal capsular polysaccharides from serotypes 1, 6B, 14, 19F and 23F were determined by cultured B cell enzyme-linked immunospot (ELISPOT) in 35 children aged 12-23 months who received pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV). The relationships between plasma antibodies and memory B cell frequencies were also assessed. After two doses of PHiD-CV, the proportion of subjects with detectable memory B cells against pneumococcal capsular polysaccharides increased significantly for serotypes 1 (3-45%; P < 0·01), 19F (21-66%; P < 0·01) and 23F (13-36%; P = 0·02), but not serotypes 6B (24-42%; P = 0·24) and 14 (21-40%; P = 0·06). Correlations between antibodies and memory B cells were weak. Carriage of serotype 19F at enrolment was associated with poor memory B cell responses against this serotype at subsequent time-points (day 30: non-carriers, 82% versus carriers, 0%, P < 0·01; day 210: non-carriers, 72% versus carriers, 33%, P = 0·07). PHiD-CV is capable of inducing memory B cells against some of the component pneumococcal capsular polysaccharides.

  17. NK cells require antigen-specific memory CD4+ T cells to mediate superior effector functions during HSV-2 recall responses in vitro.

    Science.gov (United States)

    Chen, Branson; Lee, Amanda J; Chew, Marianne V; Ashkar, Ali A

    2016-12-14

    Natural killer (NK) cells have an important role in mounting protective innate responses against genital herpes simplex virus type 2 (HSV-2) infections. However their role as effectors in adaptive immune responses against HSV-2 is unclear. Here, we demonstrate that NK cells from C57BL/6 mice in an ex vivo splenocyte culture produce significantly more interferon γ (IFN-γ) upon re-exposure to HSV-2 antigens in a mouse model of genital HSV-2 immunization. We find that naïve NK cells do not require any prior stimulation or priming to be activated to produce IFN-γ. Our results demonstrate that HSV-2-experienced CD4(+) T cells have a crucial role in coordinating NK cell activation and that their presence during HSV-2 antigen presentation is required to activate NK cells in this model of secondary immune response. We also examined the requirement of cell-to-cell contacts for both CD4(+) T cells and NK cells. NK cells are dependent on direct interactions with other HSV-2-experienced splenocytes, and CD4(+) T cells need to be in close proximity to NK cells to activate them. This study revealed that NK cells do not exhibit any memory toward HSV-2 antigens and, in fact, require specific interactions with HSV-2-experienced CD4(+) T cells to produce IFN-γ.

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

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    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.

  19. Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15.

    Science.gov (United States)

    Herndler-Brandstetter, Dietmar; Brunner, Stefan; Weiskopf, Daniela; van Rijn, Ruth; Landgraf, Katja; Dejaco, Christian; Duftner, Christina; Schirmer, Michael; Kloss, Frank; Gassner, Robert; Lepperdinger, Günter; Grubeck-Loebenstein, Beatrix

    2011-08-01

    Immunologic memory is a critical feature of the adaptive immune system to fight recurrent infections. However, the mechanisms that shape the composition and function of the human memory T-cell pool remain incompletely understood. We here demonstrate that post-thymic human T-cell differentiation was associated with the downregulation, but not loss, of the inhibitory molecule CD5. The sensitivity of human CD8(+) and CD4(+) memory T cells to interleukin (IL)-15 was inversely associated with the level of CD5 expression. CD5 expression was downregulated by IL-15-mediated signaling in vitro and CD5(lo) memory T cells accumulated in the bone marrow. Persistent antigenic stimulation, as in the case of cytomegalovirus infection and rheumatoid arthritis (RA), was also associated with an increased number of CD5(lo) memory T cells. In conclusion, CD5 may be a useful marker to identify memory T-cell subsets with distinct responsiveness to the homeostatic cytokine IL-15.

  20. Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

    Science.gov (United States)

    Pensieroso, Simone; Cagigi, Alberto; Palma, Paolo; Nilsson, Anna; Capponi, Claudia; Freda, Elio; Bernardi, Stefania; Thorstensson, Rigmor; Chiodi, Francesca; Rossi, Paolo

    2009-01-01

    HIV-1 infection induces a progressive disruption of the B cell compartment impairing long-term immune responses to routine immunizations. Depletion of specific memory B cell pools occurs during the 1st stages of the infection and cannot be reestablished by antiretroviral treatment. We reasoned that an early control of viral replication through treatment could preserve the normal development of the memory B cell compartment and responses to routine childhood vaccines. Accordingly, we evaluated the effects of different highly-active antiretroviral therapy (HAART) schedules in 70 HIV-1 vertically-infected pediatric subjects by B cell phenotypic analyses, antigen-specific B cell enzyme-linked immunosorbent spot (ELISpot) and ELISA for common vaccination and HIV-1 antigens. Initiation of HAART within the 1st year of life permits the normal development and maintenance of the memory B cell compartment. On the contrary, memory B cells from patients treated later in time are remarkably reduced and their function is compromised regardless of viral control. A cause for concern is that both late-treated HIV-1 controllers and noncontrollers loose protective antibody titers against common vaccination antigens. Timing of HAART initiation is the major factor predicting the longevity of B cell responses in vaccinated HIV-1-infected children. PMID:19416836

  1. Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells

    OpenAIRE

    Kauffman, Robert C.; Bhuiyan, Taufiqur R.; Nakajima, Rie; Mayo-Smith, Leslie M.; Rashu, Rasheduzzaman; Hoq, Mohammad Rubel; Chowdhury, Fahima; Khan, Ashraful Islam; Rahman, Atiqur; Bhaumik, Siddhartha K.; Harris, Levelle; O'Neal, Justin T.; Trost, Jessica F.; Alam, Nur Haq; Jasinskas, Algis

    2016-01-01

    ABSTRACT We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able...

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

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    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.

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

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    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

  4. Cross-reactive memory CD4+ T cells alter the CD8+ T-cell response to heterologous secondary dengue virus infections in mice in a sequence-specific manner.

    Science.gov (United States)

    Beaumier, Coreen M; Rothman, Alan L

    2009-06-01

    Secondary dengue virus (DENV) infection is a major factor contributing to the risk for severe disease, an effect that depends upon the sequence of infection with different DENV serotypes. We previously reported sequence-dependent effects of secondary DENV infection on CD8+ T-cell responses in mice. To further evaluate the effect of infection sequence, we analyzed DENV-specific CD4+ T-cell responses and their relationship to the CD8+ T-cell response. Serotype cross-reactivity of CD4+ T-cell responses also depended upon the sequence of serotypes in this model. Furthermore, adoptive transfer of memory CD4+ T cells altered the response of memory CD8+ T cells to secondary infection. These data demonstrate the interaction of different components of the T-cell response in determining the immunological outcome of secondary DENV infection.

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

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    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.

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

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    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.

  7. Ex vivo cytokine and memory T cell responses to the 42-kDa fragment of Plasmodium falciparum merozoite surface protein-1 in vaccinated volunteers.

    Science.gov (United States)

    Huaman, Maria Cecilia; Martin, Laura B; Malkin, Elissa; Narum, David L; Miller, Louis H; Mahanty, Siddhartha; Long, Carole A

    2008-02-01

    A number of blood-stage malaria Ags are under development as vaccine candidates, but knowledge of the cellular responses to these vaccines in humans is limited. We evaluated the nature and specificity of cellular responses in healthy American volunteers vaccinated with a portion of the major merozoite surface protein-1 (MSP1) of Plasmodium falciparum, MSP1(42), formulated on Alhydrogel. Volunteers were vaccinated three times with 80 microg of either MSP1(42)-FVO/Alhydrogel or MSP1(42)-3D7/Alhydrogel. Cells collected 2 wk after the third vaccination produced Th1 cytokines, including IFN-gamma and IL-2 following Ag stimulation, and greater levels of the Th2 cytokines IL-5 and IL-13; the anti-inflammatory cytokine IL-10 and the molecule CD25 (IL-2Ralpha) were also detected. The volunteers were evaluated for the MSP1(42)-FVO or MSP1(42)-3D7 specificity of their T cell responses. Comparison of their responses to homologous and heterologous Ags showed ex vivo IFN-gamma and IL-5 levels that were significantly higher to homologous rather than to heterologous Ags. The epitopes involved in this stimulation were shown to be present in the dimorphic MSP1(33) portion of the larger MSP1(42)-3D7 polypeptide, and indirect experiment suggests the same for the MSP1(42)-FVO polypeptide. This contrasts with B cell responses, which were primarily directed to the conserved MSP1(19) portion. Furthermore, we explored the maturation of memory T cells and found that 46% of vaccinees showed specific memory T cells defined as CD4(+)CD45RO(+)CD40L(+) after long-term in vitro culture. The identification of human-specific CD4(+) memory T cells provides the foundation for future studies of these cells both after vaccination and in field studies.

  8. 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.

  9. Distinct T helper cell dependence of memory B-cell proliferation versus plasma cell differentiation.

    Science.gov (United States)

    Zabel, Franziska; Fettelschoss, Antonia; Vogel, Monique; Johansen, Pål; Kündig, Thomas M; Bachmann, Martin F

    2017-03-01

    Several memory B-cell subclasses with distinct functions have been described, of which the most effective is the class-switched (CS) memory B-cell population. We have previously shown, using virus-like particles (VLPs), that the proliferative potential of these CS memory B cells is limited and they fail to re-enter germinal centres (GCs). However, VLP-specific memory B cells quickly differentiated into secondary plasma cells (PCs) with the virtue of elevated antibody production compared with primary PCs. Whereas the induction of VLP(+) memory B cells was strongly dependent on T helper cells, we were wondering whether re-stimulation of VLP(+) memory B cells and their differentiation into secondary PCs would also require T helper cells. Global absence of T helper cells led to strongly impaired memory B cell proliferation and PC differentiation. In contrast, lack of interleukin-21 receptor-dependent follicular T helper cells or CD40 ligand signalling strongly affected proliferation of memory B cells, but differentiation into mature secondary PCs exhibiting increased antibody production was essentially normal. This contrasts with primary B-cell responses, where a strong dependence on CD40 ligand but limited importance of interleukin-21 receptor was seen. Hence, T helper cell dependence differs between primary and secondary B-cell responses as well as between memory B-cell proliferation and PC differentiation.

  10. 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.

  11. 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.

  12. 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

    Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge in ...

  13. Characterization of functional antibody and memory B-cell responses to pH1N1 monovalent vaccine in HIV-infected children and youth.

    Directory of Open Access Journals (Sweden)

    Donna J Curtis

    Full Text Available We investigated immune determinants of antibody responses and B-cell memory to pH1N1 vaccine in HIV-infected children.Ninety subjects 4 to <25 years of age received two double doses of pH1N1 vaccine. Serum and cells were frozen at baseline, after each vaccination, and at 28 weeks post-immunization. Hemagglutination inhibition (HAI titers, avidity indices (AI, B-cell subsets, and pH1N1 IgG and IgA antigen secreting cells (ASC were measured at baseline and after each vaccination. Neutralizing antibodies and pH1N1-specific Th1, Th2 and Tfh cytokines were measured at baseline and post-dose 1.At entry, 26 (29% subjects had pH1N1 protective HAI titers (≥1:40. pH1N1-specific HAI, neutralizing titers, AI, IgG ASC, IL-2 and IL-4 increased in response to vaccination (p<0.05, but IgA ASC, IL-5, IL-13, IL-21, IFNγ and B-cell subsets did not change. Subjects with baseline HAI ≥1:40 had significantly greater increases in IgG ASC and AI after immunization compared with those with HAI <1:40. Neutralizing titers and AI after vaccination increased with older age. High pH1N1 HAI responses were associated with increased IgG ASC, IFNγ, IL-2, microneutralizion titers, and AI. Microneutralization titers after vaccination increased with high IgG ASC and IL-2 responses. IgG ASC also increased with high IFNγ responses. CD4% and viral load did not predict the immune responses post-vaccination, but the B-cell distribution did. Notably, vaccine immunogenicity increased with high CD19+CD21+CD27+% resting memory, high CD19+CD10+CD27+% immature activated, low CD19+CD21-CD27-CD20-% tissue-like, low CD19+CD21-CD27-CD20-% transitional and low CD19+CD38+HLADR+% activated B-cell subsets.HIV-infected children on HAART mount a broad B-cell memory response to pH1N1 vaccine, which was higher for subjects with baseline HAI≥1:40 and increased with age, presumably due to prior exposure to pH1N1 or to other influenza vaccination/infection. The response to the vaccine was dependent

  14. The breadth, but not the magnitude, of circulating memory B cell responses to P. falciparum increases with age/exposure in an area of low transmission.

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    Sarah I Nogaro

    Full Text Available BACKGROUND: Malaria caused by Plasmodium falciparum remains a major cause of death in sub-Saharan Africa. Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly immunogenic or that the development of effective immune responses to malaria may be impaired. METHODS: We carried out two age-stratified cross-sectional surveys of anti-malarial humoral immune responses in a Gambian village where P. falciparum malaria transmission is low and sporadic. Circulating antibodies and memory B cells (MBC to four malarial antigens were measured using ELISA and cultured B cell ELISpot. FINDINGS AND CONCLUSIONS: The proportion of individuals with malaria-specific MBC and antibodies, and the average number of antigens recognised by each individual, increased with age but the magnitude of these responses did not. Malaria-specific antibody levels did not correlate with either the prevalence or median number of MBC, indicating that these two assays are measuring different aspects of the humoral immune response. Among those with immunological evidence of malaria exposure (defined as a positive response to at least one malarial antigen either by ELISA or ELISPOT, the median number of malaria-specific MBC was similar to median numbers of diphtheria-specific MBC, suggesting that the circulating memory cell pool for malaria antigens is of similar size to that for other antigens.

  15. Hippocampal place cells, context, and episodic memory.

    Science.gov (United States)

    Smith, David M; Mizumori, Sheri J Y

    2006-01-01

    Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which

  16. 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...

  17. Molecular programming of B cell memory.

    Science.gov (United States)

    McHeyzer-Williams, Michael; Okitsu, Shinji; Wang, Nathaniel; McHeyzer-Williams, Louise

    2011-12-09

    The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information - resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes - has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.

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

    Science.gov (United States)

    Steffensen, Maria Abildgaard; Jensen, Benjamin Anderschou Holbech; Holst, Peter Johannes; Bassi, Maria Rosaria; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

    2012-01-01

    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.

  19. 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.

  20. Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants.

    Science.gov (United States)

    Garcia-Knight, Miguel A; Nduati, Eunice; Hassan, Amin S; Gambo, Faith; Odera, Dennis; Etyang, Timothy J; Hajj, Nassim J; Berkley, James Alexander; Urban, Britta C; Rowland-Jones, Sarah L

    2015-01-01

    Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy

  1. Maintenance of HIV-Specific Memory B-Cell Responses in Elite Controllers Despite Low Viral Burdens.

    Science.gov (United States)

    Buckner, Clarisa M; Kardava, Lela; Zhang, Xiaozhen; Gittens, Kathleen; Justement, J Shawn; Kovacs, Colin; McDermott, Adrian B; Li, Yuxing; Sajadi, Mohammad M; Chun, Tae-Wook; Fauci, Anthony S; Moir, Susan

    2016-08-01

    Human immunodeficiency virus (HIV)-specific B-cell responses in infected individuals are maintained by active HIV replication. Suppression of viremia by antiretroviral therapy (ART) leads to quantitative and qualitative changes that remain unclear. Accordingly, B-cell responses were investigated in elite controllers (ECs), who maintain undetectable HIV levels without ART, and in individuals whose viremia was suppressed by ART. Despite a higher HIV burden in the ART group, compared with the EC group, frequencies of HIV-specific B cells were higher in the EC group, compared with those in the ART group. However, the initiation of ART in several ECs was associated with reduced frequencies of HIV-specific B cells, suggesting that responses are at least in part sustained by HIV replication. Furthermore, B-cell responses to tetanus toxin but not influenza hemagglutinin in the ART group were lower than those in the EC group. Thus, the superior HIV-specific humoral response in ECs versus ART-treated individuals is likely due to a more intact humoral immune response in ECs and/or distinct responses to residual HIV replication.

  2. Polyfunctional cytokine production by central memory T cells from cattle in response to Mycobacterium bovis infection and BCG vaccination

    Science.gov (United States)

    Polyfunctional T cells simultaneously produce IFN-gamma, IL-2 and TNF-alpha and play relevant roles in several chronic infections, including TB. Mycobacterium bovis infection of cattle elicits ex vivo polyfunctional T cell responses. Vaccine-elicited IFN-gamma Tcm (CD4 plus CD45RO plus CCR7 plus) re...

  3. 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.

  4. Selecting B cells and plasma cells to memory

    OpenAIRE

    2005-01-01

    Humoral immunity appears to be based on immunological memory provided by memory plasma cells, which secrete protective antibodies, and memory B cells, which react to antigen challenge by differentiating into plasma cells. How these differentiation pathways relate to each other, how cells are selected into these memory populations, and how these populations are maintained remains enigmatic.

  5. Reduction of Ca2+-transporting systems in memory T cells.

    Science.gov (United States)

    Sigova, A A; Dedkova, E N; Zinchenko, V P; Litvinov, I S

    2000-01-01

    Antigen-specific B and T lymphocytes make up the material grounds of immune memory, their main functional distinction from the so-called "naive" cells is due to the rapid and enhanced response to the antigen-pathogen. An essential distinction between the memory and naive T cells is different sensitivity of these two subpopulations of T lymphocytes to Ca2+-ionophores. Comparative analysis of Ca2+ responses of the immune memory T lymphocytes and naive T cells of mouse CBA/J line to the addition of Ca2+-mobilizing agents concanavalin A, thapsigargin, and ionomycin was carried out. These compounds in concentrations increasing [Ca2+]i in naive cells had no effect on [Ca2+]i in memory cells. Thus, the Ca2+ entrance into memory cells was not activated by exhaustion of intracellular resources. Estimation of intracellular resources of Ca2+, mobilized by ionomycin and thapsigargin in Ca2+ free medium has shown the absence in memory T cells of the intracellular Ca2+ pool, which may be one of factors of their resistance to ionophores. Reduction of the system of Ca2+ influx into memory T cells was shown using the SH-reagent thimerosal. Memory T cells appear to be resistant to "Ca2+ -paradox." Their incubation with 0.5 mM EDTA in the presence or absence of Ca2+ -mobilizing compounds followed by addition of 2 mM CaCl2 did not result in induction of Ca2+ influx into these cells.

  6. Increased TNF-alpha/IFN-gamma/IL-2 and decreased TNF-alpha/IFN-gamma production by central memory T cells are associated with protective responses against bovine tuberculosis following BCG vaccination

    Directory of Open Access Journals (Sweden)

    Mayara Fernanda Maggioli

    2016-10-01

    Full Text Available Central memory T cells (Tcm and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB; however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector / memory populations from bacille Calmette Guerin (BCG vaccinated and non-vaccinated calves prior to and after aerosol challenge with virulent Mycobacterium bovis. Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and M. bovis-infected calves; only differing in magnitude (i.e., infected > vaccinated. BCG vaccination, however, did alter the kinetics of the ensuing response to virulent M. bovis infection. Early after challenge (three weeks post-infection, non-vaccinates had greater antigen-specific IFN-γ/TNF-α and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains were detected in memory subsets, as well as in effector cells, as early as three weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB.

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

    Science.gov (United States)

    García-Arriaza, Juan; Nájera, José Luis; Gómez, Carmen E; Tewabe, Nolawit; Sorzano, Carlos Oscar S; Calandra, Thierry; Roger, Thierry; Esteban, Mariano

    2011-01-01

    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.

  8. Memory B cells in mouse models.

    Science.gov (United States)

    Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mårtensson, I-L

    2013-08-01

    One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases.

  9. Antigen-specific memory B cell development.

    Science.gov (United States)

    McHeyzer-Williams, Louise J; McHeyzer-Williams, Michael G

    2005-01-01

    Helper T (Th) cell-regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cell-B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.

  10. 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.

  11. 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.

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

    Science.gov (United States)

    Steinberg, Marcos W; Huang, Yujun; Wang-Zhu, Yiran; Ware, Carl F; Cheroutre, Hilde; Kronenberg, Mitchell

    2013-01-01

    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.

  13. BTLA Interaction with HVEM Expressed on CD8+ T Cells Promotes Survival and Memory Generation in Response to a Bacterial Infection

    Science.gov (United States)

    Wang-Zhu, Yiran; Ware, Carl F.; Cheroutre, Hilde; Kronenberg, Mitchell

    2013-01-01

    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. PMID:24205057

  14. 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.

  15. The Role of Costimulatory Molecules in the Development of Memory and Effector T Helper 2 Cells During an in vivo Immune Response to the Murine Gastrointestinal Parasite Heligmosomoides polygyrus

    Science.gov (United States)

    2007-11-02

    not well understood. One model used to study the Th immune response involves oral infection of mice with the gastrointestinal nematode parasite...the development of the Th2 response to the gastrointestinal nematode parasite Heligmosomoides polygyrus.” Discussion...4-producing effector and memory Th2 cells following priming with the murine gastrointestinal nematode parasite H. polygyrus. Previous studies

  16. Increased TNF-alpha/IFN-gamma/IL-2 and decreased TNF-alpha/IFN-gamma production by central memory T cells are associated with protective responses against bovine tuberculosis following BCG vaccination

    Science.gov (United States)

    Central memory T cells (Tcm’s) and polyfunctional CD4 T responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by ...

  17. Restoration of CD4+ Responses to Copathogens in HIV-Infected Individuals on Antiretroviral Therapy Is Dependent on T Cell Memory Phenotype.

    Science.gov (United States)

    Riou, Catherine; Tanko, Ramla F; Soares, Andreia P; Masson, Lindi; Werner, Lise; Garrett, Nigel J; Samsunder, Natasha; Abdool Karim, Quarraisha; Abdool Karim, Salim S; Burgers, Wendy A

    2015-09-01

    Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4(+) T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4(+) T cells specific for common copathogens is still unclear. To better understand the dynamics of Ag-specific CD4(+) T cells during ART, we assessed the frequency, functional capacity, and memory profile of CD4(+) T cells specific for Mycobacterium tuberculosis and CMV in 15 HIV-infected individuals before and 1 y after ART initiation. After ART initiation, the frequency of M. tuberculosis-specific CD4(+) T cells showed little change, whereas CMV-specific CD4(+) T cells were significantly lower (p = 0.003). There was no difference in the polyfunctional or memory profile of Ag-specific CD4(+) T cells before and after ART. The replenishment of Ag-specific CD4(+) T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4(+) T cells exhibiting a late differentiated profile (CD45RO(+)CD27(-)) had a lower capacity to replenish (p = 0.019; r = -0.5) compared with cells with an early differentiated profile (CD45RO(+)CD27(+); p = 0.04; r = 0.45). In conclusion, restoration of copathogen-specific memory CD4(+) T cells during treated HIV infection is related to their memory phenotype, in which early differentiated cells (such as most M. tuberculosis-specific cells) have a higher replenishment capacity compared with late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of copathogen immunity in HIV-infected individuals on ART.

  18. Memory T-Cell-Mediated Immune Responses Specific to an Alternative Core Protein in Hepatitis C Virus Infection

    Science.gov (United States)

    Bain, Christine; Parroche, Peggy; Lavergne, Jean Pierre; Duverger, Blandine; Vieux, Claude; Dubois, Valérie; Komurian-Pradel, Florence; Trépo, Christian; Gebuhrer, Lucette; Paranhos-Baccala, Glaucia; Penin, François; Inchauspé, Geneviève

    2004-01-01

    In vitro studies have described the synthesis of an alternative reading frame form of the hepatitis C virus (HCV) core protein that was named F protein or ARFP (alternative reading frame protein) and includes a domain coded by the +1 open reading frame of the RNA core coding region. The expression of this protein in HCV-infected patients remains controversial. We have analyzed peripheral blood from 47 chronically or previously HCV-infected patients for the presence of T lymphocytes and antibodies specific to the ARFP. Anti-ARFP antibodies were detected in 41.6% of the patients infected with various HCV genotypes. Using a specific ARFP 99-amino-acid polypeptide as well as four ARFP predicted class I-restricted 9-mer peptides, we show that 20% of the patients display specific lymphocytes capable of producing gamma interferon, interleukin-10, or both cytokines. Patients harboring three different viral genotypes (1a, 1b, and 3) carried T lymphocytes reactive to genotype 1b-derived peptides. In longitudinal analysis of patients receiving therapy, both core and ARFP-specific T-cell- and B-cell-mediated responses were documented. The magnitude and kinetics of the HCV antigen-specific responses differed and were not linked with viremia or therapy outcome. These observations provide strong and new arguments in favor of the synthesis, during natural HCV infection, of an ARFP derived from the core sequence. Moreover, the present data provide the first demonstration of the presence of T-cell-mediated immune responses directed to this novel HCV antigen. PMID:15367612

  19. 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

  20. Molecular Programming of Immunological Memory in Natural Killer Cells.

    Science.gov (United States)

    Beaulieu, Aimee M; Madera, Sharline; Sun, Joseph C

    2015-01-01

    Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells have traditionally been classified as a component of the innate immune system, they have recently been shown in mice and humans to exhibit certain features of immunological memory, including an ability to undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e. memory cells), and mediate recall responses against previously encountered pathogens--all characteristics previously ascribed only to adaptive immune responses by B and T cells in mammals. To date, the molecular events that govern the generation of NK cell memory are not completely understood. Using a mouse model of cytomegalovirus infection, we demonstrate that individual pro-inflammatory IL-12, IL-18, and type I-IFN signaling pathways are indispensible and play non-redundant roles in the generation of virus-specific NK cell memory. Furthermore, we discovered that antigen-specific proliferation and protection by NK cells is mediated by the transcription factor Zbtb32, which is induced by pro-inflammatory cytokines and promotes a cell cycle program in activated NK cells. A greater understanding of the molecular mechanisms controlling NK cell responses will provide novel strategies for tailoring vaccines to target infectious disease.

  1. Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4⁺ T cell responses.

    Directory of Open Access Journals (Sweden)

    Hlumani Ndlovu

    2014-02-01

    Full Text Available IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28⁻/⁻ mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28(-/loxCre⁺/⁻+TM to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28⁻/⁻ mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28(-/loxCre⁺/⁻ mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28⁻/⁻ mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5⁺ T(FH cell population. Furthermore, total number of CD4⁺ T cells and B220⁺ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28⁻/⁻ mice and tamoxifen treated CD28(-/loxCre⁺/⁻ mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4⁺ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28(-/loxCre⁺/⁻ mice. Therefore, it can be concluded that CD28

  2. Pregnancy persistently affects memory T cell populations.

    Science.gov (United States)

    Kieffer, Tom E C; Faas, Marijke M; Scherjon, Sicco A; Prins, Jelmer R

    2017-02-01

    Pregnancy is an immune challenge to the maternal immune system. The effects of pregnancy on maternal immunity and particularly on memory T cells during and after pregnancy are not fully known. This observational study aims to show the short term and the long term effects of pregnancy on the constitution, size and activation status of peripheral human memory T-lymphocyte populations. Effector memory (EM) and central memory (CM) T-lymphocytes were analyzed using flow cytometry of peripheral blood from 14 nulligravid, 12 primigravid and 15 parous women that were on average 18 months postpartum. The short term effects were shown by the significantly higher CD4+ EM cell and activated CD4+ memory cell proportions in primigravid women compared to nulligravid women. The persistent effects found in this study were the significantly higher proportions of CD4+ EM, CD4+ CM and activated memory T cells in parous women compared to nulligravid women. In contrast to CD4+ cells, activation status of CD8+ memory cells did not differ between the groups. This study shows that pregnancy persistently affects the pre-pregnancy CD4+ memory cell pool in human peripheral blood. During pregnancy, CD4+ T-lymphocytes might differentiate into EM cells followed by persistent higher proportions of CD4+ CM and EM cells postpartum. The persistent effects of pregnancy on memory T cells found in this study support the hypothesis that memory T cells are generated during pregnancy and that these cells could be involved in the lower complication risks in multiparous pregnancies in humans.

  3. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy.

    Science.gov (United States)

    Reyes-Avilés, Elane; Kostadinova, Lenche; Rusterholtz, Anne; Cruz-Lebrón, Angelica; Falck-Ytter, Yngve; Anthony, Donald D

    2015-01-01

    Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.

  4. SONOS Nonvolatile Memory Cell Programming Characteristics

    Science.gov (United States)

    MacLeod, Todd C.; Phillips, Thomas A.; Ho, Fat D.

    2010-01-01

    Silicon-oxide-nitride-oxide-silicon (SONOS) nonvolatile memory is gaining favor over conventional EEPROM FLASH memory technology. This paper characterizes the SONOS write operation using a nonquasi-static MOSFET model. This includes floating gate charge and voltage characteristics as well as tunneling current, voltage threshold and drain current characterization. The characterization of the SONOS memory cell predicted by the model closely agrees with experimental data obtained from actual SONOS memory cells. The tunnel current, drain current, threshold voltage and read drain current all closely agreed with empirical data.

  5. Modeling of SONOS Memory Cell Erase Cycle

    Science.gov (United States)

    Phillips, Thomas A.; MacLeod, Todd C.; Ho, Fat H.

    2011-01-01

    Utilization of Silicon-Oxide-Nitride-Oxide-Silicon (SONOS) nonvolatile semiconductor memories as a flash memory has many advantages. These electrically erasable programmable read-only memories (EEPROMs) utilize low programming voltages, have a high erase/write cycle lifetime, are radiation hardened, and are compatible with high-density scaled CMOS for low power, portable electronics. In this paper, the SONOS memory cell erase cycle was investigated using a nonquasi-static (NQS) MOSFET model. Comparisons were made between the model predictions and experimental data.

  6. 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.

  7. PD-1 blockade expands intratumoral T memory cells

    Science.gov (United States)

    Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse; Frederiksen, Juliet; Cornish, Andrew; Avramis, Earl; Seja, Elizabeth; Kivork, Christine; Siebert, Janet; Kaplan-Lefko, Paula; Wang, Xiaoyan; Chmielowski, Bartosz; Glaspy, John A.; Tumeh, Paul C.; Chodon, Thinle; Pe’er, Dana; Comin-Anduix, Begoña

    2016-01-01

    Tumor responses to 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 multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells (moMDSCs) significantly increased in patients’ biopsies taken on treatment. The percentage of cells with a T regulatory phenotype, monocytes, and NK cells did not change while on PD-1 blockade therapy. CD8+ T memory cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4+ T effector memory cells significantly decreased on treatment, whereas CD4+ T effector cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 were detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and MDSCs in tumors, with the CD8+ T effector memory subset being the major T-cell phenotype expanded in patients with a response to therapy. PMID:26787823

  8. Transcription factor ABF-1 suppresses plasma cell differentiation but facilitates memory B cell formation.

    Science.gov (United States)

    Chiu, Yi-Kai; Lin, I-Ying; Su, Shin-Tang; Wang, Kuan-Hsiung; Yang, Shii-Yi; Tsai, Dong-Yan; Hsieh, Yi-Ting; Lin, Kuo-I

    2014-09-01

    Ag-primed B cells that result from an immune response can form either memory B cells or Ab-secreting plasma cells; however, the molecular machinery that controls this cellular fate is poorly understood. In this study, we show that activated B cell factor-1 (ABF-1), which encodes a basic helix-loop-helix transcriptional repressor, participates in this regulation. ABF-1 was prevalently expressed in purified memory B cells and induced by T follicular helper cell-mediated signals. ABF-1 expression declined by the direct repression of B lymphocyte-induced maturation protein-1 during differentiation. Ectopic expression of ABF-1 reduced the formation of Ab-secreting cells in an in vitro differentiation system of human memory B cells. Accordingly, knockdown of ABF-1 potentiates the formation of Ab-secreting cells. A transgenic mouse that expresses inducible ABF-1 in a B cell-specific manner was generated to demonstrate that the formation of germinal center and memory B cells was augmented by induced ABF-1 in an immune response, whereas the Ag-specific plasma cell response was dampened. This effect was associated with the ability of ABF-1 to limit cell proliferation. Together, our results demonstrate that ABF-1 facilitates formation of memory B cells but prevents plasma cell differentiation.

  9. 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.

  10. The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response

    Science.gov (United States)

    The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE+ cells in memory responses is particularly unclear. IgE B cell differentiation is characterized by a transient GC phase, a bias towards the plasma cell (PC) fate,...

  11. Viral particles drive rapid differentiation of memory B cells into secondary plasma cells producing increased levels of antibodies.

    Science.gov (United States)

    Zabel, Franziska; Mohanan, Deepa; Bessa, Juliana; Link, Alexander; Fettelschoss, Antonia; Saudan, Philippe; Kündig, Thomas M; Bachmann, Martin F

    2014-06-15

    Extensive studies have been undertaken to describe naive B cells differentiating into memory B cells at a cellular and molecular level. However, relatively little is known about the fate of memory B cells upon Ag re-encounter. We have previously established a system based on virus-like particles (VLPs), which allows tracking of VLP-specific B cells by flow cytometry as well as histology. Using allotype markers, it is possible to adoptively transfer memory B cells into a naive mouse and track responses of naive and memory B cells in the same mouse under physiological conditions. We have observed that VLP-specific memory B cells quickly differentiated into plasma cells that drove the early onset of a strong humoral IgG response. However, neither IgM(+) nor IgG(+) memory B cells proliferated extensively or entered germinal centers. Remarkably, plasma cells derived from memory B cells preferentially homed to the bone marrow earlier and secreted increased levels of Abs when compared with primary plasma cells derived from naive B cells. Hence, memory B cells have the unique phenotype to differentiate into highly effective secondary plasma cells.

  12. 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.

  13. 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

    is followed by sustained expansion of the memory CD8 T-cell population, and the generated memory cells do not appear to have been driven towards exhaustive differentiation. Based on these findings, we suggest that adenovirus based prime-boost regimens (including Ad5 and Ad5-like vectors) represent...... 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...... leads to the generation of a population of memory cells characterized by relatively low CD27 expression and high CD127 and KLRG1 expression. These memory CD8 T cells are capable of proliferating in response to viral challenge, and protect against infection with live virus. Furthermore, viral challenge...

  14. 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.

  15. IgE responses in mouse and man and the persistence of IgE memory.

    Science.gov (United States)

    Gould, Hannah J; Ramadani, Faruk

    2015-01-01

    Rapid and robust recall or 'memory' responses are an essential feature of adaptive immunity. They constitute a defense against reinfection by pathogens, yet arguably do more harm than good in allergic disease. Immunoglobulin (Ig)E antibodies mediate the allergic reaction characterized by immediate hypersensitivity, a manifestation of IgE memory. The origin of IgE memory remains obscure, mainly due to the low proportion of IgE-expressing B cells in the total B cell population. The recent development of ultrasensitive methods for tracking these cells in vivo has overcome this obstacle, and their use has revealed unexpected pathways to IgE memory in the mouse. Here, we review these findings and consider their bearing on our understanding of IgE memory and allergic disease in man.

  16. 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.

  17. 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...

  18. Epigenetic memory for stress response and adaptation in plants.

    Science.gov (United States)

    Kinoshita, Tetsu; Seki, Motoaki

    2014-11-01

    In contrast to the majority of animal species, plants are sessile organisms and are, therefore, constantly challenged by environmental perturbations. Over the past few decades, our knowledge of how plants perceive environmental stimuli has increased considerably, e.g. the mechanisms for transducing environmental stress stimuli into cellular signaling cascades and gene transcription networks. In addition, it has recently been shown that plants can remember past environmental events and can use these memories to aid responses when these events recur. In this mini review, we focus on recent progress in determination of the epigenetic mechanisms used by plants under various environmental stresses. Epigenetic mechanisms are now known to play a vital role in the control of gene expression through small RNAs, histone modifications and DNA methylation. These are inherited through mitotic cell divisions and, in some cases, can be transmitted to the next generation. They therefore offer a possible mechanism for stress memories in plants. Recent studies have yielded evidence indicating that epigenetic mechanisms are indeed essential for stress memories and adaptation in plants.

  19. Cellular Dynamics of Memory B Cell Populations: IgM+ and IgG+ Memory B Cells Persist Indefinitely as Quiescent Cells.

    Science.gov (United States)

    Jones, Derek D; Wilmore, Joel R; Allman, David

    2015-11-15

    Despite their critical role in long-term immunity, the life span of individual memory B cells remains poorly defined. Using a tetracycline-regulated pulse-chase system, we measured population turnover rates and individual t1/2 of pre-established Ag-induced Ig class-switched and IgM-positive memory B cells over 402 d. Our results indicate that, once established, both IgG-positive and less frequent IgM-positive memory populations are exceptionally stable, with little evidence of attrition or cellular turnover. Indeed, the vast majority of cells in both pools exhibited t1/2 that appear to exceed the life span of the mouse, contrasting dramatically with mature naive B cells. These results indicate that recall Ab responses are mediated by stable pools of extremely long-lived cells, and suggest that Ag-experienced B cells employ remarkably efficient survival mechanisms.

  20. Cellular dynamics of memory B cell populations: IgM+ and IgG+ memory B cells persist indefinitely as quiescent cells1

    Science.gov (United States)

    Jones, Derek D.; Wilmore, Joel R.; Allman, David

    2015-01-01

    Despite their critical role in long-term immunity, the lifespan of individual memory B cells remains poorly defined. Using a tetracycline-regulated pulse-chase system, we measured population turnover rates and individual half-lives of pre-established antigen-induced immunoglobulin (Ig) class-switched and IgM-positive memory B cells over 402 days. Our results indicate that, once established, both IgG-positive and less frequent IgM-positive memory populations are exceptionally stable, with little evidence of attrition or cellular turnover. Indeed, the vast majority of cells in both pools exhibited half-lives that appear to exceed the lifespan of the mouse, contrasting dramatically with mature naïve B cells. These results indicate that recall antibody responses are mediated by stable pools of extremely long-lived cells, and suggest that antigen-experienced B cells employ remarkably efficient survival mechanisms. PMID:26438523

  1. 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.

  2. Antigen experience shapes phenotype and function of memory Th1 cells.

    Directory of Open Access Journals (Sweden)

    Aaruni Khanolkar

    Full Text Available Primary and secondary (boosted memory CD8 T cells exhibit differences in gene expression, phenotype and function. The impact of repeated antigen stimulations on memory CD4 T cells is largely unknown. To address this issue, we utilized LCMV and Listeria monocytogenes infection of mice to characterize primary and secondary antigen (Ag-specific Th1 CD4 T cell responses. Ag-specific primary memory CD4 T cells display a CD62L(loCCR7(hi CD27(hi CD127(hi phenotype and are polyfunctional (most produce IFNγ, TNFα and IL-2. Following homologous prime-boost immunization we observed pathogen-specific differences in the rate of CD62L and CCR7 upregulation on memory CD4 T cells as well as in IL-2+IFNγco-production by secondary effectors. Phenotypic and functional plasticity of memory Th1 cells was observed following heterologous prime-boost immunization, wherein secondary memory CD4 T cells acquired phenotypic and functional characteristics dictated by the boosting agent rather than the primary immunizing agent. Our data also demonstrate that secondary memory Th1 cells accelerated neutralizing Ab formation in response to LCMV infection, suggesting enhanced capacity of this population to provide quality help for antibody production. Collectively these data have important implications for prime-boost vaccination strategies that seek to enhance protective immune responses mediated by Th1 CD4 T cell responses.

  3. Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8(+) T cells

    DEFF Research Database (Denmark)

    Schmidt, Jonas D; Ahlström, Malin G; Johansen, Jeanne D;

    2016-01-01

    BACKGROUND: Skin-resident memory T (TRM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore......, the mechanisms whereby TRM cells induce rapid recall responses need further investigation. OBJECTIVES: To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin. METHODS: To address these questions, we analysed responses......, long-lasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN-γ-producing CD8(+) TRM cells....

  4. Pro-apoptotic protein Noxa regulates memory T cell population size and protects against lethal immunopathology.

    Science.gov (United States)

    Wensveen, Felix M; Klarenbeek, Paul L; van Gisbergen, Klaas P J M; Pascutti, Maria F; Derks, Ingrid A M; van Schaik, Barbera D C; Ten Brinke, Anja; de Vries, Niek; Cekinovic, Durdica; Jonjic, Stipan; van Lier, René A W; Eldering, Eric

    2013-02-01

    Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple clones with slightly different affinities, thereby creating T cell memory with a certain degree of diversity. Currently, the mechanisms that control size, diversity, and cross-reactivity of the memory T cell pool are incompletely defined. Previously, we established a role for apoptosis, mediated by the BH3-only protein Noxa, in controlling diversity of the effector T cell population. This function might positively or negatively impact T cell memory in terms of function, pool size, and cross-reactivity during recall responses. Therefore, we investigated the role of Noxa in T cell memory during acute and chronic infections. Upon influenza infection, Noxa(-/-) mice generate a memory compartment of increased size and clonal diversity. Reinfection resulted in an increased recall response, whereas cross-reactive responses were impaired. Chronic infection of Noxa(-/-) mice with mouse CMV resulted in enhanced memory cell inflation, but no obvious pathology. In contrast, in a model of continuous, high-level T cell activation, reduced apoptosis of activated T cells rapidly led to severe organ pathology and premature death in Noxa-deficient mice. These results establish Noxa as an important regulator of the number of memory cells formed during infection. Chronic immune activation in the absence of Noxa leads to excessive accumulation of primed cells, which may result in severe pathology.

  5. High Titers of Circulating Maternal Antibodies Suppress Effector and Memory B-Cell Responses Induced by an Attenuated Rotavirus Priming and Rotavirus-Like Particle-Immunostimulating Complex Boosting Vaccine Regimen

    Science.gov (United States)

    Nguyen, Trang V.; Yuan, Lijuan; Azevedo, Marli S. P.; Jeong, Kwang-il; Gonzalez, Ana M.; Iosef, Cristiana; Lovgren-Bengtsson, Karin; Morein, Bror; Lewis, Peggy; Saif, Linda J.

    2006-01-01

    We investigated maternal antibody (MatAb) effects on protection and immune responses to rotavirus vaccines. Gnotobiotic pigs were injected intraperitoneally at birth with pooled serum from sows hyperimmunized with human rotavirus (HRV); control pigs received no sow serum. Pigs with or without MatAbs received either sequential attenuated HRV (AttHRV) oral priming and intranasal boosting with VP2/VP6 virus-like particle (VLP)-immunostimulating complex (ISCOM) (AttHRV/VLP) or intranasal VLP-ISCOM prime/boost (VLP) vaccines at 3 to 5 days of age. Subsets of pigs were challenged at 28 or 42 days postinoculation with virulent Wa HRV to assess protection. Isotype-specific antibody-secreting cell (ASC) responses to HRV were quantitated by enzyme-linked immunospot assay to measure effector and memory B-cell responses in intestinal and systemic lymphoid tissues pre- and/or postchallenge. Protection rates against HRV challenge (contributed by active immunity and passive circulating MatAbs) were consistently (but not significantly) lower in the MatAb-AttHRV/VLP groups than in the corresponding groups without MatAbs. Intestinal B-cell responses in the MatAb-AttHRV/VLP group were most suppressed with significantly reduced or no intestinal immunoglobulin A (IgA) and IgG effector and memory B-cell responses or antibody titers pre- and postchallenge. This suppression was not alleviated but was enhanced after extending vaccination/challenge from 28 to 42 days. In pigs vaccinated with nonreplicating VLP alone that failed to induce protection, MatAb effects differed, with intestinal and systemic IgG ASCs and prechallenge memory B cells suppressed but the low intestinal IgA and IgM ASC responses unaffected. Thus, we demonstrate that MatAbs differentially affect both replicating and nonreplicating HRV vaccines and suggest mechanisms of MatAb interference. This information should facilitate vaccine design to overcome MatAb suppression. PMID:16603615

  6. Ferroelectric symmetry-protected multibit memory cell

    Science.gov (United States)

    Baudry, Laurent; Lukyanchuk, Igor; Vinokur, Valerii M.

    2017-01-01

    The tunability of electrical polarization in ferroelectrics is instrumental to their applications in information-storage devices. The existing ferroelectric memory cells are based on the two-level storage capacity with the standard binary logics. However, the latter have reached its fundamental limitations. Here we propose ferroelectric multibit cells (FMBC) utilizing the ability of multiaxial ferroelectric materials to pin the polarization at a sequence of the multistable states. Employing the catastrophe theory principles we show that these states are symmetry-protected against the information loss and thus realize novel topologically-controlled access memory (TAM). Our findings enable developing a platform for the emergent many-valued non-Boolean information technology and target challenges posed by needs of quantum and neuromorphic computing. PMID:28176866

  7. Ferroelectric symmetry-protected multibit memory cell

    Science.gov (United States)

    Baudry, Laurent; Lukyanchuk, Igor; Vinokur, Valerii M.

    2017-02-01

    The tunability of electrical polarization in ferroelectrics is instrumental to their applications in information-storage devices. The existing ferroelectric memory cells are based on the two-level storage capacity with the standard binary logics. However, the latter have reached its fundamental limitations. Here we propose ferroelectric multibit cells (FMBC) utilizing the ability of multiaxial ferroelectric materials to pin the polarization at a sequence of the multistable states. Employing the catastrophe theory principles we show that these states are symmetry-protected against the information loss and thus realize novel topologically-controlled access memory (TAM). Our findings enable developing a platform for the emergent many-valued non-Boolean information technology and target challenges posed by needs of quantum and neuromorphic computing.

  8. 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.

  9. Persistent expansion of CD4(+) effector memory T cells in Wegener's granulomatosis

    NARCIS (Netherlands)

    Abdulahad, W. H.; van der Geld, Y. M.; Stegeman, C. A.; Kallenberg, C. G. M.

    2006-01-01

    In order to test the hypothesis that Wegener's granulomatosis (WG) is associated with an ongoing immune effector response, even in remission, we examined the distribution of peripheral naive and memory T-lymphocytes in this disease, and analyzed the function-related phenotypes of the memory T-cell p

  10. 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.

  11. CD8 T cell memory: it takes all kinds

    Directory of Open Access Journals (Sweden)

    Stephen Christopher Jameson

    2012-11-01

    Full Text Available Understanding the mechanisms that regulate the differentiation and maintenance of CD8+ memory T cells is fundamental to the development of effective T cell based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8+ memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8+ memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine design. Here we discuss how the diversity of the memory CD8+ T cell pool challenges the notion that ‘one size fits all’ for pathogen control, and how distinct memory subsets may be suited for distinct aspects of protective immunity.

  12. 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.

  13. Regulation of B Cell to Plasma Cell Transition within the Follicular B Cell Response.

    Science.gov (United States)

    Nera, K-P; Kyläniemi, M K; Lassila, O

    2015-09-01

    Persistent humoral immunity depends on the follicular B cell response and on the generation of somatically mutated high-affinity plasma cells and memory B cells. Upon activation by an antigen, cognately activated follicular B cells and follicular T helper (TFH ) cells initiate germinal centre (GC) reaction during which high-affinity effector cells are generated. The differentiation of activated follicular B cells into plasma cells and memory B cells is guided by complex selection events, both at the cellular and molecular level. The transition of B cell into a plasma cell during the GC response involves alterations in the microenvironment and developmental state of the cell, which are guided by cell-extrinsic signals. The developmental cell fate decisions in response to these signals are coordinated by cell-intrinsic gene regulatory network functioning at epigenetic, transcriptional and post-transcriptional levels.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. Dissecting the human CD4+T cell memory pool

    OpenAIRE

    Rivino, Laura; Rusconi, Sandro; Geginat, Jens

    2007-01-01

    Memory cells can persist for a whole lifetime. Consequently, these cells must possess characteristics which endows them with the capacity to survive in the absence of their cognate antigen, to self-renewal and to rapidly and efficiently respond upon secondary encounter of antigen. It has become increasingly clear that the memory pool can fulfil these diverse requirements because of its extreme heterogeneity which allows a division of labour among the different memory cell subsets. In my study...

  19. 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.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Impaired Memory Retrieval Correlates with Individual Differences in Cortisol Response but Not Autonomic Response

    Science.gov (United States)

    Tranel, Daniel; Adolphs, Ralph; Buchanan, Tony W.

    2006-01-01

    Stress can enhance or impair memory performance. Both cortisol release and sympathetic nervous system responses have been implicated in these differential effects. Here we investigated how memory retrieval might be affected by stress-induced cortisol release, independently of sympathetic nervous system stress responses. Thirty-two healthy…

  3. Fast-Response-Time Shape-Memory-Effect Foam Actuators

    Science.gov (United States)

    Jardine, Peter

    2010-01-01

    Bulk shape memory alloys, such as Nitinol or CuAlZn, display strong recovery forces undergoing a phase transformation after being strained in their martensitic state. These recovery forces are used for actuation. As the phase transformation is thermally driven, the response time of the actuation can be slow, as the heat must be passively inserted or removed from the alloy. Shape memory alloy TiNi torque tubes have been investigated for at least 20 years and have demonstrated high actuation forces [3,000 in.-lb (approximately equal to 340 N-m) torques] and are very lightweight. However, they are not easy to attach to existing structures. Adhesives will fail in shear at low-torque loads and the TiNi is not weldable, so that mechanical crimp fits have been generally used. These are not reliable, especially in vibratory environments. The TiNi is also slow to heat up, as it can only be heated indirectly using heater and cooling must be done passively. This has restricted their use to on-off actuators where cycle times of approximately one minute is acceptable. Self-propagating high-temperature synthesis (SHS) has been used in the past to make porous TiNi metal foams. Shape Change Technologies has been able to train SHS derived TiNi to exhibit the shape memory effect. As it is an open-celled material, fast response times were observed when the material was heated using hot and cold fluids. A methodology was developed to make the open-celled porous TiNi foams as a tube with integrated hexagonal ends, which then becomes a torsional actuator with fast response times. Under processing developed independently, researchers were able to verify torques of 84 in.-lb (approximately equal to 9.5 Nm) using an actuator weighing 1.3 oz (approximately equal to 37 g) with very fast (less than 1/16th of a second) initial response times when hot and cold fluids were used to facilitate heat transfer. Integrated structural connections were added as part of the net shape process, eliminating

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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.

  7. Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4⁺ effector memory T cells.

    Science.gov (United States)

    Zhou, Fang; Zhang, Guang-Xian; Rostami, Abdolmohamad

    2016-02-01

    CD4(+) memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4(+) memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4(+) effector memory T cells in vitro and in vivo. Simultaneously, intravenous transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4(+) T cells, not central memory CD4(+) T cells, which play a major role in chronic inflammatory responses in mice with EAE. Intravenous transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4(+) effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo.

  8. Multiple layers of B cell memory with different effector functions.

    Science.gov (United States)

    Dogan, Ismail; Bertocci, Barbara; Vilmont, Valérie; Delbos, Frédéric; Mégret, Jérome; Storck, Sébastien; Reynaud, Claude-Agnès; Weill, Jean-Claude

    2009-12-01

    Memory B cells are at the center of longstanding controversies regarding the presence of antigen for their survival and their re-engagement in germinal centers after secondary challenge. Using a new mouse model of memory B cell labeling dependent on the cytidine deaminase AID, we show that after immunization with a particulate antigen, B cell memory appeared in several subsets, comprising clusters of immunoglobulin M-positive (IgM(+)) and IgG1(+) B cells in germinal center-like structures that persisted up to 8 months after immunization, as well as IgM(+) and IgG1(+) B cells with a memory phenotype outside of B cell follicles. After challenge, the IgG subset differentiated into plasmocytes, whereas the IgM subset reinitiated a germinal center reaction. This model, in which B cell memory appears in several layers with different functions, reconciles previous conflicting propositions.

  9. Hormonal contraception use alters stress responses and emotional memory.

    Science.gov (United States)

    Nielsen, Shawn E; Segal, Sabrina K; Worden, Ian V; Yim, Ilona S; Cahill, Larry

    2013-02-01

    Emotionally arousing material is typically better remembered than neutral material. Since norepinephrine and cortisol interact to modulate emotional memory, sex-related influences on stress responses may be related to sex differences in emotional memory. Two groups of healthy women - one naturally cycling (NC women, n=42) and one using hormonal contraceptives (HC women, n=36) - viewed emotionally arousing and neutral images. Immediately after, they were assigned to Cold Pressor Stress (CPS) or a control procedure. One week later, participants received a surprise free recall test. Saliva samples were collected and later assayed for salivary alpha-amylase (biomarker for norepinephrine) and cortisol. Compared to NC women, HC women exhibited significantly blunted stress hormone responses to the images and CPS. Recall of emotional images differed between HC and NC women depending on noradrenergic and cortisol responses. These findings may have important implications for understanding the neurobiology of emotional memory disorders, especially those that disproportionately affect women.

  10. 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

    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......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...... 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...

  11. 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.

  12. A Candidate HIV/AIDS Vaccine (MVA-B) Lacking Vaccinia Virus Gene C6L Enhances Memory HIV-1-Specific T-Cell Responses

    OpenAIRE

    Juan García-Arriaza; José Luis Nájera; Carmen E Gómez; Nolawit Tewabe; Sorzano, Carlos Oscar S.; Thierry Calandra; Thierry Roger; Mariano Esteban

    2011-01-01

    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-...

  13. 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.

  14. Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia.

    Science.gov (United States)

    Hosokawa, Kohei; Muranski, Pawel; Feng, Xingmin; Townsley, Danielle M; Liu, Baoying; Knickelbein, Jared; Keyvanfar, Keyvan; Dumitriu, Bogdan; Ito, Sawa; Kajigaya, Sachiko; Taylor, James G; Kaplan, Mariana J; Nussenblatt, Robert B; Barrett, A John; O'Shea, John; Young, Neal S

    2016-02-15

    Memory stem T cells (TSCMs) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. Hallmarks of autoimmune disease pathogenesis are abnormal CD4(+) and CD8(+) T cell activation. We investigated the TSCM subset in 55, 34, 43, and 5 patients with acquired aplastic anemia (AA), autoimmune uveitis, systemic lupus erythematosus, and sickle cell disease, respectively, as well as in 41 age-matched healthy controls. CD8(+) TSCM frequency was significantly increased in AA compared with healthy controls. An increased CD8(+) TSCM frequency at diagnosis was associated with responsiveness to immunosuppressive therapy, and an elevated CD8(+) TSCM population after immunosuppressive therapy correlated with treatment failure or relapse in AA patients. IFN-γ and IL-2 production was significantly increased in various CD8(+) and CD4(+) T cell subsets in AA patients, including CD8(+) and CD4(+) TSCMs. CD8(+) TSCM frequency was also increased in patients with autoimmune uveitis or sickle cell disease. A positive correlation between CD4(+) and CD8(+) TSCM frequencies was found in AA, autoimmune uveitis, and systemic lupus erythematosus. Evaluation of PD-1, CD160, and CD244 expression revealed that TSCMs were less exhausted compared with other types of memory T cells. Our results suggest that the CD8(+) TSCM subset is a novel biomarker and a potential therapeutic target for AA.

  15. 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.

  16. 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.

  17. Autoimmune Memory T Helper 17 Cell Function and Expansion Are Dependent on Interleukin-23

    Directory of Open Access Journals (Sweden)

    Christopher J. Haines

    2013-05-01

    Full Text Available Interleukin-23 (IL-23 is essential for the differentiation of pathogenic effector T helper 17 (Th17 cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17+ and RORγt+ precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways.

  18. Autoimmune memory T helper 17 cell function and expansion are dependent on interleukin-23.

    Science.gov (United States)

    Haines, Christopher J; Chen, Yi; Blumenschein, Wendy M; Jain, Renu; Chang, Charlie; Joyce-Shaikh, Barbara; Porth, Katherine; Boniface, Katia; Mattson, Jeanine; Basham, Beth; Anderton, Stephen M; McClanahan, Terrill K; Sadekova, Svetlana; Cua, Daniel J; McGeachy, Mandy J

    2013-05-30

    Interleukin-23 (IL-23) is essential for the differentiation of pathogenic effector T helper 17 (Th17) cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17+ and RORγt+ precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways.

  19. 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...

  20. Structural Acoustic Response of Shape Memory Alloy Hybrid Composite Panels

    Science.gov (United States)

    Turner, Travis L.

    1996-01-01

    A method has been developed to predict the structural acoustic response of shape memory alloy hybrid composite panels subjected to acoustic excitation. The panel is modeled by a finite element analysis and the radiated field is predicted using Rayleigh's integral. Transmission loss predictions for the case of an aluminum panel excited by a harmonic acoustic pressure are shown to compare very well with a classical analysis. Predictions of the normal velocity response and transmitted acoustic pressure for a clamped aluminum panel show excellent agreement with experimental measurements. Predicted transmission loss performance for a composite panel with and without shape memory alloy reinforcement are also presented. The preliminary results demonstrate that the transmission loss can be significantly increased with shape memory alloy reinforcement.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. A stochastic model of chromatin modification: cell population coding of winter memory in plants.

    Science.gov (United States)

    Satake, Akiko; Iwasa, Yoh

    2012-06-07

    Biological memory, a sustained cellular response to a transient stimulus, has been found in many natural systems. The best example in plants is the winter memory by which plants can flower in favorable conditions in spring. For this winter memory, epigenetic regulation of FLOWERING LOCUS C (FLC), which acts as a floral repressor, plays a key role. Exposure to prolonged periods of cold results in the gradual suppression of FLC, which allows plants to measure the length of cold and to flower only after a sufficiently long winter. Although many genes involved in histone modifications have been isolated, molecular mechanisms of winter memory are not well understood. Here, we develop a model for chromatin modification, in which the dynamics of a single nucleosome are aggregated to on/off behavior of FLC expression at the cellular level and further integrated to a change of FLC expression at the whole-plant level. We propose cell-population coding of winter memory: each cell is described as a bistable system that shows heterogeneous timing of the transition from on to off in FLC expression under cold and measures the length of cold as the proportion of cells in the off state. This mechanism well explains robust FLC regulation and stable inheritance of winter memory after cell division in response to noisy signals. Winter memory lasts longer if deposition of the repressive histone mark occurs faster. A difference in deposition speed would discriminate between stable maintenance of FLC repression in annuals and transient expression in perennials.

  6. Plasmodium vivax infection induces expansion of activated naïve/memorycells and differentiation into a central memory profile.

    Science.gov (United States)

    Silva, Ana Luiza Teixeira; Lacerda, Marcus Vinícius; Fujiwara, Ricardo Toshio; Bueno, Lilian Lacerda; Braga, Erika Martins

    2013-11-01

    Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we characterized the profile of circulating naïve and memory (including central and effector) CD4⁺ T cells responses of individuals naturally infected by Plasmodium vivax. In the current study, we demonstrated that acute P. vivax infection induces a significant increase in the absolute number of both naïve and memory cells, which were responsible for the production of anti-inflammatory (IL-10) and pro-inflammatory (IFN-γ) cytokines. Finally, we described the profile of memory cell subtypes (T(CM)-CD45RO(high)CCR7⁺ and T(EM)-CD45RO(high)CCR7⁻), as well as the pattern of cell migration based on CD62L selectin expression, demonstrating that P. vivax-infected donors presented with a predominantly central memory cell profile. Our results indicate that the expansion of both naïve and memory T cells, responsible for the production of both pro-inflammatory and regulatory cytokines, which might also contribute to the modulation of immune responses during P. vivax infection.

  7. T cell memory. Skin-resident memory CD8⁺ T cells trigger a state of tissue-wide pathogen alert.

    Science.gov (United States)

    Ariotti, Silvia; Hogenbirk, Marc A; Dijkgraaf, Feline E; Visser, Lindy L; Hoekstra, Mirjam E; Song, Ji-Ying; Jacobs, Heinz; Haanen, John B; Schumacher, Ton N

    2014-10-03

    After an infection, pathogen-specific tissue-resident memory T cells (T(RM) cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create T(RM) cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how T(RM) cells provide such pathogen protection. Here, we demonstrate that activated T(RM) cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This "pathogen alert" allows skin T(RM) cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8(+) T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.

  8. Phenotype and functions of memory Tfh cells in human blood.

    Science.gov (United States)

    Schmitt, Nathalie; Bentebibel, Salah-Eddine; Ueno, Hideki

    2014-09-01

    Our understanding of the origin and functions of human blood CXCR5(+) CD4(+) T cells found in human blood has changed dramatically in the past years. These cells are currently considered to represent a circulating memory compartment of T follicular helper (Tfh) lineage cells. Recent studies have shown that blood memory Tfh cells are composed of phenotypically and functionally distinct subsets. Here, we review the current understanding of human blood memory Tfh cells and the subsets within this compartment. We present a strategy to define these subsets based on cell surface profiles. Finally, we discuss how increased understanding of the biology of blood memory Tfh cells may contribute insight into the pathogenesis of autoimmune diseases and the mode of action of vaccines.

  9. Carriers recombination processes in charge trapping memory cell by simulation

    Institute of Scientific and Technical Information of China (English)

    Song Yun-Cheng; Liu Xiao-Yan; Du Gang; Kang Jin-Feng; Han Ru-Qi

    2008-01-01

    We have evaluated the effects of recombination processes in a charge storage layer, either between trapped electrons and trapped holes or between trapped carriers and free carriers, on charge trapping memory cell's performances by numerical simulation. Recombination is an indispensable mechanism in charge trapping memory. It helps charge convert process between negative and positive charges in the charge storage layer during charge trapping memory programming/erasing operation. It can affect the speed of programming and erasing operations.

  10. 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.

  11. Emotional Intensity and Emotion Regulation in Response to Autobiographical Memories During Dysphoria

    DEFF Research Database (Denmark)

    del Palacio Gonzalez, Adriana; Berntsen, Dorthe; Watson, Lynn Ann

    2017-01-01

    Retrieving personal memories may provoke different emotions and a need for emotion regulation. Emotional responses have been studied scarcely in relation to autobiographical memory retrieval. We examined the emotional response to everyday involuntary (spontaneously arising) and voluntary (strateg...... new insights into the understudied topic of emotional responses to everyday memories and suggest a novel interpretation of the intrusive nature of memories in psychological disorders, such as depression.......Retrieving personal memories may provoke different emotions and a need for emotion regulation. Emotional responses have been studied scarcely in relation to autobiographical memory retrieval. We examined the emotional response to everyday involuntary (spontaneously arising) and voluntary...... (strategically retrieved) memories, and how this response may be different during dysphoria. Participants (20 dysphoric and 23 non-depressed) completed a structured diary where the intensity of basic emotions and regulation strategies employed upon retrieval of memories were rated. Brooding, memory suppression...

  12. 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.

  13. 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.

  14. Impaired memory retrieval correlates with individual differences in cortisol response but not autonomic response

    OpenAIRE

    Buchanan, Tony W.; Tranel, Daniel; Adolphs, Ralph

    2006-01-01

    Stress can enhance or impair memory performance. Both cortisol release and sympathetic nervous system responses have been implicated in these differential effects. Here we investigated how memory retrieval might be affected by stress-induced cortisol release, independently of sympathetic nervous system stress responses. Thirty-two healthy participants (16 women) learned emotionally arousing and neutral words. One hour later, half of the participants underwent a stressor (cold pressor test) an...

  15. A TCR affinity threshold regulates memory CD4 T cell differentiation following vaccination.

    Science.gov (United States)

    Baumgartner, Christina K; Yagita, Hideo; Malherbe, Laurent P

    2012-09-01

    Diverse Ag-specific memory TCR repertoires are essential for protection against pathogens. Subunit vaccines that combine peptide or protein Ags with TLR agonists are very potent at inducing T cell immune responses, but their capacity to elicit stable and diverse memory CD4 T cell repertoires has not been evaluated. In this study, we examined the evolution of a complex Ag-specific population during the transition from primary effectors to memory T cells after peptide or protein vaccination. Both vaccination regimens induced equally diverse effector CD4 TCR repertoires, but peptide vaccines skewed the memory CD4 TCR repertoire toward high-affinity clonotypes whereas protein vaccines maintained low-affinity clonotypes in the memory compartment. CD27-mediated signaling was essential for the maintenance of low-affinity clonotypes after protein vaccination but was not sufficient to promote their survival following peptide vaccination. The rapid culling of the TCR repertoire in peptide-immunized mice coincided with a prolonged proliferation phase during which low-affinity clonotypes disappeared despite exhibiting no sign of enhanced apoptosis. Our study reveals a novel affinity threshold for memory CD4 T cell differentiation following vaccination and suggests a role for nonapoptotic cell death in the regulation of CD4 T cell clonal selection.

  16. Retention of Ag-specific memory CD4(+) T cells in the draining lymph node indicates lymphoid tissue resident memory populations.

    Science.gov (United States)

    Marriott, Clare L; Dutton, Emma E; Tomura, Michio; Withers, David R

    2017-03-15

    Several different memory T-cell populations have now been described based upon surface receptor expression and migratory capabilities. Here we have assessed murine endogenous memory CD4(+) T cells generated within a draining lymph node and their subsequent migration to other secondary lymphoid tissues. Having established a model response targeting a specific peripheral lymph node, we temporally labelled all the cells within draining lymph node using photoconversion. Tracking of photoconverted and non-photoconverted Ag-specific CD4(+) T cells revealed the rapid establishment of a circulating memory population in all lymph nodes within days of immunisation. Strikingly, a resident memory CD4(+) T cell population became established in the draining lymph node and persisted for several months in the absence of detectable migration to other lymphoid tissue. These cells most closely resembled effector memory T cells, usually associated with circulation through non-lymphoid tissue, but here, these cells were retained in the draining lymph node. These data indicate that lymphoid tissue resident memory CD4(+) T-cell populations are generated in peripheral lymph nodes following immunisation.

  17. Dissociable Memory- and Response-Related Activity in Parietal Cortex during Auditory Spatial Working Memory

    Directory of Open Access Journals (Sweden)

    Claude Alain

    2010-12-01

    Full Text Available Attending and responding to sound location generates increased activity in parietal cortex which may index auditory spatial working memory and/or goal-directed action. Here, we used an n-back task (Experiment 1 and an adaptation paradigm (Experiment 2 to distinguish memory-related activity from that associated with goal-directed action. In Experiment 1, participants indicated, in separate blocks of trials, whether the incoming stimulus was presented at the same location as in the previous trial (1-back or two trials ago (2-back. Prior to a block of trials, participants were told to use their left or right index finger. Accuracy and reaction times were worse for the 2-back than for the 1-back condition. The analysis of fMRI data revealed greater sustained task-related activity in the inferior parietal lobule (IPL and superior frontal sulcus during 2-back than 1-back after accounting for response-related activity elicited by the targets. Target detection and response execution were also associated with enhanced activity in the IPL bilaterally, though the activation was anterior to that associated with sustained task-related activity. In Experiment 2, we used an event-related design in which participants listened (no response required to trials that comprised four sounds presented either at the same location or at four different locations. We found larger IPL activation for changes in sound location than for sounds presented at the same location. The IPL activation overlapped with that observed during auditory spatial working memory task. Together, these results provide converging evidence supporting the role of parietal cortex in auditory spatial working memory which can be dissociated from response selection and execution.

  18. 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.

  19. Memory cell operation based on small Josephson junctions arrays

    Science.gov (United States)

    Braiman, Y.; Nair, N.; Rezac, J.; Imam, N.

    2016-12-01

    In this paper we analyze a cryogenic memory cell circuit based on a small coupled array of Josephson junctions. All the basic memory operations (e.g., write, read, and reset) are implemented on the same circuit and different junctions in the array can in principle be utilized for these operations. The presented memory operation paradigm is fundamentally different from conventional single quantum flux operation logics (SFQ). As an example, we demonstrate memory operation driven by a SFQ pulse employing an inductively coupled array of three Josephson junctions. We have chosen realistic Josephson junction parameters based on state-of-the-art fabrication capabilities and have calculated access times and access energies for basic memory cell operations. We also implemented an optimization procedure based on the simulated annealing algorithm to calculate the optimized and typical values of access times and access energies.

  20. Dynamic T cell migration program provides resident memory within intestinal epithelium

    Science.gov (United States)

    Choo, Daniel; Vezys, Vaiva; Wherry, E. John; Duraiswamy, Jaikumar; Akondy, Rama; Wang, Jun; Casey, Kerry A.; Barber, Daniel L.; Kawamura, Kim S.; Fraser, Kathryn A.; Webby, Richard J.; Brinkmann, Volker; Butcher, Eugene C.; Newell, Kenneth A.

    2010-01-01

    Migration to intestinal mucosa putatively depends on local activation because gastrointestinal lymphoid tissue induces expression of intestinal homing molecules, whereas skin-draining lymph nodes do not. This paradigm is difficult to reconcile with reports of intestinal T cell responses after alternative routes of immunization. We reconcile this discrepancy by demonstrating that activation within spleen results in intermediate induction of homing potential to the intestinal mucosa. We further demonstrate that memory T cells within small intestine epithelium do not routinely recirculate with memory T cells in other tissues, and we provide evidence that homing is similarly dynamic in humans after subcutaneous live yellow fever vaccine immunization. These data explain why systemic immunization routes induce local cell-mediated immunity within the intestine and indicate that this tissue must be seeded with memory T cell precursors shortly after activation. PMID:20156972

  1. 记忆B细胞与血清记忆%Memory B cells and serological memory

    Institute of Scientific and Technical Information of China (English)

    丁文萍; 廖爱华

    2008-01-01

    Memory B cells behave as 'memory stem cells' capable of generating plasma cells and antibodies in an antigen-dependent as well as in an antigen-independent fashion. Memory B-cells involves in two populations of quiescent memory B cells and long-lived plasma cells.Although it is clear that both of them generate from germinal centers,the signal and circumstances that trigger germinal-centre B cells to enter and then persist in memory compartment are poorly defined. Also,how they migrate from germinal centers,how they survive for a long time and what determines the overall size and composition of the memory B-cell and plasma-cell compartments are still unknown.The problems remain resolved,which will play an important role in immune regulation and prevention of self-immune diseases.%记忆B细胞被认为是记忆干细胞,通过抗原依赖和非抗原依赖的方式,能转化为浆细胞而产生抗体.B细胞的记忆形成涉及静止记忆B细胞和长寿命浆细胞.尽管已知这些细胞来源于生发中心,但刺激生发中心B细胞进入并维持记忆池所需的信号和环境尚不清楚.且它们是怎样从生发中心迁出,哪些因素决定其长期存活,记忆B细胞池与浆细胞池的组成和容量是多少等都还不十分清楚.这些问题的解决对免疫调控,防治自身免疫性疾病有重要的价值.

  2. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.

    Science.gov (United States)

    Deenick, Elissa K; Avery, Danielle T; Chan, Anna; Berglund, Lucinda J; Ives, Megan L; Moens, Leen; Stoddard, Jennifer L; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Tsumura, Miyuki; Kobayashi, Masao; Arkwright, Peter D; Averbuch, Diana; Engelhard, Dan; Roesler, Joachim; Peake, Jane; Wong, Melanie; Adelstein, Stephen; Choo, Sharon; Smart, Joanne M; French, Martyn A; Fulcher, David A; Cook, Matthew C; Picard, Capucine; Durandy, Anne; Klein, Christoph; Holland, Steven M; Uzel, Gulbu; Casanova, Jean-Laurent; Ma, Cindy S; Tangye, Stuart G

    2013-11-18

    Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.

  3. 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.

  4. Afterglow processes responsible for memory effect in nitrogen

    Energy Technology Data Exchange (ETDEWEB)

    Pejovic, M. M. [Faculty of Electronic Engineering, University of Nis, Aleksandra Medvedeva 14, Nis (Serbia); Center of Scientific Research of the Serbian Academy of Sciences and Arts, University of Nis, Univerzitetski trg 2, Nis (Serbia); Nesic, N. T.; Pejovic, M. M.; Zivanovic, E. N. [Faculty of Electronic Engineering, University of Nis, Aleksandra Medvedeva 14, Nis (Serbia)

    2012-07-01

    The mechanisms responsible for memory effect in nitrogen at 6.6 mbars have been analysed based on experimental data of electrical breakdown time delay as a function of afterglow period. The analysis has shown that positive ions remaining from previous discharge, as well as metastable and highly vibrationally excited molecules, are responsible for memory effect in the early afterglow. These molecules lead to the formation of positive ions in mutual collisions in the afterglow. Positive ions initiate secondary electron emission from the cathode of a nitrogen-filled tube when voltage higher than static breakdown voltage is applied on the electrodes. On the other hand, N({sup 4}S) atoms have a large influence on memory effect in late afterglow. They recombine on the cathode surface forming metastable molecules, which release secondary electrons in collision with the cathode. The higher values of electrical breakdown time delay in the case of the tube with borosilicate glass walls than in the case of the tube with copper walls are a consequence of faster de-excitation of neutral active particles on the glass. Indirect confirmation of this assumption has been obtained when the tubes were irradiated with gamma radiation.

  5. T Cell Receptor and Cytokine Signaling Can Function at Different Stages to Establish and Maintain Transcriptional Memory and Enable T Helper Cell Differentiation

    Science.gov (United States)

    Bevington, Sarah L.; Cauchy, Pierre; Withers, David R.; Lane, Peter J. L.; Cockerill, Peter N.

    2017-01-01

    Experienced T cells exhibit immunological memory via a rapid recall response, responding to restimulation much faster than naïve T cells. The formation of immunological memory starts during an initial slow response, when naïve T cells become transformed to proliferating T blast cells, and inducible immune response genes are reprogrammed as active chromatin domains. We demonstrated that these active domains are supported by thousands of priming elements which cooperate with inducible transcriptional enhancers to enable efficient responses to stimuli. At the conclusion of this response, a small proportion of these cells return to the quiescent state as long-term memory T cells. We proposed that priming elements can be established in a hit-and-run process dependent on the inducible factor AP-1, but then maintained by the constitutive factors RUNX1 and ETS-1. This priming mechanism may also function to render genes receptive to additional differentiation-inducing factors such as GATA3 and TBX21 that are encountered under polarizing conditions. The proliferation of recently activated T cells and the maintenance of immunological memory in quiescent memory T cells are also dependent on various cytokine signaling pathways upstream of AP-1. We suggest that immunological memory is established by T cell receptor signaling, but maintained by cytokine signaling.

  6. T Cell Receptor and Cytokine Signaling Can Function at Different Stages to Establish and Maintain Transcriptional Memory and Enable T Helper Cell Differentiation.

    Science.gov (United States)

    Bevington, Sarah L; Cauchy, Pierre; Withers, David R; Lane, Peter J L; Cockerill, Peter N

    2017-01-01

    Experienced T cells exhibit immunological memory via a rapid recall response, responding to restimulation much faster than naïve T cells. The formation of immunological memory starts during an initial slow response, when naïve T cells become transformed to proliferating T blast cells, and inducible immune response genes are reprogrammed as active chromatin domains. We demonstrated that these active domains are supported by thousands of priming elements which cooperate with inducible transcriptional enhancers to enable efficient responses to stimuli. At the conclusion of this response, a small proportion of these cells return to the quiescent state as long-term memory T cells. We proposed that priming elements can be established in a hit-and-run process dependent on the inducible factor AP-1, but then maintained by the constitutive factors RUNX1 and ETS-1. This priming mechanism may also function to render genes receptive to additional differentiation-inducing factors such as GATA3 and TBX21 that are encountered under polarizing conditions. The proliferation of recently activated T cells and the maintenance of immunological memory in quiescent memory T cells are also dependent on various cytokine signaling pathways upstream of AP-1. We suggest that immunological memory is established by T cell receptor signaling, but maintained by cytokine signaling.

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

    Science.gov (United States)

    Chan, C W; Hussain, I; Waugh, D G; Lawrence, J; Man, H C

    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.

  8. Cross-situational consistency in recognition memory response bias.

    Science.gov (United States)

    Kantner, Justin; Lindsay, D Stephen

    2014-10-01

    Individuals taking an old-new recognition memory test differ widely in their bias to respond "old," ranging from strongly conservative to strongly liberal, even without any manipulation intended to affect bias. Kantner and Lindsay (2012) found stability of bias across study-test cycles, suggesting that bias is a cognitive trait. That consistency, however, could have arisen because participants perceived the two tests as being part of the same experiment in the same context. In the present study, we tested for stability across two recognition study-test procedures embedded in markedly different experiments, held weeks apart, that participants did not know were connected. Bias showed substantial cross-situational stability. Moreover, bias weakly predicted identifications on an eyewitness memory task and accuracy on a go-no-go task. Although we found little in the way of relationships between bias and five personality measures, these findings suggest that response bias is a stable and broadly influential characteristic of recognizers.

  9. 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.

  10. 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.

  11. Thermal response of novel shape memory polymer-shape memory alloy hybrids

    Science.gov (United States)

    Rossiter, Jonathan; Takashima, Kazuto; Mukai, Toshiharu

    2014-03-01

    Shape memory polymers (SMP) and shape memory alloys (SMA) have both been proven important smart materials in their own fields. Shape memory polymers can be formed into complex three-dimensional structures and can undergo shape programming and large strain recovery. These are especially important for deployable structures including those for space applications and micro-structures such as stents. Shape memory alloys on the other hand are readily exploitable in a range of applications where simple, silent, light-weight and low-cost repeatable actuation is required. These include servos, valves and mobile robotic artificial muscles. Despite their differences, one important commonality between SMPs and SMAs is that they are both typically activated by thermal energy. Given this common characteristic it is important to consider how these two will behave when in close environmental proximity, and hence exposed to the same thermal stimulus, and when they are incorporated into a hybrid SMA-SMP structure. In this paper we propose and examine the operation of SMA-SMP hybrids. The relationship between the two temperatures Tg, the glass transition temperature of the polymer, and Ta, the nominal austenite to martensite transition temperature of the alloy is considered. We examine how the choice of these two temperatures affects the thermal response of the hybrid. Electrical stimulation of the SMA is also considered as a method not only of actuating the SMA but also of inducing heating in the surrounding polymer, with consequent effects on actuator behaviour. Likewise by varying the rate and degree of thermal stimulation of the SMA significantly different actuation and structural stiffness can be achieved. Novel SMP-SMA hybrid actuators and structures have many ready applications in deployable structures, robotics and tuneable engineering systems.

  12. Memory

    Science.gov (United States)

    ... it has to decide what is worth remembering. Memory is the process of storing and then remembering this information. There are different types of memory. Short-term memory stores information for a few ...

  13. Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways.

    Science.gov (United States)

    Berkowska, Magdalena A; Driessen, Gertjan J A; Bikos, Vasilis; Grosserichter-Wagener, Christina; Stamatopoulos, Kostas; Cerutti, Andrea; He, Bing; Biermann, Katharina; Lange, Johan F; van der Burg, Mirjam; van Dongen, Jacques J M; van Zelm, Menno C

    2011-08-25

    Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27⁻IgG⁺ and CD27⁺IgM⁺ B cells are derived from primary germinal center reactions, and CD27⁺IgA⁺ and CD27⁺IgG⁺ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27⁻IgA⁺ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27⁻IgA⁺ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.

  14. Prolonged antigen presentation by immune complex-binding dendritic cells programs the proliferative capacity of memory CD8 T cells.

    Science.gov (United States)

    León, Beatriz; Ballesteros-Tato, André; Randall, Troy D; Lund, Frances E

    2014-07-28

    The commitment of naive CD8 T cells to effector or memory cell fates can occur after a single day of antigenic stimulation even though virus-derived antigens (Ags) are still presented by DCs long after acute infection is resolved. However, the effects of extended Ag presentation on CD8 T cells are undefined and the mechanisms that regulate prolonged Ag presentation are unknown. We showed that the sustained presentation of two different epitopes from influenza virus by DCs prevented the premature contraction of the primary virus-specific CD8 T cell response. Although prolonged Ag presentation did not alter the number of memory CD8 T cells that developed, it was essential for programming the capacity of these cells to proliferate, produce cytokines, and protect the host after secondary challenge. Importantly, prolonged Ag presentation by DCs was dependent on virus-specific, isotype-switched antibodies (Abs) that facilitated the capture and cross-presentation of viral Ags by FcγR-expressing DCs. Collectively, our results demonstrate that B cells and Abs can regulate the quality and functionality of a subset of antiviral CD8 T cell memory responses and do so by promoting sustained Ag presentation by DCs during the contraction phase of the primary T cell response.

  15. 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.

  16. Epigenetic memory and cell fate reprogramming in plants.

    Science.gov (United States)

    Birnbaum, Kenneth D; Roudier, François

    2017-02-01

    Plants have a high intrinsic capacity to regenerate from adult tissues, with the ability to reprogram adult cell fates. In contrast, epigenetic mechanisms have the potential to stabilize cell identity and maintain tissue organization. The question is whether epigenetic memory creates a barrier to reprogramming that needs to be erased or circumvented in plant regeneration. Early evidence suggests that, while chromatin dynamics impact gene expression in the meristem, a lasting constraint on cell fate is not established until late stages of plant cell differentiation. It is not yet clear whether the plasticity of plant cells arises from the ability of cells to erase identity memory or to deploy cells that may exhibit cellular specialization but still lack an epigenetic restriction on cell fate alteration.

  17. Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation.

    Science.gov (United States)

    Kometani, Kohei; Nakagawa, Rinako; Shinnakasu, Ryo; Kaji, Tomohiro; Rybouchkin, Andrei; Moriyama, Saya; Furukawa, Koji; Koseki, Haruhiko; Takemori, Toshitada; Kurosaki, Tomohiro

    2013-07-25

    Memory B cells are essential for generating rapid and robust secondary antibody responses. It has been thought that the unique cytoplasmic domain of IgG causes the prompt activation of antigen-experienced IgG memory B cells. To assess this model, we have generated a mouse containing IgG1 B cells that have never encountered antigen. We found that, upon challenge, antigen-experienced IgG1 memory B cells rapidly differentiated into plasma cells, whereas nonexperienced IgG1 B cells did not, suggesting the importance of the stimulation history. In addition, our results suggest that repression of the Bach2 transcription factor, which results from antigen experience, contributes to predisposition of IgG1 memory B cells to differentiate into plasma cells.

  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.

  19. The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases.

    Science.gov (United States)

    Gardiner, Clair M; Mills, Kingston H G

    2016-08-01

    Immunological memory mediated by antigen-specific T and B cells is the foundation of adaptive immunity and is fundamental to the heightened and rapid protective immune response induced by vaccination or following re-infection with the same pathogen. While the innate immune system has classically been considered to be non-specific and devoid of memory, it now appears that it can be trained following exposure to microbes or their products and that this may confer a form of memory on innate immune cells. The evidence for immunological memory outside of T and B cells has been best established for natural killer (NK) cells, where it has been known for decades that NK cells have heighten responses following immunological re-challenge. Furthermore, recent studies have demonstrated that monocyte/macrophages, and probably dendritic cells, can be re-programmed through epigenetic modification, following exposure to pathogens or their products, resulting in heighted responses following a second stimulation. Unlike antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Indirect evidence for this comes from reports on the non-specific beneficial effect of certain live vaccines, such as Bacillus Calmette Guerin (BCG) against unrelated childhood infectious diseases. It also appears that certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more anti-inflammatory and less pro-inflammatory cyokines, thus opening up the possibility of exploiting innate immune training as a new therapeutic approach for inflammatory diseases.

  20. 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.

  1. Optimal memory configuration analysis in tri-hybrid solid-state drives with storage class memory and multi-level cell/triple-level cell NAND flash memory

    Science.gov (United States)

    Matsui, Chihiro; Yamada, Tomoaki; Sugiyama, Yusuke; Yamaga, Yusuke; Takeuchi, Ken

    2017-04-01

    This paper analyzes the best mix of memories in a tri-hybrid solid-state drive (SSD) with storage class memory (SCM) and multi-level cell (MLC)/triple-level cell (TLC) NAND flash memory. SCM is fast but its cost is high. Although MLC NAND flash memory is slow, it is more cost effective than SCM. For further cost efficiency, TLC NAND flash memory is denser and less expensive than MLC NAND flash. Performance of tri-hybrid SSD is evaluated in various memory configurations. Moreover, the optimum memory configuration is changed according to the application characteristics. If 10% cost increase is allowed compared to the MLC NAND flash only SSD, SCM/MLC NAND flash hybrid SSD provides the best performance with hot/random workload, whereas SCM/MLC/TLC NAND flash tri-hybrid SSD achieves the best for hot/sequential and cold/random workloads. In addition, it is possible to add long latency but low-cost SCM to the tri-hybrid SSD. As a result, tri-hybrid SSD with slow SCM achieves the best performance.

  2. Shark immunity bites back: affinity maturation and memory response in the nurse shark, Ginglymostoma cirratum.

    Science.gov (United States)

    Dooley, Helen; Flajnik, Martin F

    2005-03-01

    The cartilaginous fish are the oldest phylogenetic group in which all of the molecular components of the adaptive immune system have been found. Although early studies clearly showed that sharks could produce an IgM-based response following immunization, evidence for memory, affinity maturation and roles for the other isotypes (notably IgNAR) in this group remained inconclusive. The data presented here illustrate that the nurse shark (Ginglymostoma cirratum) is able to produce not only an IgM response, but we also show for the first time a highly antigen-specific IgNAR response. Additionally, under appropriate conditions, a memory response for both isotypes can be elicited. Analysis of the response shows differential expression of pentameric and monomeric IgM. Pentameric IgM provides the 'first line of defense' through high-avidity, low-affinity interaction with antigen. In contrast, monomeric IgM and IgNAR seem responsible for the specific, antigen-driven response. We propose the presence of distinct lineages of B cells in sharks. As there is no conventional isotype switching, each lineage seems pre-determined to express a single isotype (IgM versus IgNAR). However, our data suggest that there may also be specific lineages for the different forms (pentameric versus monomeric) of the IgM isotype.

  3. 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.

  4. The Vast Universe of T Cell Diversity: Subsets of Memory Cells and Their Differentiation.

    Science.gov (United States)

    Jandus, Camilla; Usatorre, Amaia Martínez; Viganò, Selena; Zhang, Lianjun; Romero, Pedro

    2017-01-01

    The T cell receptor confers specificity for antigen recognition to T cells. By the first encounter with the cognate antigen, reactive T cells initiate a program of expansion and differentiation that will define not only the ultimate quantity of specific cells that will be generated, but more importantly their quality and functional heterogeneity. Recent achievements using mouse model infection systems have helped to shed light into the complex network of factors that dictate and sustain memory T cell differentiation, ranging from antigen load, TCR signal strength, metabolic fitness, transcriptional programs, and proliferative potential. The different models of memory T cell differentiation are discussed in this chapter, and key phenotypic and functional attributes of memory T cell subsets are presented, both for mouse and human cells. Therapeutic manipulation of memory T cell generation is expected to provide novel unique ways to optimize current immunotherapies, both in infection and cancer.

  5. Differential T cell receptor-mediated signaling in naive and memory CD4 T cells.

    Science.gov (United States)

    Farber, D L; Acuto, O; Bottomly, K

    1997-08-01

    Naive and memory CD4 T cells differ in cell surface phenotype, function, activation requirements, and modes of regulation. To investigate the molecular bases for the dichotomies between naive and memory CD4 T cells and to understand how the T cell receptor (TCR) directs diverse functional outcomes, we investigated proximal signaling events triggered through the TCR/CD3 complex in naive and memory CD4 T cell subsets isolated on the basis of CD45 isoform expression. Naive CD4 T cells signal through TCR/CD3 similar to unseparated CD4 T cells, producing multiple tyrosine-phosphorylated protein species overall and phosphorylating the T cell-specific ZAP-70 tyrosine kinase which is recruited to the CD3zeta subunit of the TCR. Memory CD4 T cells, however, exhibit a unique pattern of signaling through TCR/CD3. Following stimulation through TCR/CD3, memory CD4 T cells produce fewer species of tyrosine-phosphorylated substrates and fail to phosphorylate ZAP-70, yet unphosphorylated ZAP-70 can associate with the TCR/CD3 complex. Moreover, a 26/28-kDa phosphorylated doublet is associated with CD3zeta in resting and activated memory but not in naive CD4 T cells. Despite these differences in the phosphorylation of ZAP-70 and CD3-associated proteins, the ZAP-70-related kinase, p72syk, exhibits similar phosphorylation in naive and memory T cell subsets, suggesting that this kinase could function in place of ZAP-70 in memory CD4 T cells. These results indicate that proximal signals are differentially coupled to the TCR in naive versus memory CD4 T cells, potentially leading to distinct downstream signaling events and ultimately to the diverse functions elicited by these two CD4 T cell subsets.

  6. Memory-based mismatch response to frequency changes in rats.

    Directory of Open Access Journals (Sweden)

    Piia Astikainen

    Full Text Available Any occasional changes in the acoustic environment are of potential importance for survival. In humans, the preattentive detection of such changes generates the mismatch negativity (MMN component of event-related brain potentials. MMN is elicited to rare changes ('deviants' in a series of otherwise regularly repeating stimuli ('standards'. Deviant stimuli are detected on the basis of a neural comparison process between the input from the current stimulus and the sensory memory trace of the standard stimuli. It is, however, unclear to what extent animals show a similar comparison process in response to auditory changes. To resolve this issue, epidural potentials were recorded above the primary auditory cortex of urethane-anesthetized rats. In an oddball condition, tone frequency was used to differentiate deviants interspersed randomly among a standard tone. Mismatch responses were observed at 60-100 ms after stimulus onset for frequency increases of 5% and 12.5% but not for similarly descending deviants. The response diminished when the silent inter-stimulus interval was increased from 375 ms to 600 ms for +5% deviants and from 600 ms to 1000 ms for +12.5% deviants. In comparison to the oddball condition the response also diminished in a control condition in which no repetitive standards were presented (equiprobable condition. These findings suggest that the rat mismatch response is similar to the human MMN and indicate that anesthetized rats provide a valuable model for studies of central auditory processing.

  7. 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.

  8. 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 thr......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 threshold voltages of 0.9V. Both hand calculations and PSPICE simulations showed that the cells designed allowed a maximum signal range better than +/-13 micoamp, with a supply voltage down to 1V and a quiescent bias current of 1 microamp, resulting in a very high current efficiency and effective power...

  9. Modeling of thermomechanical response of porous shape memory alloys

    Science.gov (United States)

    Lagoudas, Dimitris C.; Entchev, Pavlin B.; Vandygriff, Eric L.; Qidwai, Muhammad A.; DeGiorgi, Virginia G.

    2000-06-01

    Shape memory alloys (SMAs) have emerged as a class of materials with unique thermal and mechanical properties that have found numerous applications in various engineering areas. While the shape memory and pseudoelasticity effects have been extensively studied, only a few studies have been done on the high capacity of energy dissipation of SMAs. Because of this property, SMAs hold the promise of making high-efficiency damping devices that are superior to those made of conventional materials. In addition to the energy absorption capability of the dense SMA material, porous SMAs offer the possibility of higher specific damping capacity under dynamic loading conditions, du to scattering of waves. Porous SMAs also offer the possibility of impedance matching by grading the porosity at connecting joints with other structural materials. As a first step, the focus of this work, is on establishing the static properties of porous SMA material. To accomplish this, a micromechanics-based analysis of the overall behavior of porous SMA is carried out. The porous SMA is modeled as a composite with SMA matrix, which is modeled using an incremental formulation, and pores as inhomogeneities of zero stiffness. The macroscopic constitutive behavior of the effective medium is established using the incremental More-Tanaka averaging method for a random distribution of pores, and a FEM analysis of a unit cell for a periodic arrangement of pores. Results form both analyses are compared under various loading conditions.

  10. Target organ localization of memory CD4(+) T cells in patients with chronic beryllium disease.

    Science.gov (United States)

    Fontenot, Andrew P; Canavera, Scott J; Gharavi, Laia; Newman, Lee S; Kotzin, Brian L

    2002-11-01

    Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace, and it remains an important public health concern. Evidence suggests that CD4(+) T cells play a critical role in the development of this disease. Using intracellular cytokine staining, we found that the frequency of beryllium-specific CD4(+) T cells in the lungs (bronchoalveolar lavage) of 12 CBD patients ranged from 1.4% to 29% (mean 17.8%), and these T cells expressed a Th1-type phenotype in response to beryllium sulfate (BeSO(4)). Few, if any, beryllium-specific CD8(+) T cells were identified. In contrast, the frequency of beryllium-responsive CD4(+) T cells in the blood of these subjects ranged from undetectable to 1 in 500. No correlation was observed between the frequency of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells as detected by intracellular staining and lymphocyte proliferation in culture after BeSO(4) exposure. Staining for surface marker expression showed that nearly all BAL T cells exhibit an effector memory cell phenotype. These results demonstrate a dramatically high frequency and compartmentalization of antigen-specific effector memory CD4(+) cells in the lungs of CBD patients. These studies provide insight into the phenotypic and functional characteristics of antigen-specific T cells invading other inaccessible target organs in human disease.

  11. Short-lived IFN-γ effector responses, but long-lived IL-10 memory responses, to malaria in an area of low malaria endemicity.

    Directory of Open Access Journals (Sweden)

    Jiraprapa Wipasa

    Full Text Available Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. CD4+ T cell effector memory (CD45RO+ IFN-γ (24 hours ex vivo restimulation and cultured IL-10 (6 day secretion into culture supernatant responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3 years. In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

  12. 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.

  13. Sex differences in stress effects on response and spatial memory formation.

    Science.gov (United States)

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

    2014-03-01

    Stress and stress hormones are known to affect learning and memory processes. However, although effects of stress on hippocampus-dependent declarative learning and memory are well-documented, relatively little attention has been paid to the impact of stress on striatum-dependent stimulus-response (S-R) learning and memory. Recent evidence indicates that glucocorticoid stress hormones shortly after learning enhance S-R memory consolidation, whereas stress prior to retention testing impairs S-R memory retrieval. Whether stress affects also the acquisition of S-R memories in humans remains unclear. For this reason, we examined here the effects of acute stress on S-R memory formation and contrasted these stress effects with those on hippocampus-dependent spatial memory. Healthy men and women underwent a stressor (socially evaluated cold pressor test, SECPT) or a control manipulation before they completed an S-R task and two spatial learning tasks. Memory was assessed one week later. Our data showed that stress impaired S-R memory performance in men but not in women. Conversely, spatial memory was impaired by stress in women but not in men. These findings provide further evidence that stress may alter learning and memory processes beyond the hippocampus. Moreover, our data underline that participants' sex may play a critical role in the impact of stress on multiple memory systems.

  14. Thermoelectric Effects in Simulations of Phase Change Memory Mushroom Cells

    Science.gov (United States)

    Faraclas, Azer; Bakan, Gokhan; Gokirmak, Ali; Silva, Helena

    2012-02-01

    Phase change memory is a potential candidate for the future of high-speed non-volatile memory, however significant improvements in cell design is crucial for its success in the mainstream market. Due to the asymmetric geometry of phase change mushroom cells and the high temperature gradients generated, thermoelectric effects play a key role in determining energy consumption, cell performance, and reliability. In this study, rotationally symmetric 2D finite element simulations using COMSOL Multiphysics are implemented for GeSbTe (GST). Temperature dependent material parameters (electrical conductivity, thermal conductivity, heat capacity, and Seebeck coefficient) are included in the model for accuracy. Switching the direction of current shows a large change in peak molten volume within the cell, as well as current and power consumption.

  15. Working memory load predicts visual search efficiency: Evidence from a novel pupillary response paradigm.

    Science.gov (United States)

    Attar, Nada; Schneps, Matthew H; Pomplun, Marc

    2016-10-01

    An observer's pupil dilates and constricts in response to variables such as ambient and focal luminance, cognitive effort, the emotional stimulus content, and working memory load. The pupil's memory load response is of particular interest, as it might be used for estimating observers' memory load while they are performing a complex task, without adding an interruptive and confounding memory test to the protocol. One important task in which working memory's involvement is still being debated is visual search, and indeed a previous experiment by Porter, Troscianko, and Gilchrist (Quarterly Journal of Experimental Psychology, 60, 211-229, 2007) analyzed observers' pupil sizes during search to study this issue. These authors found that pupil size increased over the course of the search, and they attributed this finding to accumulating working memory load. However, since the pupil response is slow and does not depend on memory load alone, this conclusion is rather speculative. In the present study, we estimated working memory load in visual search during the presentation of intermittent fixation screens, thought to induce a low, stable level of arousal and cognitive effort. Using standard visual search and control tasks, we showed that this paradigm reduces the influence of non-memory-related factors on pupil size. Furthermore, we found an early increase in working memory load to be associated with more efficient search, indicating a significant role of working memory in the search process.

  16. A Latent Variables Examination of Processing Speed, Response Inhibition, and Working Memory during Typical Development

    Science.gov (United States)

    McAuley, Tara; White, Desiree A.

    2011-01-01

    This study addressed three related aims: (a) to replicate and extend previous work regarding the nonunitary nature of processing speed, response inhibition, and working memory during development; (b) to quantify the rate at which processing speed, response inhibition, and working memory develop and the extent to which the development of these…

  17. 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.

  18. 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.

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

    Science.gov (United States)

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

    2009-08-27

    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 (T(EM)) 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 and tumor destruction nearly identical to that of vaccine-stimulated T(EM) cells. This programmed response was associated with an interval of antigen-independent interferon-gamma (IFN-gamma) release that facilitated the dynamic expression of the major histocompatibility complex class I restriction element H-2D(b) on responding tumor cells, leading to recognition and subsequent tumor lysis. Delaying cell transfer for more than 24 hours after stimulation or infusion of cells deficient in IFN-gamma entirely abrogated the benefit of the programmed response, whereas transfer of cells unable to respond to IFN-gamma had no detriment to antitumor immunity. These findings extend the phenomenon of a programmable effector response to memory CD8(+) T cells and have major implications for the design of current adoptive-cell transfer trials.

  20. 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).

  1. 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.

  2. A novel single-dose dengue subunit vaccine induces memory immune responses.

    Directory of Open Access Journals (Sweden)

    Chen-Yi Chiang

    Full Text Available To protect against dengue viral infection, a novel lipidated dengue subunit vaccine was rationally designed to contain the consensus amino acid sequences derived from four serotypes of dengue viruses. We found that the lipidated consensus dengue virus envelope protein domain III (LcED III is capable of activating antigen-presenting cells and enhancing cellular and humoral immune responses. A single-dose of LcED III immunization in mice without extra adjuvant formulation is sufficient to elicit neutralizing antibodies against all four serotypes of dengue viruses. In addition, strong memory responses were elicited in mice immunized with a single-dose of LcED III. Quick, anamnestic neutralizing antibody responses to a live dengue virus challenge were elicited at week 28 post-immunization. These results demonstrate the promising possibility of a future successful tetravalent vaccine against dengue viral infections that utilizes one-dose vaccination with LcED III.

  3. 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.

  4. Alefacept (anti-CD2 causes a selective reduction in circulating effector memory T cells (Tem and relative preservation of central memory T cells (Tcm in psoriasis

    Directory of Open Access Journals (Sweden)

    Novitskaya Inna

    2007-06-01

    Full Text Available Abstract Background Alefacept (anti-CD2 biological therapy selectively targets effector memory T cells (Tem in psoriasis vulgaris, a model Type 1 autoimmune disease. Methods Circulating leukocytes were phenotyped in patients receiving alefacept for moderate to severe psoriasis. Results In all patients, this treatment caused a preferential decrease in effector memory T cells (CCR7- CD45RA- (mean 63% reduction for both CD4+ and CD8+ Tem, while central memory T cells (Tcm (CCR7+CD45RA- were less affected, and naïve T cells (CCR7+CD45RA+ were relatively spared. Circulating CD8+ effector T cells and Type 1 T cells (IFN-γ-producing were also significantly reduced. Conclusion Alefacept causes a selective reduction in circulating effector memory T cells (Tem and relative preservation of central memory T cells (Tcm in psoriasis.

  5. Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol.

    Science.gov (United States)

    Wu, Y W C; Du, X; van den Buuse, M; Hill, R A

    2015-01-20

    The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol-parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/-) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF(+/-) mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.

  6. Associations of Unilateral Whisker and Olfactory Signals Induce Synapse Formation and Memory Cell Recruitment in Bilateral Barrel Cortices: Cellular Mechanism for Unilateral Training Toward Bilateral Memory

    Science.gov (United States)

    Gao, Zilong; Chen, Lei; Fan, Ruicheng; Lu, Wei; Wang, Dangui; Cui, Shan; Huang, Li; Zhao, Shidi; Guan, Sudong; Zhu, Yan; Wang, Jin-Hui

    2016-01-01

    Somatosensory signals and operative skills learned by unilateral limbs can be retrieved bilaterally. In terms of cellular mechanism underlying this unilateral learning toward bilateral memory, we hypothesized that associative memory cells in bilateral cortices and synapse innervations between them were produced. In the examination of this hypothesis, we have observed that paired unilateral whisker and odor stimulations led to odorant-induced whisker motions in bilateral sides, which were attenuated by inhibiting the activity of barrel cortices. In the mice that showed bilateral cross-modal responses, the neurons in both sides of barrel cortices became to encode this new odor signal alongside the innate whisker signal. Axon projections and synapse formations from the barrel cortex, which was co-activated with the piriform cortex, toward its contralateral barrel cortex (CBC) were upregulated. Glutamatergic synaptic transmission in bilateral barrel cortices was upregulated and GABAergic synaptic transmission was downregulated. The associative activations of the sensory cortices facilitate new axon projection, glutamatergic synapse formation and GABAergic synapse downregulation, which drive the neurons to be recruited as associative memory cells in the bilateral cortices. Our data reveal the productions of associative memory cells and synapse innervations in bilateral sensory cortices for unilateral training toward bilateral memory. PMID:28018178

  7. Associations of unilateral whisker and olfactory signals induce synapse formation and memory cell recruitment in bilateral barrel cortices: cellular mechanism for unilateral training toward bilateral memory

    Directory of Open Access Journals (Sweden)

    Zilong Gao

    2016-12-01

    Full Text Available Somatosensory signals and operative skills learned by unilateral limbs can be retrieved bilaterally. In terms of cellular mechanism underlying this unilateral learning toward bilateral memory, we hypothesized that associative memory cells in bilateral cortices and synapse innervations between them were produced. In the examination of this hypothesis, we have observed that paired unilateral whisker and odor stimulations led to odorant-induced whisker motions in bilateral sides, which were attenuated by inhibiting the activity of barrel cortices. In the mice that showed bilateral cross-modal responses, the neurons in both sides of barrel cortices became to encode this new odor signal alongside the innate whisker signal. Axon projections and synapse formations from the barrel cortex, which was co-activated with the piriform cortex, toward its contralateral barrel cortex were upregulated. Glutamatergic synaptic transmission in bilateral barrel cortices was upregulated and GABAergic synaptic transmission was downregulated. The associative activations of the sensory cortices facilitate new axon projection, glutamatergic synapse formation and GABAergic synapse downregulation, which drive the neurons to be recruited as associative memory cells in the bilateral cortices. Our data reveals the productions of associative memory cells and synapse innervations in bilateral sensory cortices for unilateral training toward bilateral memory.

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

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    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

  9. ANCA patients have T cells responsive to complementary PR-3 antigen

    OpenAIRE

    2008-01-01

    Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3138-169-peptide; while ...

  10. CMV and the art of memory maintenance.

    Science.gov (United States)

    Klenerman, Paul; Dunbar, P Rod

    2008-10-17

    The CD8(+) T cell responses to CMV gradually increase in magnitude over time-so-called memory "inflation." In this issue of Immunity, Snyder et al. (2008) examine the dynamics of memory inflation and demonstrate continuous turnover of inflating T cells, drawing on both memory cells and naive cells to replace them.

  11. Glucocorticoids mediate stress-induced impairment of retrieval of stimulus-response memory.

    Science.gov (United States)

    Atsak, Piray; Guenzel, Friederike M; Kantar-Gok, Deniz; Zalachoras, Ioannis; Yargicoglu, Piraye; Meijer, Onno C; Quirarte, Gina L; Wolf, Oliver T; Schwabe, Lars; Roozendaal, Benno

    2016-05-01

    Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1mg/kg), the corticosterone-synthesis inhibitor metyrapone (35mg/kg) or were left untreated 1h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress

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

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    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.

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

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    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.

  14. Making memory at birth: understanding the differentiation of natural killer T cells.

    Science.gov (United States)

    Engel, Isaac; Kronenberg, Mitchell

    2012-04-01

    Glycolipid reactive natural killer T cells with an invariant TCR α-chain (iNKT cells) are a conserved population of T lymphocytes with a distinct anatomical distribution and functional properties. The differentiation pathway of iNKT cells branches off from mainstream thymocyte differentiation at the double positive stage, and recent work has revealed how signaling events early in the iNKT cell pathway imprint a memory-like behavior on these cells. Additionally, unique molecular interactions governing iNKT cell development and tissue distribution have been uncovered recently, building up our knowledge of the complex network of interactions that form this population. Novel autologous antigens for these cells have been identified, although it has not yet been resolved if there is single endogenous antigen responsible for both positive selection and/or peripheral activation.

  15. 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.

  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. 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…

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. Modulation of Memory T Cells to Control Acquired Bone Marrow Failure

    Science.gov (United States)

    2016-01-01

    Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837-851 (2002). 11. Lanzavecchia...analysis of histone methylation reveals chromatin state- based regulation of gene transcription and function of memory CD8+ T cells. Immunity 30, 912...AWARD NUMBER: W81XWH-11-1-0294 TITLE: Modulation of Memory T Cells to Control Acquired Bone Marrow Failure PRINCIPAL INVESTIGATOR: Yi

  3. In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo.

    Science.gov (United States)

    Nojima, Takuya; Haniuda, Kei; Moutai, Tatsuya; Matsudaira, Moeko; Mizokawa, Sho; Shiratori, Ikuo; Azuma, Takachika; Kitamura, Daisuke

    2011-09-06

    In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B(mem)) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse naïve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM/D, but not IgE, differentiate into B(mem) cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B(mem) cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B(mem) cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

  4. Chemoprophylaxis with sporozoite immunization in P. knowlesi rhesus monkeys confers protection and elicits sporozoite-specific memory T cells in the liver

    Science.gov (United States)

    Spring, Michele D.; Yongvanitchit, Kosol; Kum-Arb, Utaiwan; Limsalakpetch, Amporn; Im-Erbsin, Rawiwan; Ubalee, Ratawan; Vanachayangkul, Pattaraporn; Remarque, Edmond J.; Angov, Evelina; Smith, Philip L.; Saunders, David L.

    2017-01-01

    Whole malaria sporozoite vaccine regimens are promising new strategies, and some candidates have demonstrated high rates of durable clinical protection associated with memory T cell responses. Little is known about the anatomical distribution of memory T cells following whole sporozoite vaccines, and immunization of nonhuman primates can be used as a relevant model for humans. We conducted a chemoprophylaxis with sporozoite (CPS) immunization in P. knowlesi rhesus monkeys and challenged via mosquito bites. Half of CPS immunized animals developed complete protection, with a marked delay in parasitemia demonstrated in the other half. Antibody responses to whole sporozoites, CSP, and AMA1, but not CelTOS were detected. Peripheral blood T cell responses to whole sporozoites, but not CSP and AMA1 peptides were observed. Unlike peripheral blood, there was a high frequency of sporozoite-specific memory T cells observed in the liver and bone marrow. Interestingly, sporozoite-specific CD4+ and CD8+ memory T cells in the liver highly expressed chemokine receptors CCR5 and CXCR6, both of which are known for liver sinusoid homing. The majority of liver sporozoite-specific memory T cells expressed CD69, a phenotypic marker of tissue-resident memory (TRM) cells, which are well positioned to rapidly control liver-stage infection. Vaccine strategies that aim to elicit large number of liver TRM cells may efficiently increase the efficacy and durability of response against pre-erythrocytic parasites. PMID:28182750

  5. Identification of Caucasian CD4 T cell epitopes on the circumsporozoite protein of Plasmodium vivax. T cell memory.

    Science.gov (United States)

    Bilsborough, J; Carlisle, M; Good, M F

    1993-07-15

    We have identified a population of Caucasians with a defined past history of infection with Plasmodium vivax malaria. Using purified synthetic peptides overlapping the sequence of the circumsporozoite protein, we determined the percentage of individuals whose T cells proliferated or secreted IFN-gamma in response to peptide stimulation, for both this population and a population of nonmalaria-exposed control individuals. A number of peptides were recognized by both groups, but 11 peptides were uniquely recognized by the exposed population, and thus represented malaria-specific T cell epitopes. CD4 T cells were found to be responsible for the proliferative response. Humans last exposed to vivax sporozoites as long ago as 49 yr responded as well or better to these malaria-specific epitopes as individuals exposed within the previous month. Since such malaria-induced memory response may not be a feature of Plasmodium falciparum infections, and since P. falciparum does not have a persisting hypnozoite stage, our data argue that the persistence of T cell memory to vivax epitopes may result from antigenic persistence in the liver.

  6. Simultaneous Assessment of Rotavirus-Specific Memory B Cells and Serological Memory after B Cell Depletion Therapy with Rituximab

    Science.gov (United States)

    Herrera, Daniel; Rojas, Olga L.; Duarte-Rey, Carolina; Mantilla, Rubén D.; Ángel, Juana; Franco, Manuel A.

    2014-01-01

    The mechanisms that contribute to the maintenance of serological memory are still unclear. Rotavirus (RV) memory B cells (mBc) are enriched in IgM+ and CD27- subpopulations, which are associated with autoimmune diseases pathogenesis. In patients with autoimmune diseases treated with Rituximab (RTX), some autoantibodies (auto-Abs) decrease after treatment, but other auto-Abs and pathogen-specific IgG Abs remain unchanged. Thus, maintenance of autoimmune and pathogen-specific serological memory may depend on the type of antigen and/or Ab isotype evaluated. Antigen-specific mBc and antigen-specific Abs of different isotypes have not been simultaneously assessed in patients after RTX treatment. To study the relationship between mBc subpopulations and serological memory we characterized total, RV- and tetanus toxoid (TT)-specific mBc by flow cytometry in patients with autoimmune diseases before and after treatment with RTX. We also measured total, RV- and TT-Abs, and some auto-Abs by kinetic nephelometry, ELISA, and EliA tests, respectively. Minor differences were observed between the relative frequencies of RV-mBc in healthy controls and patients with autoimmune disease. After RTX treatment, naïve Bc and total, RV- and TT-specific mBc [IgM+, switched (IgA+/IgG+), IgM+ only, IgD+ only, and CD27- (IgA+/IgG+/IgM+)] were significantly diminished. An important decrease in total plasma IgM and minor decreases in total IgG and IgA levels were also observed. IgM rheumatoid factor, IgG anti-CCP, and IgG anti-dsDNA were significantly diminished. In contrast, RV-IgA, RV-IgG and RV-IgG1, and TT-IgG titers remained stable. In conclusion, in patients with autoimmunity, serological memory against RV and TT seem to be maintained by long-lived plasma cells, unaffected by RTX, and an important proportion of total IgM and serological memory against some auto-antigens seem to be maintained by short-lived plasma cells, dependent on mBc precursors depleted by RTX. PMID:24819618

  7. Prolonged presence of effector-memory CD8 T cells in the central nervous system after dengue virus encephalitis.

    Science.gov (United States)

    van der Most, Robbert G; Murali-Krishna, Kaja; Ahmed, Rafi

    2003-01-01

    Dengue virus infection in the central nervous system (CNS) of immunized mice results in a strong influx of CD8 T cells into the brain. Whereas the kinetics of the splenic antiviral response are conventional, i.e. expansion followed by a rapid drop in the frequency of specific CD8 T cells, dengue virus-specific CD8 T cells are retained in the CNS at a high frequency. These CD8 T cells display a partially activated phenotype (CD69(high), Ly-6A/E(high), CD62L(low)), characteristic for effector-memory T cells. CD43 expression, visualized by staining with the 1B11 mAb, decreased in time, suggesting that these persisting CD8 T cells differentiated into memory cells. These data add to the growing evidence implicating the CNS as a non-lymphoid tissue capable of supporting prolonged T cell survival/maintenance.

  8. Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals

    OpenAIRE

    Andrew Lucas; Michaela Lucas; Anette Strhyn; Keane, Niamh M.; Elizabeth McKinnon; Rebecca Pavlos; Ellen M Moran; Viola Meyer-Pannwitt; Silvana Gaudieri; Lloyd D'Orsogna; Spyros Kalams; Ostrov, David A.; Søren Buus; Bjoern Peters; Simon Mallal

    2015-01-01

    Background 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 hig...

  9. 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.

  10. 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

    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...... 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...

  11. 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.

  12. TLR9-adjuvanted pneumococcal conjugate vaccine induces antibody-independent memory responses in HIV-infected adults.

    Science.gov (United States)

    Offersen, Rasmus; Melchjorsen, Jesper; Paludan, Søren R; Østergaard, Lars; Tolstrup, Martin; Søgaard, Ole S

    2012-08-01

    HIV-patients have excess of pneumococcal infection. We immunized 40 HIV-patients twice with pneumococcal conjugate vaccine (Prevnar, Pfizer) +/- a TLR9 agonist (CPG 7909). Peripheral blood mononuclear cells were stimulated with pneumococcal polysaccharides and cytokine concentrations measured. The CPG 7909 adjuvant group had significantly higher relative cytokine responses than the placebo group for IL-1β, IL-2R, IL-6, IFN-γ and MIP-β, which, did not correlate with IgG antibody responses. These findings suggests that CPG 7909 as adjuvant to pneumococcal conjugate vaccine induces cellular memory to pneumococcal polysaccharides in HIV-patients, independently of the humoral response.

  13. Miniaturized vortex transitional Josephson memory cell by a vertically integrated device structure

    Energy Technology Data Exchange (ETDEWEB)

    Nagasawa, Shuichi; Tahara, Shuichi; Numata, Hideaki; Tsuchida, Sanae (NEC Corp., Tsukuba (Japan))

    1994-03-01

    We have developed the smallest Josephson nondestructive read-out (NDRO) memory cell, called a vortex transitional (VT) memory cell, for a Josephson high-speed 16-Kbit RAM. Its size is 22 x 22 microns(sup 2), which is only 16% of the size of previously developed VT memory cells used in Josephson 4-Kbit RAM. This is achieved by developing a vertically integrated device structure and refining small-junction technology. The cell consists of Nb/AlO(sub x)/Nb junctions, three Nb wirings, SiO2 insulators and Mo resistors. The VT memory cells operate properly, with a large operating margin of +/- 20%. 13 refs.

  14. 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.

  15. Germinal center selection and the development of memory B and plasma cells.

    Science.gov (United States)

    Shlomchik, Mark J; Weisel, Florian

    2012-05-01

    A hallmark of adaptive immune responses is the generation of long-lived protection after primary exposure to a pathogen. In humoral responses, this protection stems from a combination of sustained antibody titers and long-lived memory B cells (MBCs), with the former deriving from long-lived plasma cells (PCs). Both types of cell are thought to primarily derive from the germinal center (GC), a unique structure that forms during the immune response to many types of antigenic stimuli. GCs are seeded by antigen-specific B and T cells that were previously activated in the early stages of the response. The GC does not directly or immediately generate effector function; rather, it is a site of intense B-cell proliferation and cell death. GC B cells undergo both somatic hypermutation and isotype switch, and a Darwinian process very efficiently selects B cells with higher fitness for survival and expansion. GC B cells adopt a unique activation and transcriptional state, and the cells become poised to differentiate to either MBCs or PCs. Despite this general understanding of the events in the GC, the mechanisms that control both affinity selection as well as differentiation have not been well worked out. In this review, we address what is known about what determines whether GC B cells become MBCs or PCs. This is discussed in the broader context of the origins of both cell types, whether from the GC or potentially other sources. We present a model encompassing recent data from several laboratories including our own that suggests that the GC undergoes a temporal switch that alters the nature of its output from MBCs to PCs as the response progresses. We will discuss B-cell receptor signaling in the GC as it relates to potential mechanisms for affinity-based selection during the reaction.

  16. DNA methylation supports intrinsic epigenetic memory in mammalian cells.

    Directory of Open Access Journals (Sweden)

    2006-04-01

    Full Text Available We have investigated the role of DNA methylation in the initiation and maintenance of silenced chromatin in somatic mammalian cells. We found that a mutated transgene, in which all the CpG dinucleotides have been eliminated, underwent transcriptional silencing to the same extent as the unmodified transgene. These observations demonstrate that DNA methylation is not required for silencing. The silenced CpG-free transgene exhibited all the features of heterochromatin, including silencing of transcriptional activity, delayed DNA replication, lack of histone H3 and H4 acetylation, lack of H3-K4 methylation, and enrichment in tri-methyl-H3-K9. In contrast, when we tested for transgene reactivation using a Cre recombinase-mediated inversion assay, we observed a marked difference between a CpG-free and an unmodified transgene: the CpG-free transgene resumed transcription and did not exhibit markers of heterochromatin whereas the unmodified transgene remained silenced. These data indicate that methylation of CpG residues conferred epigenetic memory in this system. These results also suggest that replication delay, lack of histone H3 and H4 acetylation, H3-K4 methylation, and enrichment in tri-methyl-H3-K9 are not sufficient to confer epigenetic memory. We propose that DNA methylation within transgenes serves as an intrinsic epigenetic memory to permanently silence transgenes and prevent their reactivation.

  17. 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...

  18. 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.

  19. 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...

  20. Thermal dispersion and secondary crystallization of phase change memory cells

    Science.gov (United States)

    Deng, Y. F.; Li, Z.; Peng, J. H.; Liu, C.; Miao, X. S.

    2013-12-01

    The heat accumulation effect associated with heat dispersion process in phase change memory cell was analyzed. The pulse operating scheme was optimized. The pulse sequences with different intervals show distinct heat accumulation effect. A compact model with pulse sequence expansion was proposed, and the simulation result is close to the experiment data for a pulse sequence with interval 20 ns. The simulated R-V curves show that threshold voltage reduces with the decreasing pulse interval. The secondary crystallization and amorphization were used to explain the heat accumulation effect for high speed operation, cycling, and so on.

  1. Continuous controllable amorphization ratio of nanoscale phase change memory cells

    Science.gov (United States)

    He, Q.; Li, Z.; Peng, J. H.; Deng, Y. F.; Zeng, B. J.; Zhou, W.; Miao, X. S.

    2014-06-01

    The controllable heat behavior, including heat generation and dissipation, is one of the most important physical problems of nanoscale phase-change memory (PCM). A method based on heat accumulation effect to control heat behavior by synthetically modulating the three parameters of applied double pulses is proposed to achieve any expected amorphization ratio. A compact model of nanoscale PCM cells is used to simulate the thermal behavior and amorphization ratio under the condition of single parameter and multi-parameter change of applied double pulses. The results are in good agreement with the experimental results. Repeated experiments also prove the feasibility of continuous controllable amorphization ratio of nanoscale phase-change materials.

  2. 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.

  3. Plasmodium falciparum apical membrane antigen 1 vaccine elicits multifunctional CD4 cytokine-producing and memory T cells.

    Science.gov (United States)

    Huaman, Maria Cecilia; Mullen, Gregory E D; Long, Carole A; Mahanty, Siddhartha

    2009-08-20

    The Plasmodium falciparum apical membrane antigen 1 (AMA1) is a leading vaccine candidate and was tested for safety and immunogenicity in human Phase I Clinical Trials. PBMC from vaccine recipients were analyzed by flow cytometric methods to determine the nature of T-cell responses and AMA1-reactive memory T cells. Both CD4 and CD8 T cells produced a number of cytokines following AMA1 re-stimulation, with IL-5-producing cells at the highest frequency, consistent with a Th2 bias. The relative frequency of multifunctional cells synthesizing Th1 cytokines IFN-gamma, IL-2 and TNF-alpha changed after each vaccination. Interestingly, median fluorescence intensity measurements revealed that cells producing more than one cytokine contributed greater quantities of each cytokine than cell populations that produced each of the cytokines alone. AMA1 vaccination also elicited the development of memory cell populations, and both central and effector memory T cells were identified concurrently after the AMA1 vaccination. The detailed profile of multifunctional T-cell responses to AMA1 presented here will advance our ability to assess the immunogenicity of human malarial vaccines.

  4. 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.

  5. 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.

  6. 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...

  7. Short neuropeptide F acts as a functional neuromodulator for olfactory memory in Kenyon cells of Drosophila mushroom bodies.

    Science.gov (United States)

    Knapek, Stephan; Kahsai, Lily; Winther, Asa M E; Tanimoto, Hiromu; Nässel, Dick R

    2013-03-20

    In insects, many complex behaviors, including olfactory memory, are controlled by a paired brain structure, the so-called mushroom bodies (MB). In Drosophila, the development, neuroanatomy, and function of intrinsic neurons of the MB, the Kenyon cells, have been well characterized. Until now, several potential neurotransmitters or neuromodulators of Kenyon cells have been anatomically identified. However, whether these neuroactive substances of the Kenyon cells are functional has not been clarified yet. Here we show that a neuropeptide precursor gene encoding four types of short neuropeptide F (sNPF) is required in the Kenyon cells for appetitive olfactory memory. We found that activation of Kenyon cells by expressing a thermosensitive cation channel (dTrpA1) leads to a decrease in sNPF immunoreactivity in the MB lobes. Targeted expression of RNA interference against the sNPF precursor in Kenyon cells results in a highly significant knockdown of sNPF levels. This knockdown of sNPF in the Kenyon cells impairs sugar-rewarded olfactory memory. This impairment is not due to a defect in the reflexive sugar preference or odor response. Consistently, knockdown of sNPF receptors outside the MB causes deficits in appetitive memory. Altogether, these results suggest that sNPF is a functional neuromodulator released by Kenyon cells.

  8. 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.

  9. Effects of Postnatal Serotonin Agonism on Fear Response and Memory

    Science.gov (United States)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

  10. Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice.

    Science.gov (United States)

    Maurice, Tangui; Duclot, Florian; Meunier, Johann; Naert, Gaëlle; Givalois, Laurent; Meffre, Julie; Célérier, Aurélie; Jacquet, Chantal; Copois, Virginie; Mechti, Nadir; Ozato, Keiko; Gongora, Céline

    2008-06-01

    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 acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.

  11. Memory CD4+ T cells are suppressed by CD8+ regulatory T cells in vitro and in vivo

    Science.gov (United States)

    Long, Xin; Cheng, Qi; Liang, Huifang; Zhao, Jianping; Wang, Jian; Wang, Wei; Tomlinson, Stephen; Chen, Lin; Atkinson, Carl; Zhang, Bixiang; Chen, Xiaoping; Zhu, Peng

    2017-01-01

    Background: Acute graft rejection mediated by alloreactive memory CD4+ T cells is a major obstacle to transplantation tolerance. It has been reported that CD8+ T regulatory cells (Tregs) have the ability to induce graft tolerance by restraining the function of activated CD4+ T cells, but not including memory T cells. The aim of this study is to elucidate the effect of CD8+ Tregs on alloreactive memory CD4+ T cells. Methods: We detected Qa-1 expression and performed proliferative assay on memory CD4+ T cells. All memory CD4+ T cells were purified from mice receiving skin allografts. We performed inhibitory and cytotoxic assays on CD8+ Tregs, which were isolated from a T cell vaccination mouse model, and IL-2, IL-4, IL-10 and IFN-γ levels were measured in co-culture supernatants by ELISA. To confirm CD8+ Tregs inhibition of memory CD4+ T cells in-vivo, we utilized a murine model of cardiac allograft transplantation. Results: Memory CD4+ T cells mediated acute allograft rejection, and CD8+ Tregs suppressed the proliferation of memory CD4+ T cells. In vitro, memory CD4+ T cells were inhibited and lysed by CD8+ Tregs. There was a positive correlation between IFN-γ levels, and cell lysis rate induced by CD8+ Tregs. In-vivo studies demonstrated CD8+ Tregs prolonged graft survival times, by inhibiting CD4+ memory T cells, through a Qa-1-peptide-TCR pathway. Conclusions: CD8+ Tregs inhibit CD4+ memory T cell-mediated acute murine cardiac allograft rejection, and further prolong graft survival times. These results provide new insights into immune regulation of organ rejection. PMID:28123634

  12. The response of macrophages to a Cu-Al-Ni shape memory alloy.

    Science.gov (United States)

    Colić, Miodrag; Tomić, Sergej; Rudolf, Rebeka; Anzel, Ivan; Lojen, Gorazd

    2010-09-01

    Cu-Al-Ni shape memory alloys (SMAs) have been investigated as materials for medical devices, but little is known about their biocompatibility. The aim of this work was to study the response of rat peritoneal macrophages (PMØ) to a Cu-Al-Ni SMA in vitro, by measuring the functional activity of mitochondria, necrosis, apoptosis, and production of proinflammatory cytokines. Rapidly solidified (RS) thin ribbons were used for the tests. The control alloy was a permanent mold casting of the same composition, but without the shape memory effect. Our results showed that the control alloy was severely cytotoxic, whereas RS ribbons induced neither necrosis nor apoptosis of PMØ. These findings correlated with the data that RS ribbons are significantly more resistant to corrosion compared to the control alloy, as judged by the lesser release of Cu and Ni in the conditioning medium. However, the ribbons generated intracellular reactive oxygen species and upregulated the production of IL-6 by PMØ. These effects were almost completely abolished by conditioning the RS ribbons for 5 weeks. In conclusion, RS significantly improves the corrosion stability and biocompatibility of Cu-Al-Ni SMA. The biocompatibility of this functional material could be additionally enhanced by conditioning the ribbons in cell culture medium.

  13. 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

  14. 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.

  15. Cell-mediated immune response

    DEFF Research Database (Denmark)

    Meyer, Sonja Izquierdo; Fuglsang, Katrine; Blaakaer, Jan

    2014-01-01

    OBJECTIVE: This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. DATA SOURCES AND STUDY SELECTION: A focused...... and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two...... triggered a detectable cell-mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). CONCLUSIONS...

  16. Dopaminergic neurons write and update memories with cell-type-specific rules.

    Science.gov (United States)

    Aso, Yoshinori; Rubin, Gerald M

    2016-07-21

    Associative learning is thought to involve parallel and distributed mechanisms of memory formation and storage. In Drosophila, the mushroom body (MB) is the major site of associative odor memory formation. Previously we described the anatomy of the adult MB and defined 20 types of dopaminergic neurons (DANs) that each innervate distinct MB compartments (Aso et al., 2014a, 2014b). Here we compare the properties of memories formed by optogenetic activation of individual DAN cell types. We found extensive differences in training requirements for memory formation, decay dynamics, storage capacity and flexibility to learn new associations. Even a single DAN cell type can either write or reduce an aversive memory, or write an appetitive memory, depending on when it is activated relative to odor delivery. Our results show that different learning rules are executed in seemingly parallel memory systems, providing multiple distinct circuit-based strategies to predict future events from past experiences.

  17. Antigen and Memory CD8 T Cells: Were They Both Right?

    Directory of Open Access Journals (Sweden)

    Epelman Slava

    2007-06-01

    Full Text Available Picture yourself as a researcher in immunology. To begin your project, you ask a question: Do CD8 T cells require antigen to maintain a memory response? This question is of prime importance to numerous medical fields. In chronologic order, you digest the literature, but unfortunately, you hit a major stumbling block in the 1990s. The crux of the problem is that which so often happens in science: two well-recognized, capable groups emerge with diametrically opposed conclusions, leaving you pondering which set of wellcontrolled data to believe. Fortunately, years later, a surprising group of articles sheds light on this mystery and subtly reconciles these two positions.

  18. Design and Simulation of a Quaternary Memory Cell based on a Physical Memristor

    DEFF Research Database (Denmark)

    Nannarelli, Alberto; Taylor, Jonathan

    2016-01-01

    Memristors were theorized more than fifty years ago, but only recently physical devices with memristor’s behavior have been fabricated and shipped. In this work, we experiment on one of these physical memristors by designing a memristorbased memory cell, implementing the cell, and testing it. Our...... experiments demonstrate that the memristor technology is not yet mature for practical applications, but, nevertheless, when production will provide reliable and dependable devices, memristorbased memory systems may replace CMOS memories with some advantages....

  19. 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.

  20. 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...

  1. 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.

  2. 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.

  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. Parallel programmable nonvolatile memory using ordinary static random access memory cells

    Science.gov (United States)

    Mizutani, Tomoko; Takeuchi, Kiyoshi; Saraya, Takuya; Shinohara, Hirofumi; Kobayashi, Masaharu; Hiramoto, Toshiro

    2017-04-01

    A technique of using an ordinary static random access memory (SRAM) array for a programmable nonvolatile (NV) memory is proposed. The parallel NV writing of the entire array is achieved by simply applying high-voltage stress to the power supply terminal, after storing inverted desired data in the static random access memory (SRAM) array. Successful 2 kbit NV writing is demonstrated using a device-matrix-array (DMA) test element group (TEG) fabricated by 0.18 µm technology.

  5. Differential effects of stress-induced cortisol responses on recollection and familiarity-based recognition memory.

    Science.gov (United States)

    McCullough, Andrew M; Ritchey, Maureen; Ranganath, Charan; Yonelinas, Andrew

    2015-09-01

    Stress-induced changes in cortisol can impact memory in various ways. However, the precise relationship between cortisol and recognition memory is still poorly understood. For instance, there is reason to believe that stress could differentially affect recollection-based memory, which depends on the hippocampus, and familiarity-based recognition, which can be supported by neocortical areas alone. Accordingly, in the current study we examined the effects of stress-related changes in cortisol on the processes underlying recognition memory. Stress was induced with a cold-pressor test after incidental encoding of emotional and neutral pictures, and recollection and familiarity-based recognition memory were measured one day later. The relationship between stress-induced cortisol responses and recollection was non-monotonic, such that subjects with moderate stress-related increases in cortisol had the highest levels of recollection. In contrast, stress-related cortisol responses were linearly related to increases in familiarity. In addition, measures of cortisol taken at the onset of the experiment showed that individuals with higher levels of pre-learning cortisol had lower levels of both recollection and familiarity. The results are consistent with the proposition that hippocampal-dependent memory processes such as recollection function optimally under moderate levels of stress, whereas more cortically-based processes such as familiarity are enhanced even with higher levels of stress. These results indicate that whether post-encoding stress improves or disrupts recognition memory depends on the specific memory process examined as well as the magnitude of the stress-induced cortisol response.

  6. 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.

  7. Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes.

    Science.gov (United States)

    Narni-Mancinelli, Emilie; Campisi, Laura; Bassand, Delphine; Cazareth, Julie; Gounon, Pierre; Glaichenhaus, Nicolas; Lauvau, Grégoire

    2007-09-03

    Cytolysis, interferon gamma and tumor necrosis factor (TNF) alpha secretion are major effector mechanisms of memory CD8+ T cells that are believed to be required for immunological protection in vivo. By using mutants of the intracellular bacterium Listeria monocytogenes, we found that none of these effector activities is sufficient to protect against secondary infection with wild-type (WT) bacteria. We demonstrated that CCL3 derived from reactivated memory CD8+ T cells is required for efficient killing of WT bacteria. CCL3 induces a rapid TNF-alpha secretion by innate inflammatory mononuclear phagocytic cells (MPCs), which further promotes the production of radical oxygen intermediates (ROIs) by both MPCs and neutrophils. ROI generation is the final bactericidal mechanism involved in L. monocytogenes clearance. These results therefore uncover two levels of regulation of the antibacterial secondary protective response: (a) an antigen-dependent phase in which memory CD8+ T cells are reactivated and control the activation of the innate immune system, and (b) an antigen-independent phase in which the MPCs coordinate innate immunity and promote the bactericidal effector activities. In this context, CCL3-secreting memory CD8+ T cells are able to mediate "bystander" killing of an unrelated pathogen upon antigen-specific reactivation, a mechanism that may be important for the design of therapeutic vaccines.

  8. 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)).

  9. Recombinant poxvirus boosting of DNA-primed rhesus monkeys augments peak but not memory T lymphocyte responses.

    Science.gov (United States)

    Santra, Sampa; Barouch, Dan H; Korioth-Schmitz, Birgit; Lord, Carol I; Krivulka, Georgia R; Yu, Faye; Beddall, Margaret H; Gorgone, Darci A; Lifton, Michelle A; Miura, Ayako; Philippon, Valerie; Manson, Kelledy; Markham, Phillip D; Parrish, John; Kuroda, Marcelo J; Schmitz, Jörn E; Gelman, Rebecca S; Shiver, John W; Montefiori, David C; Panicali, Dennis; Letvin, Norman L

    2004-07-27

    Although a consensus has emerged that an HIV vaccine should elicit a cytotoxic T lymphocyte (CTL) response, the characteristics of an effective vaccine-induced T lymphocyte response remain unclear. We explored this issue in the simian human immunodeficiency virus/rhesus monkey model in the course of assessing the relative immunogenicity of vaccine regimens that included a cytokine-augmented plasmid DNA prime and a boost with DNA or recombinant pox vectors. Recombinant vaccinia virus, recombinant modified vaccinia Ankara (MVA), and recombinant fowlpox were comparable in their immunogenicity. Moreover, whereas the magnitude of the peak vaccine-elicited T lymphocyte responses in the recombinant pox virus-boosted monkeys was substantially greater than that seen in the monkeys immunized with plasmid DNA alone, the magnitudes of recombinant pox boosted CTL responses decayed rapidly and were comparable to those of the DNA-alone-vaccinated monkeys by the time of viral challenge. Consistent with these comparable memory T cell responses, the clinical protection seen in all groups of experimentally vaccinated monkeys was similar. This study, therefore, indicates that the steady-state memory, rather than the peak effector vaccine-elicited T lymphocyte responses, may be the critical immune correlate of protection for a CTL-based HIV vaccine.

  10. Combination of volatile and non-volatile functions in a single memory cell and its scalability

    Science.gov (United States)

    Kim, Hyungjin; Hwang, Sungmin; Lee, Jong-Ho; Park, Byung-Gook

    2017-04-01

    A single memory cell which combines volatile memory and non-volatile memory functions has been demonstrated with an independent asymmetric dual-gate structure. Owing to the second gate whose dielectric is composed of oxide/nitride/oxide layers, floating body effect was observed even on a fully depleted silicon-on-insulator device and the non-volatile memory function was measured. In addition, read retention characteristics of the volatile memory function depending on the non-volatile memory state were evaluated and analyzed. Further scalability in body thickness was also verified through simulation studies. These results indicate that the proposed device is a promising candidate for high-density embedded memory applications.

  11. 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.

  12. Interleukin-7 and -15 maintain pathogenic memory Th17 cells in autoimmunity.

    Science.gov (United States)

    Chen, Yihe; Chauhan, Sunil K; Tan, Xuhua; Dana, Reza

    2017-02-01

    Th17 cells are principal mediators of many autoimmune conditions. Recently, memory Th17 cells have been revealed as crucial in mediating the chronicity of various refractory autoimmune disorders; however, the underlying mechanisms maintaining memory Th17 cells have remained elusive. Here, using a preclinical model of ocular autoimmune disease we show that both IL-7 and IL-15 are critical for maintaining pathogenic memory Th17 cells. Neutralization of these cytokines leads to substantial reduction of memory Th17 cells; both IL-7 and IL-15 provide survival signals via activating STAT5, and IL-15 provides additional proliferation signals via activating both STAT5 and Akt. Topical neutralization of ocular IL-7 or IL-15 effectively reduces memory Th17 cells at the inflammatory site and draining lymphoid tissues, while topical neutralization of IL-17 alone, the major pathogenic cytokine secreted by Th17 cells, does not diminish memory Th17 cells at the draining lymphoid tissues. Our results suggest that the effective removal of pathogenic memory Th17 cells via abolishing environmental IL-7 or IL-15 is likely to be a novel strategy in the treatment of autoimmune diseases.

  13. Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype.

    Science.gov (United States)

    Chimote, Ameet A; Hajdu, Peter; Kottyan, Leah C; Harley, John B; Yun, Yeoheung; Conforti, Laura

    2016-05-01

    Ca(2+) signaling controls activation and effector functions of T lymphocytes. Ca(2+) levels also regulate NFAT activation and CD40 ligand (CD40L) expression in T cells. CD40L in activated memory T cells binds to its cognate receptor, CD40, on other cell types resulting in the production of antibodies and pro-inflammatory mediators. The CD40L/CD40 interaction is implicated in the pathogenesis of autoimmune disorders and CD40L is widely recognized as a therapeutic target. Ca(2+) signaling in T cells is regulated by Kv1.3 channels. We have developed lipid nanoparticles that deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to CD45RO(+) memory T cells and reduce the activation-induced Ca(2+) influx. Herein we report that Kv1.3-NPs reduced NFAT activation and CD40L expression exclusively in CD45RO(+) T cells. Furthermore, Kv1.3-NPs suppressed cytokine release and induced a phenotype switch of T cells from predominantly memory to naïve. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials.

  14. 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.

  15. Memory CD8(+) T cells elicited by HIV-1 lipopeptide vaccines display similar phenotypic profiles but differences in term of magnitude and multifunctionality compared with FLU- or EBV-specific memory T cells in humans.

    Science.gov (United States)

    Figueiredo, Suzanne; Charmeteau, Benedicte; Surenaud, Mathieu; Salmon, Dominique; Launay, Odile; Guillet, Jean-Gérard; Hosmalin, Anne; Gahery, Hanne

    2014-01-16

    Differentiation marker, multifunctionality and magnitude analyses of specific-CD8(+) memory T cells are crucial to improve development of HIV vaccines designed to generate cell-mediated immunity. Therefore, we fully characterized the HIV-specific CD8(+) T cell responses induced in volunteers vaccinated with HIV lipopeptide vaccines for phenotypic markers, tetramer staining, cytokine secretion, and cytotoxic activities. The frequency of ex vivo CD8(+) T cells elicited by lipopeptide vaccines is very rare and central-memory phenotype and functions of these cells were been shown to be important in AIDS immunity. So, we expanded them using specific peptides to compare the memory T cell responses induced in volunteers by HIV vaccines with responses to influenza (FLU) or Epstein Barr virus (EBV). By analyzing the differentiation state of IFN-γ-secreting CD8(+) T cells, we found a CCR7(-)CD45RA(-)CD28(+int)/CD28(-) profile (>85%) belonging to a subset of intermediate-differentiated effector T cells for HIV, FLU, and EBV. We then assessed the quality of the response by measuring various T cell functions. The percentage of single IFN-γ T cell producers in response to HIV was 62% of the total of secreting T cells compared with 35% for FLU and EBV, dual and triple (IFN-γ/IL-2/CD107a) T cell producers could also be detected but at lower levels (8% compared with 37%). Finally, HIV-specific T cells secreted IFN-γ and TNF-α, but not the dual combination like FLU- and EBV-specific T cells. Thus, we found that the functional profile and magnitude of expanded HIV-specific CD8(+) T precursors were more limited than those of to FLU- and EBV-specific CD8(+) T cells. These data show that CD8(+) T cells induced by these HIV vaccines have a similar differentiation profile to FLU and EBV CD8(+) T cells, but that the vaccine potency to induce multifunctional T cells needs to be increased in order to improve vaccination strategies.

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

    Directory of Open Access Journals (Sweden)

    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

  18. Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naive and memory T-cell subsets.

    Directory of Open Access Journals (Sweden)

    Willard Tinago

    Full Text Available BACKGROUND: Although effective antiretroviral therapy(ART increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described. METHODS: A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory, CD45RO+CD62L-(effector memory and CD45RO-CD62L+(naïve alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts, HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated. RESULTS: We recruited 190 subjects, age 42(36-48 years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors, 78.4% with HIVRNA1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3% were naïve, 36.8(29.0-40.0% central memory and 27.4(20.0-38.5% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5% were naïve, 19.9(12.7-26.6% central memory and 41.0(31.8-52.5% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007, higher nadir CD4+ count(+0.011,p1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0% versus 14.4(9.4-21.6%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567 versus 765(603-1084 cells/mm3, p<0.001. CONCLUSIONS: Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.

  19. Memory phenotype CD4 T cells undergoing rapid, nonburst-like, cytokine-driven proliferation can be distinguished from antigen-experienced memory cells.

    Directory of Open Access Journals (Sweden)

    Souheil-Antoine Younes

    2011-10-01

    Full Text Available Memory phenotype (CD44(bright, CD25(negative CD4 spleen and lymph node T cells (MP cells proliferate rapidly in normal or germ-free donors, with BrdU uptake rates of 6% to 10% per day and Ki-67 positivity of 18% to 35%. The rapid proliferation of MP cells stands in contrast to the much slower proliferation of lymphocytic choriomeningitis virus (LCMV-specific memory cells that divide at rates ranging from <1% to 2% per day over the period from 15 to 60 days after LCMV infection. Anti-MHC class II antibodies fail to inhibit the in situ proliferation of MP cells, implying a non-T-cell receptor (TCR-driven proliferation. Such proliferation is partially inhibited by anti-IL-7Rα antibody. The sequence diversity of TCRβ CDR3 gene segments is comparable among the proliferating and quiescent MP cells from conventional and germ-free mice, implying that the majority of proliferating MP cells have not recently derived from a small cohort of cells that expand through multiple continuous rounds of cell division. We propose that MP cells constitute a diverse cell population, containing a subpopulation of slowly dividing authentic antigen-primed memory cells and a majority population of rapidly proliferating cells that did not arise from naïve cells through conventional antigen-driven clonal expansion.

  20. VHDL-based programming environment for Floating-Gate analog memory cell

    Directory of Open Access Journals (Sweden)

    Carlos Alberto dos Reis Filho

    2005-02-01

    Full Text Available An implementation in CMOS technology of a Floating-Gate Analog Memory Cell and Programming Environment is presented. A digital closed-loop control compares a reference value set by user and the memory output and after cycling, the memory output is updated and the new value stored. The circuit can be used as analog trimming for VLSI applications where mechanical trimming associated with postprocessing chip is prohibitive due to high costs.

  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. Lateralized odor preference training in rat pups reveals an enhanced network response in anterior piriform cortex to olfactory input that parallels extended memory.

    Science.gov (United States)

    Fontaine, Christine J; Harley, Carolyn W; Yuan, Qi

    2013-09-18

    The present study examines synaptic plasticity in the anterior piriform cortex (aPC) using ex vivo slices from rat pups given lateralized odor preference training. In the early odor preference learning model, a brief 10 min training session yields 24 h memory, while four daily sessions yield 48 h memory. Odor preference memory can be lateralized through naris occlusion as the anterior commissure is not yet functional. AMPA receptor-mediated postsynaptic responses in the aPC to lateral olfactory tract input, shown to be enhanced at 24 h, are no longer enhanced 48 h after a single training session. Following four spaced lateralized trials, the AMPA receptor-mediated fEPSP is enhanced in the trained aPC at 48 h. Calcium imaging of aPC pyramidal cells within 48 h revealed decreased firing thresholds in the pyramidal cell network. Thus multiday odor preference training induced increased odor input responsiveness in previously weakly activated aPC cells. These results support the hypothesis that increased synaptic strength in olfactory input networks mediates odor preference memory. The increase in aPC network activation parallels behavioral memory.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Explicit memory creation during sleep demonstrates a causal role of place cells in navigation.

    Science.gov (United States)

    de Lavilléon, Gaetan; Lacroix, Marie Masako; Rondi-Reig, Laure; Benchenane, Karim

    2015-04-01

    Hippocampal place cells assemblies are believed to support the cognitive map, and their reactivations during sleep are thought to be involved in spatial memory consolidation. By triggering intracranial rewarding stimulations by place cell spikes during sleep, we induced an explicit memory trace, leading to a goal-directed behavior toward the place field. This demonstrates that place cells' activity during sleep still conveys relevant spatial information and that this activity is functionally significant for navigation.

  7. Habituation and the Response to Discrepancy: Implications for Memory, Retrieval, and Processing Perceptual Information.

    Science.gov (United States)

    McCall, Robert B.

    Function of attention in infants is explored. Assuming (1) that infants respond differently to novel situations than to familiar ones; (2) that the infant's pattern of response is a partial reflection of the process of acquiring a perceptual memory of the stimulus, and (3) that sex differences may occur in the rate of habituation, 120 infants…

  8. 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.

  9. 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…

  10. Cells involved in the immune response. XXIX Establishment of optimal conditions for the primary and secondary immune responses by rabbit lymphoid cells in vitro.

    Science.gov (United States)

    Richter, M; Behelak, Y

    1975-01-01

    Attempts were made to initiate the primary and secondary humoral immune responses to sheep red blood cells (SRBC) in vitro as determined by the hemolytic plaque-forming cell (PFC) response, with cell suspensions prepared from a variety of lymphoid organs of the rabbit- thymus, bone marrow, spleen, appendix, sacculus rotundus, Peyer's patches, popliteal lymph node and circulating leukocytes. A number of different media and gaseous phases were utilized in order to establish the optimal conditions for the immune response in vitro. The induction of a secondary PFC response was consistently obtained with 'memory' spleen cells obtained from rabbits 3-6 months following intravenous immunization with SRBC but not with cells of any of the other lymphoid organs, and this response probably represents the activity of memory cells which reside in the rabbit spleen. A primary response was observed only with 'normal' spleen cells, and the medium which faciliated the response was different from that which facilitated the induction of the secondary response in vitro. It was also observed, using a medium in which normal spleen cells were incapable of generating PFC', that mixed cultures of normal spleen and normal appendix or bone marrow cells could give a marked PFC reponse in vitro. Whether the PFC response to SRBCs obtained with the lymphoid cells of normal, unimmunized rabbits represent a true primary response, a secondary response, or a response of a different nature as a consequence of continuous subthreshold immunization of the rabbit with enteric microorganisms which cross-react with the antigen, remains to be determined. However, out initial successes with cultures consisting of cells of at least two distinct lymphoid organs in cases where the cells of any one of these organs could not respond, suggest that interaction of at least two functionally distinct cells is required and that the repsonse observed in vitro is probably a primary immune response.

  11. Circadian control of antigen-specific T cell responses

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  13. 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

  14. 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....... This paper presents the theoretical basis for the design of "floating-gate'' switched current memory cells by giving a detailed description and analysis of the most important impacts degrading the performance of the cells. To support the theoretical assumptions circuits based on "floating-gate'' switched...... current memory cells were designed using a CMOS process with threshold voltages V-T0n = \\V-T0p\\ = 0.9 V for the n- and p-channel devices. Both hand calculations and PSPICE simulations showed that the designed example switched current memory cell allowed a maximum signal range better than +/-18 mu...

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

    Directory of Open Access Journals (Sweden)

    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.

  16. 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 Numbers of HBsAg-specific B-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 (pnumbers of HBsAg-specific B-cells were significantly correlated (RS=0.66, psignificant 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.

  17. 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.

  18. 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.

  19. 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.

  20. Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype.

    Science.gov (United States)

    Demento, Stacey L; Cui, Weiguo; Criscione, Jason M; Stern, Eric; Tulipan, Jacob; Kaech, Susan M; Fahmy, Tarek M

    2012-06-01

    Particulate vaccines are emerging promising technologies for the creation of tunable prophylactics against a wide variety of conditions. Vesicular and solid biodegradable polymer platforms, exemplified by liposomes and polyesters, respectively, are two of the most ubiquitous platforms in vaccine delivery studies. Here we directly compared the efficacy of each in a long-term immunization study and in protection against a model bacterial antigen. Immunization with poly(lactide-co-glycolide) (PLGA) nanoparticles elicited prolonged antibody titers compared to liposomes and alum. The magnitude of the cellular immune response was also highest in mice vaccinated with PLGA, which also showed a higher frequency of effector-like memory T cell phenotype, leading to an effective clearance of intracellular bacteria. The difference in performance of these two common particulate platforms is shown not to be due to material differences but appears to be connected to the kinetics of antigen delivery. Thus, this study highlights the importance of sustained antigen release mediated by particulate platforms and its role in the long-term appearance of effector memory cellular response.

  1. 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.

  2. Epigenetic memory in somatic cell nuclear transfer and induced pluripotency: evidence and implications.

    Science.gov (United States)

    Firas, Jaber; Liu, Xiaodong; Polo, Jose M

    2014-07-01

    Six decades ago, seminal work conducted by John Gurdon on genome conservation resulted in major advancements towards nuclear reprogramming technologies such as somatic cell nuclear transfer (SCNT), cell fusion and transcription factor mediated reprogramming. This revolutionized our views regarding cell fate conversion and development. These technologies also shed light on the role of the epigenome in cellular identity, and how the memory of the cell of origin affects the reprogrammed cell. This review will discuss recent work on epigenetic memory retained in pluripotent cells derived by SCNT and transcription factor mediated reprogramming, and the challenges attached to it.

  3. Bone Marrow Mesenchymal Stem Cells Enhance the Differentiation of Human Switched Memory B Lymphocytes into Plasma Cells in Serum-Free Medium

    Science.gov (United States)

    Gervais-St-Amour, Catherine

    2016-01-01

    The differentiation of human B lymphocytes into plasma cells is one of the most stirring questions with regard to adaptive immunity. However, the terminal differentiation and survival of plasma cells are still topics with much to be discovered, especially when targeting switched memory B lymphocytes. Plasma cells can migrate to the bone marrow in response to a CXCL12 gradient and survive for several years while secreting antibodies. In this study, we aimed to get closer to niches favoring plasma cell survival. We tested low oxygen concentrations and coculture with mesenchymal stem cells (MSC) from human bone marrow. Besides, all cultures were performed using an animal protein-free medium. Overall, our model enables the generation of high proportions of CD38+CD138+CD31+ plasma cells (≥50%) when CD40-activated switched memory B lymphocytes were cultured in direct contact with mesenchymal stem cells. In these cultures, the secretion of CXCL12 and TGF-β, usually found in the bone marrow, was linked to the presence of MSC. The level of oxygen appeared less impactful than the contact with MSC. This study shows for the first time that expanded switched memory B lymphocytes can be differentiated into plasma cells using exclusively a serum-free medium. PMID:27872867

  4. Stress and emotional memory retrieval: effects of sex and cortisol response.

    Science.gov (United States)

    Buchanan, Tony W; Tranel, Daniel

    2008-02-01

    In some situations, memory is enhanced by stressful experience, while in others, it is impaired. The specific components of the stress-response that may result in these differing effects remain unclear, and the current study sought to address this knowledge gap. Forty healthy participants (20 women, 20 men) were exposed to emotionally arousing and neutral pictures. Twenty-four hours later, 20 participants underwent a social stressor (speech and math tests), and 20 underwent a control reading task, both followed by a delayed free recall task. Cortisol responders to the stress condition (5 men and 1 woman) showed reduced memory retrieval for both neutral and emotionally arousing pictures. Men and women in the stress condition who did not produce a cortisol response showed increased retrieval of unpleasant pictures compared to controls. The results provide further evidence that cortisol is a primary effector in the stress-induced memory retrieval deficit. At the same time, stress can enhance memory retrieval performance, especially for emotional stimuli, when the cortisol response is absent.

  5. Isothermal recovery response and constitutive model of thermoset shape memory polymers

    Science.gov (United States)

    Tan, Huifeng; Zhou, Tao; Liu, Yuyan; Lan, Lan

    2012-04-01

    Deformation recovery capability is one of the important indexes to examination shape memory effect of the shape memory polymers (SMPs). And the shape memory characteristic of SMPs is closely related to different phase states and mechanical properties above and below the glass transition temperature (Tg). In this paper, we investigated the strain recovery response of a thermoset shape memory epoxy resin modified by polyurethane (PU) through uniaxial compression experiments under various isothermal conditions and strain rates and developed a "three-phase" constitutive model based on phase transition concept, which including stationary phase, active phase and frozen phase. This model established the mutual transformation relationships between frozen phase and active phase of SMPs by introducing temperature switch function, which presents the stain storage and release process of SMPs under loading and changing temperature environment. Besides, the proposed model represents the SMPs deformation process of viscous hysteresis response by employing the rheological elements description of the three phases. The numerical results agree very well with experiment results of stress-strain response curve of isothermal compression/unloading test, which validated this model can predict the finite deformation behavior of SMPs.

  6. 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.

  7. 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.

  8. Ultrafast response of phase-change memory materials

    Science.gov (United States)

    Lindenberg, Aaron

    2015-03-01

    We describe recent experiments probing the first steps in the amorphous-to-crystalline transition that underlies the behavior of phase-change materials, examining both electric-field-driven and optically-driven responses in GeSbTe and AgInSbTe alloys. First measurements using femtosecond x-ray pulses at the Linac Coherent Light Source will be described which enable direct snapshots of these transitions and associated intermediate states. We will also describe studies using single-cycle terahertz pulses as an all-optical means of biasing phase-change materials on femtosecond time-scales in order to examine the threshold-switching response on microscopically relevant time-scales. These studies indicate nonlinear scaling with the applied electric field and field-induced crystallization as evidenced by ultrafast optical reflectivity and conductivity measurements, from which a mechanistic understanding of these phase transitions can be obtained.

  9. Memory conformity affects inaccurate memories more than accurate memories.

    Science.gov (United States)

    Wright, Daniel B; Villalba, Daniella K

    2012-01-01

    After controlling for initial confidence, inaccurate memories were shown to be more easily distorted than accurate memories. In two experiments groups of participants viewed 50 stimuli and were then presented with these stimuli plus 50 fillers. During this test phase participants reported their confidence that each stimulus was originally shown. This was followed by computer-generated responses from a bogus participant. After being exposed to this response participants again rated the confidence of their memory. The computer-generated responses systematically distorted participants' responses. Memory distortion depended on initial memory confidence, with uncertain memories being more malleable than confident memories. This effect was moderated by whether the participant's memory was initially accurate or inaccurate. Inaccurate memories were more malleable than accurate memories. The data were consistent with a model describing two types of memory (i.e., recollective and non-recollective memories), which differ in how susceptible these memories are to memory distortion.

  10. 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.

  11. Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory.

    Science.gov (United States)

    Mika, Agnieszka; Mazur, Gabriel J; Hoffman, Ann N; Talboom, Joshua S; Bimonte-Nelson, Heather A; Sanabria, Federico; Conrad, Cheryl D

    2012-10-01

    Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, the fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague-Dawley rats were first trained on the RAWM and subsequently trained on FMI. After acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when sucrose reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing imprecision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher's r-to-z transformation revealed no significant differences between control and stress groups with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been directly compared within the same animals after chronic stress, using FMI, an appetitive task, and RAWM, a nonappetitive task.

  12. 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.

  13. P3 response during short-term memory retrieval revisited by a spatio-temporal analysis.

    Science.gov (United States)

    Ergen, Mehmet; Yildirim, Erol; Uslu, Atilla; Gürvit, Hakan; Demiralp, Tamer

    2012-05-01

    The most reported event related potential (ERP) parameter during short-term memory retrieval has been P3 wave and the association has been built on the relation between P3 latency and reaction times. The aim of this study is to identify an ERP component that reflects the memory scanning process preceding the decision making stage which has been associated with the P3 peak. A spatiotemporal analysis was applied on the P3 and pre-P3 period of ERP responses obtained during the retrieval phase of the Sternberg paradigm with two memory load conditions (3 and 5 letters in the memory set). In the easy task condition with the fastest reaction times (positive probes of 3 letters condition), a single P3 was observed, whereas P3 was split into two peaks in responses to probe items of more demanding task conditions. The single P3 peak and the later components of the split P3 peaks displayed the typical P3 topography. On the other hand, the topographic mapping of the earlier peak of the split P3 wave and ascending part of the single P3 peak revealed a right parietal topography. The onset time of this earlier right lateralized topography was stable among all conditions but it persisted longer in the high memory load condition. We conclude that the right-lateralized positivity in the pre-P3 period reflects the memory scanning process followed by the P3 peak with midline parietal topography reflecting the decision making process.

  14. Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination.

    Science.gov (United States)

    Fuertes Marraco, Silvia A; Soneson, Charlotte; Cagnon, Laurène; Gannon, Philippe O; Allard, Mathilde; Abed Maillard, Samia; Montandon, Nicole; Rufer, Nathalie; Waldvogel, Sophie; Delorenzi, Mauro; Speiser, Daniel E

    2015-04-08

    Efficient and persisting immune memory is essential for long-term protection from infectious and malignant diseases. The yellow fever (YF) vaccine is a live attenuated virus that mediates lifelong protection, with recent studies showing that the CD8(+) T cell response is particularly robust. Yet, limited data exist regarding the long-term CD8(+) T cell response, with no studies beyond 5 years after vaccination. We investigated 41 vaccinees, spanning 0.27 to 35 years after vaccination. YF-specific CD8(+) T cells were readily detected in almost all donors (38 of 41), with frequencies decreasing with time. As previously described, effector cells dominated the response early after vaccination. We detected a population of naïve-like YF-specific CD8(+) T cells that was stably maintained for more than 25 years and was capable of self-renewal ex vivo. In-depth analyses of markers and genome-wide mRNA profiling showed that naïve-like YF-specific CD8(+) T cells in vaccinees (i) were distinct from genuine naïve cells in unvaccinated donors, (ii) resembled the recently described stem cell-like memory subset (Tscm), and (iii) among all differentiated subsets, had profiles closest to naïve cells. Our findings reveal that CD8(+) Tscm are efficiently induced by a vaccine in humans, persist for decades, and preserve a naïveness-like profile. These data support YF vaccination as an optimal mechanistic model for the study of long-lasting memory CD8(+) T cells in humans.

  15. CD8 T cell memory recall is enhanced by novel direct interactions with CD4 T cells enabled by MHC class II transferred from APCs.

    Directory of Open Access Journals (Sweden)

    Pablo A Romagnoli

    Full Text Available Protection against many intracellular pathogens is provided by CD8 T cells, which are thought to need CD4 T cell help to develop into effective memory CD8 T cells. Because murine CD8 T cells do not transcribe MHC class II (MHC-II genes, several models have proposed antigen presenting cells (APCs as intermediaries required for CD4 T cells to deliver their help to CD8 T cells. Here, we demonstrate the presence of MHC-II molecules on activated murine CD8 T cells in vitro as well as in vivo. These MHC-II molecules are acquired via trogocytosis by CD8 T cells from their activating APCs, particularly CD11c positive dendritic cells (DCs. Transferred MHC-II molecules on activated murine CD8 T cells were functionally competent in stimulating specific indicator CD4 T cells. CD8 T cells that were "helped" in vitro and subsequently allowed to rest in vivo showed enhanced recall responses upon challenge compared to "helpless" CD8 T cells; in contrast, no differences were seen upon immediate challenge. These data indicate that direct CD8:CD4 T cell interactions may significantly contribute to help for CD8 T cells. Furthermore, this mechanism may enable CD8 T cells to communicate with different subsets of interacting CD4 T cells that could modulate immune responses.

  16. Functional classification of memory CD8+ T cells by CX3CR1 expression

    Science.gov (United States)

    Böttcher, Jan P.; Beyer, Marc; Meissner, Felix; Abdullah, Zeinab; Sander, Jil; Höchst, Bastian; Eickhoff, Sarah; Rieckmann, Jan C.; Russo, Caroline; Bauer, Tanja; Flecken, Tobias; Giesen, Dominik; Engel, Daniel; Jung, Steffen; Busch, Dirk H.; Protzer, Ulrike; Thimme, Robert; Mann, Matthias; Kurts, Christian; Schultze, Joachim L.; Kastenmüller, Wolfgang; Knolle, Percy A.

    2015-01-01

    Localization of memory CD8+ T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX3CR1 distinguishes memory CD8+ T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX3CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8+ T cells with effector function. We find CD62LhiCX3CR1+ memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX3CR1+ memory CD8+ T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX3CR1-based functional classification will help to resolve the principles of protective CD8+ T-cell memory. PMID:26404698

  17. Circulating CCR7+ICOS+ Memory T Follicular Helper Cells in Patients with Multiple Sclerosis.

    Directory of Open Access Journals (Sweden)

    Xueli Fan

    Full Text Available This study is aimed at examining the potential roles of circulating memory T follicular helper (Tfh cells in patients with multiple sclerosis (MS.The numbers of different subsets of circulating memory Tfh cells in 25 patients with relapsed MS before and after treatment as well as 14 healthy controls (HC were examined by flow cytometry. The levels of plasma IL-21 in all patients and cerebrospinal fluid (CSF IL-21 in some MS patients and controls with non-inflammatory neuronal diseases (NND were measured by ELISA.In comparison with that in the HC, the numbers of circulating CD3+CD4+CXCR5+CD45RA-, ICOS+, CCR7+ and CCR7+ICOS+ memory Tfh cells and the levels of plasma IL-21 significantly increased in MS patients, but significantly decreased in the patients with complete remission (CR. The levels of CSF IL-21 were significantly higher in the MS patients than that in the NND patients. The numbers of CCR7+ICOS+ memory Tfh cells were positively correlated with the EDSS scores, the levels of plasma and CSF IL-21, IgG, MBP-Ab or MOG-Ab.Our findings indicated that circulating memory Tfh cells, especially CCR7+ICOS+ memory Tfh cells, may be associated with the relapse of MS and may serve as a new therapeutic target.

  18. Hyper-responsiveness to acute stress, emotional problems and poorer memory in former preterm children.

    Science.gov (United States)

    Quesada, Andrea A; Tristão, Rosana M; Pratesi, Riccardo; Wolf, Oliver T

    2014-09-01

    The prevalence of preterm birth (PTB) is high worldwide, especially in developing countries like Brazil. PTB is marked by a stressful environment in intra- as well as extrauterine life, which can affect neurodevelopment and hormonal and physiological systems and lead to long-term negative outcomes. Nevertheless, little is known about PTB and related outcomes later on in childhood. Thus, the goals of the current study were threefold: (1) comparing cortisol and alpha-amylase (sAA) profiles, including cortisol awakening response (CAR), between preterm and full-term children; (2) evaluating whether preterm children are more responsive to acute stress and (3) assessing their memory skills and emotional and behavioral profiles. Basal cortisol and sAA profiles, including CAR of 30 preterm children, aged 6 to 10 years, were evaluated. Further, we assessed memory functions using the Wide Range Assessment of Memory and Learning, and we screened behavior/emotion using the Strengths and Difficulties Questionnaire. The results of preterm children were compared to an age- and sex-matched control group. One week later, participants were exposed to a standardized laboratory stressor [Trier Social Stress Test for Children (TSST-C)], in which cortisol and sAA were measured at baseline, 1, 10 and 25 min after stressor exposure. Preterm children had higher cortisol concentrations at awakening, a flattened CAR and an exaggerated response to TSST-C compared to full-term children. These alterations were more pronounced in girls. In addition, preterm children were characterized by more emotional problems and poorer memory performance. Our findings illustrate the long-lasting and in part sex-dependent effects of PTB on the hypothalamic-pituitary-adrenal (HPA) axis, internalizing behavior and memory. The findings are in line with the idea that early adversity alters the set-point of the HPA axis, thereby creating a more vulnerable phenotype.

  19. 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.

  20. 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.

  1. Limited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization.

    Science.gov (United States)

    Bemark, Mats; Hazanov, Helena; Strömberg, Anneli; Komban, Rathan; Holmqvist, Joel; Köster, Sofia; Mattsson, Johan; Sikora, Per; Mehr, Ramit; Lycke, Nils Y

    2016-09-06

    Understanding how memory B cells are induced and relate to long-lived plasma cells is important for vaccine development. Immunity to oral vaccines has been considered short-lived because of a poor ability to develop IgA B-cell memory. Here we demonstrate that long-lived mucosal IgA memory is readily achieved by oral but not systemic immunization in mouse models with NP hapten conjugated with cholera toxin and transfer of B1-8(high)/GFP(+) NP-specific B cells. Unexpectedly, memory B cells are poorly related to long-lived plasma cells and less affinity-matured. They are α4β7-integrin(+)CD73(+)PD-L2(+)CD80(+) and at systemic sites mostly IgM(+), while 80% are IgA(+) in Peyer's patches. On reactivation, most memory B cells in Peyer's patches are GL7(-), but expand in germinal centres and acquire higher affinity and more mutations, demonstrating strong clonal selection. CCR9 expression is found only in Peyer's patches and appears critical for gut homing. Thus, gut mucosal memory possesses unique features not seen after systemic immunization.

  2. Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia

    OpenAIRE

    Janikashvili, Nona; LaCasse, Collin J.; Larmonier, Claire; Trad, Malika; Herrell, Amanda; Bustamante, Sara; Bonnotte, Bernard; Har-Noy, Michael; Larmonier, Nicolas; Katsanis, Emmanuel

    2011-01-01

    Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4+ T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4+CD25+FoxP3+ regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generatio...

  3. IFN-γ-producing CD4+ T cells promote generation of protective germinal center-derived IgM+ B cell memory against Salmonella Typhi.

    Science.gov (United States)

    Perez-Shibayama, Christian; Gil-Cruz, Cristina; Pastelin-Palacios, Rodolfo; Cervantes-Barragan, Luisa; Hisaki, Emiliano; Chai, Qian; Onder, Lucas; Scandella, Elke; Regen, Tommy; Waisman, Ari; Isibasi, Armando; Lopez-Macias, Constantino; Ludewig, Burkhard

    2014-06-01

    Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C- and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-γ-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-γ and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-γR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs.

  4. Behavioural and brain responses related to Internet search and memory.

    Science.gov (United States)

    Dong, Guangheng; Potenza, Marc N

    2015-10-01

    The ready availability of data via searches on the Internet has changed how many people seek and perhaps store and recall information, although the brain mechanisms underlying these processes are not well understood. This study investigated brain mechanisms underlying Internet-based vs. non-Internet-based searching. The results showed that Internet searching was associated with lower accuracy in recalling information as compared with traditional book searching. During functional magnetic resonance imaging, Internet searching was associated with less regional brain activation in the left ventral stream, the association area of the temporal-parietal-occipital cortices, and the middle frontal cortex. When comparing novel items with remembered trials, Internet-based searching was associated with higher brain activation in the right orbitofrontal cortex and lower brain activation in the right middle temporal gyrus when facing those novel trials. Brain activations in the middle temporal gyrus were inversely correlated with response times, and brain activations in the orbitofrontal cortex were positively correlated with self-reported search impulses. Taken together, the results suggest that, although Internet-based searching may have facilitated the information-acquisition process, this process may have been performed more hastily and be more prone to difficulties in recollection. In addition, people appear less confident in recalling information learned through Internet searching and that recent Internet searching may promote motivation to use the Internet.

  5. A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells.

    Science.gov (United States)

    Weisel, Florian J; Zuccarino-Catania, Griselda V; Chikina, Maria; Shlomchik, Mark J

    2016-01-19

    There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed these observations in wild-type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, for vaccine development, and for understanding long-term pathogen resistance.

  6. Preservation of vaccine-induced long-term B cell memory and the effects of immunosuppressive treatment

    OpenAIRE

    Ingelman-Sundberg, Hanna M.

    2015-01-01

    Immune memory after vaccination is largely dependent on the combination of antibody production from long-lived plasma cells, and a supporting pool of antigen-primed memory B cells. It has been observed that individuals with certain immunosuppressive conditions or treatments have a weakened B cell memory, but the mechanisms behind remain elusive. The aim of this thesis was to evaluate B cell immunity in healthy children, and how HIV-1 infection, antineoplastic therapy, and rheum...

  7. Metabolic features of the cell danger response.

    Science.gov (United States)

    Naviaux, Robert K

    2014-05-01

    The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental

  8. Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol

    OpenAIRE

    Wu, Y W C; Du, X; van den Buuse, M; Hill, R. A.

    2015-01-01

    The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate ...

  9. Stress and emotional memory retrieval: Effects of sex and cortisol response

    OpenAIRE

    Buchanan, Tony W.; Tranel, Daniel

    2007-01-01

    In some situations, memory is enhanced by stressful experience, while in others, it is impaired. The specific components of the stress–response that may result in these differing effects remain unclear, and the current study sought to address this knowledge gap. Forty healthy participants (20 women, 20 men) were exposed to emotionally arousing and neutral pictures. Twenty-four hours later, 20 participants underwent a social stressor (speech and math tests), and 20 underwent a control reading ...

  10. 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.

  11. 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.

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

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    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.

  13. Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice.

    Science.gov (United States)

    Shao, Wei; Chen, Jibing; Dai, Helong; Peng, Yuanzheng; Wang, Feng; Xia, Junjie; Thorlacius, Henrik; Zhu, Qi; Qi, Zhongquan

    2011-08-30

    Donor-reactive memory T cells mediated accelerated rejection is known as a barrier to the survival of transplanted organs. We investigated the combination of different monoclonal antibodies (mAbs) and donor-specific transfusion (DST) in memory T cells-based adoptive mice model. In the presence of donor-reactive memory T cells, the mean survival time (MST) of grafts in the anti-CD40L/LFA-1/DST group was 49.8d. Adding anti-CD44/CD70 mAbs to anti-CD40L/LFA-1/DST treatment. The MST was more than 100 d (MST>100 d). Compared with anti-CD40L/LFA-1/DST group, anti-CD40L/LFA-1/CD44/CD70/DST group notably reduced the expansion of memory T cells, enhanced the proportion of CD4+Foxp3+ regulatory T cells (Tregs) and suppressed donor-specific responses. Our data suggest that anti-CD40L/LFA-1/CD44/CD70mAbs and DST can synergistically inhibit accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice.

  14. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.

    Science.gov (United States)

    Hurton, Lenka V; Singh, Harjeet; Najjar, Amer M; Switzer, Kirsten C; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A; Champlin, Richard E; Cooper, Laurence J N

    2016-11-29

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR(+) T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19(+) leukemia. Long-lived T cells were CD45RO(neg)CCR7(+)CD95(+), phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR(+) T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

  15. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

    Science.gov (United States)

    Hurton, Lenka V.; Singh, Harjeet; Najjar, Amer M.; Switzer, Kirsten C.; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A.; Champlin, Richard E.; Cooper, Laurence J. N.

    2016-01-01

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials. PMID:27849617

  16. Detecting Antigen-Specific T Cell Responses: From Bulk Populations to Single Cells

    Directory of Open Access Journals (Sweden)

    Chansavath Phetsouphanh

    2015-08-01

    Full Text Available A new generation of sensitive T cell-based assays facilitates the direct quantitation and characterization of antigen-specific T cell responses. Single-cell analyses have focused on measuring the quality and breadth of a response. Accumulating data from these studies demonstrate that there is considerable, previously-unrecognized, heterogeneity. Standard assays, such as the ICS, are often insufficient for characterization of rare subsets of cells. Enhanced flow cytometry with imaging capabilities enables the determination of cell morphology, as well as the spatial localization of the protein molecules within a single cell. Advances in both microfluidics and digital PCR have improved the efficiency of single-cell sorting and allowed multiplexed gene detection at the single-cell level. Delving further into the transcriptome of single-cells using RNA-seq is likely to reveal the fine-specificity of cellular events such as alternative splicing (i.e., splice variants and allele-specific expression, and will also define the roles of new genes. Finally, detailed analysis of clonally related antigen-specific T cells using single-cell TCR RNA-seq will provide information on pathways of differentiation of memory T cells. With these state of the art technologies the transcriptomics and genomics of Ag-specific T cells can be more definitively elucidated.

  17. 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

  18. Response of a Shape Memory Alloy Beam Model under Narrow Band Noise Excitation

    Directory of Open Access Journals (Sweden)

    Gen Ge

    2014-01-01

    Full Text Available To describe the hysteretic nonlinear characteristic of the strain-stress relation of shape memory alloy (SMA, a Van-der-Pol hysteretic cycle is applied to simulate the hysteretic loops. Then, the model of a simply supported SMA beam subject to transverse narrow band noise excitation with nonlinear damping was proposed. The deterministic and the stochastic responses are studied, respectively, applying the multiple scale method. The stability of the steady state responses is analyzed by Floquet theory and the moment method. The numerical simulation results quite agree with the theoretical analysis.

  19. 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.

  20. 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

  1. Unit Cell Analysis of the Superelastic Behavior of Open-Cell Tetrakaidecahedral Shape Memory Alloy Foam under Quasi-Static Loading

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    Guillaume Maîtrejean

    2014-01-01

    Full Text Available Cellular solid materials and, more specifically, foams are increasingly common in many industrial applications due to their attractive characteristics. The tetrakaidecahedral foam microstructure, which can be observed in many types of foams, is studied in the present work in association with shape memory alloys (SMA material. SMA foams are of particular interest as they associate both the shape memory effect and the superelasticity with the characteristics of foam. A Unit Cell Finite Element Method approach is used, an approach that allows accurate predicting of the macroscale response of the foam with a highly reduced numerical effort. The tetrakaidecahedral foam’s responses, both in the elastic and in the superelastic stages, are then extracted and compared with results from the literature. The tetrakaidecahedral geometry is found to be of particular interest when associated with SMA as it takes more advantage of the superelastic property of the material than foams with randomly distributed porosity.

  2. 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

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

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    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.

  4. Programming voltage reduction in phase change memory cells with tungsten trioxide bottom heating layer/electrode.

    Science.gov (United States)

    Rao, Feng; Song, Zhitang; Gong, Yuefeng; Wu, Liangcai; Feng, Songlin; Chen, Bomy

    2008-11-05

    A phase change memory cell with tungsten trioxide bottom heating layer/electrode is investigated. The crystalline tungsten trioxide heating layer promotes the temperature rise in the Ge(2)Sb(2)Te(5) layer which causes the reduction in the reset voltage compared to a conventional phase change memory cell. Theoretical thermal simulation and calculation for the reset process are applied to understand the thermal effect of the tungsten trioxide heating layer/electrode. The improvement in thermal efficiency of the PCM cell mainly originates from the low thermal conductivity of the crystalline tungsten trioxide material.

  5. 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.

  6. 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.

  7. Construction of a memory battery for computerized administration, using item response theory.

    Science.gov (United States)

    Ferreira, Aristides I; Almeida, Leandro S; Prieto, Gerardo

    2012-10-01

    In accordance with Item Response Theory, a computer memory battery with six tests was constructed for use in the Portuguese adult population. A factor analysis was conducted to assess the internal structure of the tests (N = 547 undergraduate students). According to the literature, several confirmatory factor models were evaluated. Results showed better fit of a model with two independent latent variables corresponding to verbal and non-verbal factors, reproducing the initial battery organization. Internal consistency reliability for the six tests were alpha = .72 to .89. IRT analyses (Rasch and partial credit models) yielded good Infit and Outfit measures and high precision for parameter estimation. The potential utility of these memory tasks for psychological research and practice willbe discussed.

  8. The majority of human memory B cells recognizing RhD and tetanus resides in IgM+ B cells.

    Science.gov (United States)

    Della Valle, Luciana; Dohmen, Serge E; Verhagen, Onno J H M; Berkowska, Magdalena A; Vidarsson, Gestur; Ellen van der Schoot, C

    2014-08-01

    B cell memory to T cell-dependent (TD) Ags are considered to largely reside in class-switched CD27(+) cells. However, we previously observed that anti-RhD (D) Igs cloned from two donors, hyperimmunized with D(+) erythrocytes, were predominantly of the IgM isotype. We therefore analyzed in this study the phenotype and frequency of D- and tetanus toxoid-specific B cells by culturing B cells in limiting dilution upon irradiated CD40L-expressing EL4.B5 cells and testing the culture supernatant. Most Ag-specific B cells for both TD Ags were found to reside in the IgM-expressing B cells, including CD27(-) B cells, in both hyperimmunized donors and nonhyperimmunized volunteers. Only shortly after immunization a sharp increase in Ag-specific CD27(+)IgG(+) B cells was observed. Next, B cells were enriched with D(+) erythrocyte ghosts and sorted as single cells. Sequencing of IGHV, IGLV, IGKV, and BCL6 genes from these D-specific B cell clones demonstrated that both CD27(-)IgM(+) and CD27(+)IgM(+) B cells harbored somatic mutations, documenting their Ag-selected nature. Furthermore, sequencing revealed a clonal relationship between the CD27(-)IgM(+), CD27(+)IgM(+), and CD27(+)IgG(+) B cell subsets. These data strongly support the recently described multiple layers of memory B cells to TD Ags in mice, where IgM(+) B cells represent a memory reservoir which can re-enter the germinal center and ensure replenishment of class-switched memory CD27(+) B cells from Ag-experienced precursors.

  9. Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis.

    Science.gov (United States)

    Adekambi, Toidi; Ibegbu, Chris C; Kalokhe, Ameeta S; Yu, Tianwei; Ray, Susan M; Rengarajan, Jyothi

    2012-01-01

    Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb) and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI) and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4(+) T cells. However, the differences between long-lived memory CD4(+) T cells induced by latent Mtb infection (LTBI) versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4(+) T cells in healthy BCG-vaccinated individuals who were either infected (LTBI) or uninfected (BCG) with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-γ ELISPOT using cell wall antigens and ESAT-6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA(-)CD27(-)) antigen-specific effector memory CD4(+) T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA(-)CD27(+)) cells with low PD-1 expression. CD27(+) and CD27(-) as well as PD-1(+) and PD-1(-) antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-γ, TNF-α and IL-2. PD-1 was preferentially expressed on CD27(-) antigen-specific CD4(+) T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4(+) memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27(-)PD-1(+) subsets in

  10. Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis.

    Directory of Open Access Journals (Sweden)

    Toidi Adekambi

    Full Text Available Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4(+ T cells. However, the differences between long-lived memory CD4(+ T cells induced by latent Mtb infection (LTBI versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4(+ T cells in healthy BCG-vaccinated individuals who were either infected (LTBI or uninfected (BCG with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-γ ELISPOT using cell wall antigens and ESAT-6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA(-CD27(- antigen-specific effector memory CD4(+ T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA(-CD27(+ cells with low PD-1 expression. CD27(+ and CD27(- as well as PD-1(+ and PD-1(- antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-γ, TNF-α and IL-2. PD-1 was preferentially expressed on CD27(- antigen-specific CD4(+ T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4(+ memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27(-PD-1(+ subsets in LTBI is

  11. Statistical analysis of the correlations between cell performance and its initial states in contact resistive random access memory cells

    Science.gov (United States)

    Kao, Yun Feng; Hsieh, Wei Ting; Che Chen, Chun; King, Ya-Chin; Lin, Chrong Jung

    2017-04-01

    Variability has been one of the critical challenges in the implementation of large resistive random access memory (RRAM) arrays. Wide variations in set/reset, read and cycling characteristics can significantly reduce the design margin and feasibility of a memory array. Predicting the characteristics of RRAM cells is constructive to provide insights and to adjust the memory operations accordingly. In this study, a strong correlation between the cell performance and its initial state is found in contact RRAM (CRRAM) cells by 28 nm CMOS logic technology. Furthermore, a verify-reset operation is proposed to identify the type of conductive filament (CF) in a cell. Distinctive CRRAM characteristics are found to be linked directly to initial CFs, enabling preliminary screening and adaptive resets to address the large variability problems in sizable CRRAM arrays.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Design of Memory Cell for Low Power Applications

    Directory of Open Access Journals (Sweden)

    N.geetha Rani

    2015-08-01

    Full Text Available Aggressive CMOS scaling results in lower threshold voltage and thin oxide thickness for transistors manufactured in nano regime. As a result, reducing the sub-threshold and tunneling gate leakage currents has become crucial in the design of ICs. This paper presents a new method to reduce the total leakage power dissipation of static random access memories (SRAMs while maintaining their performance.

  18. 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.

  19. Demand on verbal working memory delays haemodynamic response in the inferior prefrontal cortex.

    Science.gov (United States)

    Thierry, Guillaume; Ibarrola, Danielle; Démonet, Jean-François; Cardebat, Dominique

    2003-05-01

    Event-related functional magnetic resonance imaging was used to test the involvement of the inferior prefrontal cortex in verbal working memory. Pairs of French nouns were presented to ten native French speakers who had to make semantic or grammatical gender decisions. Verbal working memory involvement was manipulated by making the categorization of the second noun optional. Decisions could be made after processing the first noun only (RELEASE condition) or after processing the two nouns (HOLD condition). Reaction times suggested faster processing for gender than for semantic category in RELEASE. Despite the absence of anatomical difference across tasks and conditions in the wide activated network, the haemodynamic response peak latencies of the inferior prefrontal cortex were significantly delayed in HOLD versus RELEASE while no such peak delay was observed in the superior temporal gyrus. Interestingly, this pattern did not interact with language tasks. This study shows that cognitive manipulation can influence haemodynamic time-course and suggests that the main cognitive process determining inferior prefrontal activation is verbal working memory rather than specific linguistic processes such as grammatical or semantic analysis.

  20. 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

  1. HIV-1 Env-Specific Memory and Germinal Center B Cells in C57BL/6 Mice

    Directory of Open Access Journals (Sweden)

    Martina Soldemo

    2014-09-01

    Full Text Available Continued efforts to define the immunogenic properties of the HIV-1 envelope glycoproteins (Env are needed to elicit effective antibody (Ab responses by vaccination. HIV-1 is a highly neutralization-resistant virus due to conformational and glycan shielding of conserved Ab determinants on the virus spike. Elicitation of broadly neutralizing Abs that bind poorly accessible epitope regions on Env is therefore extremely challenging and will likely require selective targeting of specific sub-determinants. To evaluate such approaches there is a pressing need for in vivo studies in both large and small animals, including mice. Currently, most mouse immunization studies are performed in the BALB/c strain; however, the C57BL/6 strain offers improved possibilities for mechanistic studies due to the availability of numerous knock-out strains on this genetic background. Here, we compared Env immunogenicity in BALB/c and C57BL/6 mice and found that the magnitude of the antigen-specific response was somewhat lower in C57BL/6 than in BALB/c mice by ELISA but not significantly different by B cell ELISpot measurements. We then established protocols for the isolation of single Env-specific memory B cells and germinal center (GC B cells from immunized C57BL/6 mice to facilitate future studies of the elicited response at the monoclonal Ab level. We propose that these protocols can be used to gain an improved understanding of the early recruitment of Env-specific B cells to the GC as well as the archiving of such responses in the memory B cell pool following immunization.

  2. 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.

  3. Design of All-Optical Loadable and Erasable Memory Cell by LWI and EIT Effects

    Science.gov (United States)

    Abbasian, K.; Verki, N. G.; Rostami, A.

    2011-12-01

    We have designed a loadable and erasable all optical memory unit cell by using two coupled micro-ring resonators structure. To read out stored data we have created additional phase in the upper ring by electromagnetically induced transparency (EIT) phenomenon induced by inserted Λ-type three level quantum dots in the right hand half of the upper ring. Also, for compensating the fiber loss, we have used lasing without inversion (LWI) by inserted Y-type four level QDs in the left hand half of the both rings. This optical memory unit cell can work in only one photon-scale energy.

  4. 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.

  5. Fast Response Shape Memory Effect Titanium Nickel (TiNi) Foam Torque Tubes

    Science.gov (United States)

    Jardine, Peter

    2014-01-01

    Shape Change Technologies has developed a process to manufacture net-shaped TiNi foam torque tubes that demonstrate the shape memory effect. The torque tubes dramatically reduce response time by a factor of 10. This Phase II project matured the actuator technology by rigorously characterizing the process to optimize the quality of the TiNi and developing a set of metrics to provide ISO 9002 quality assurance. A laboratory virtual instrument engineering workbench (LabVIEW'TM')-based, real-time control of the torsional actuators was developed. These actuators were developed with The Boeing Company for aerospace applications.

  6. Recognition memory strength is predicted by pupillary responses at encoding while fixation patterns distinguish recollection from familiarity.

    Science.gov (United States)

    Kafkas, Alexandros; Montaldi, Daniela

    2011-10-01

    Thirty-five healthy participants incidentally encoded a set of man-made and natural object pictures, while their pupil response and eye movements were recorded. At retrieval, studied and new stimuli were rated as novel, familiar (strong, moderate, or weak), or recollected. We found that both pupil response and fixation patterns at encoding predict later recognition memory strength. The extent of pupillary response accompanying incidental encoding was found to be predictive of subsequent memory. In addition, the number of fixations was also predictive of later recognition memory strength, suggesting that the accumulation of greater visual detail, even for single objects, is critical for the creation of a strong memory. Moreover, fixation patterns at encoding distinguished between recollection and familiarity at retrieval, with more dispersed fixations predicting familiarity and more clustered fixations predicting recollection. These data reveal close links between the autonomic control of pupil responses and eye movement patterns on the one hand and memory encoding on the other. Moreover, the data illustrate quantitative as well as qualitative differences in the incidental visual processing of stimuli, which are differentially predictive of the strength and the kind of memory experienced at recognition.

  7. Transplanted bone marrow mesenchymal stem cells improve memory in rat models of Alzheimer's disease.

    Science.gov (United States)

    Babaei, Parvin; Soltani Tehrani, Bahram; Alizadeh, Arsalan

    2012-01-01

    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 × 10(3)/μL) 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 × 10(3)/μL) 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.

  8. 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.

  9. Dual-mode operation of a twisted nematic liquid crystal cell by switching between dynamic and memory modes.

    Science.gov (United States)

    Song, Dong Han; Kim, Ki-Han; Kim, Jung-Wook; Kim, Jae Chang; Yoon, Tae-Hoon

    2011-06-01

    We propose a twisted nematic liquid crystal device that can be operated in dynamic or memory mode, based on the information content to be displayed at that time. +90°-twisted and -90°-twisted states are used as two stable states for operation in the memory mode. A vertical electric field is applied to realize gray levels for operation in the dynamic mode. The proposed device has a memory retention time of over a month for the memory mode and a response time of 12 ms for the dynamic mode. Contrast ratios of over 500∶1 can be obtained in both the dynamic and memory modes.

  10. 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.

  11. The effect of background music on episodic memory and autonomic responses: listening to emotionally touching music enhances facial memory capacity

    Science.gov (United States)

    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

  12. 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.

  13. 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...

  14. 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.

  15. The relation between T-cell expression of LFA-1 and immunological memory

    DEFF Research Database (Denmark)

    Hviid, L; Odum, N; Theander, T G

    1993-01-01

    , including the leucocyte function-associated antigens (LFA). In the present study we have examined the expression of LFA-1 on subsets of human peripheral T cells, and related it to the expression of markers of cellular activation and CD45 isotypes, and thus to immunological memory. Our results suggest......Antibodies against isotypes of the leucocyte common antigen (LCA, CD45) can be used to identify largely reciprocal subsets of human peripheral T cells, characterized by differential ability to respond to recall antigen in vitro. The transition from naive, unprimed T cells to memory cells capable...... of responding to recall stimulating has been associated with a switch in surface expression of CD45 from the CD45RA isotype to CD45RO. It has been proposed that this transition is accompanied by the coordinated up-regulation of a number of cell-surface molecules involved in cellular adhesion and/or activation...

  16. 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.

  17. 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.

  18. 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.

  19. Increased stress responsivity in schizotypy leads to diminished spatial working memory performance.

    Science.gov (United States)

    Smith, Nathan T; Lenzenweger, Mark F

    2013-10-01

    Past research has emphasized the association between stress and the manifestation of psychotic symptoms in schizophrenia, yet relatively little is known about how environmental stressors affect cognitive processes in the illness. The present study sought to determine the effects of a loud noise stressor on a range of cognitive tasks, including spatial working memory (SWM), short-term visual memory, and sustained visual attention. Twenty-nine (29) schizotypic subjects and 45 controls performed the cognitive tasks across four waves of data collection: baseline, a noisy stress condition, and two follow-up conditions. Heart rate (BPM) was measured at each wave and subjective ratings of stress were collected in response to the loud noise stressor. Schizotypic subjects exhibited significantly greater increases in BPM during the loud, noisy stressor in comparison to controls. Additionally, schizotypic subjects' subjective ratings of stress in response to the loud noise were significantly greater than the controls' ratings. As hypothesized a priori, schizotypic subjects experienced significant decreases in SWM from baseline to the noisy stress condition in comparison to controls. Performance on non-SWM cognitive tasks did not significantly differ during the noisy stress condition and SWM performance did not significantly differ during noise-free conditions. Results from the present study highlight SWM as being particularly susceptible to loud noise stressors in a schizotypic population. Although the source of the induced impairment is not clear, one possibility is that the encoding stage of SWM was negatively affected by the loud noise.

  20. Memory in induced pluripotent stem cells: reprogrammed human retinal-pigmented epithelial cells show tendency for spontaneous redifferentiation.

    Science.gov (United States)

    Hu, Qirui; Friedrich, Amy M; Johnson, Lincoln V; Clegg, Dennis O

    2010-11-01

    Induced pluripotent stem (iPS) cells have been generated from a variety of somatic cell types via introduction of transcription factors that mediate pluripotency. However, it is unknown that all cell types can be reprogrammed and whether the origin of the parental cell ultimately determines the behavior of the resultant iPS cell line. We sought to determine whether human retinal-pigmented epithelial (RPE) cells could be reprogrammed, and to test the hypothesis that reprogrammed cells retain a "memory" of their origin in terms of propensity for differentiation. We reprogrammed primary fetal RPE cells via lentiviral expression of OCT4, SOX2, LIN28, and Nanog. The iPS cell lines derived from RPE exhibited morphologies similar to human embryonic stem cells and other iPS cell lines, expressed stem cell markers, and formed teratomas-containing derivatives of all three germ layers. To test whether these iPS cells retained epigenetic imprints from the parental RPE cells, we analyzed their propensity for spontaneous differentiation back into RPE after removal of FGF2. We found that some, but not all, iPS lines exhibited a marked preference for redifferentiation into RPE. Our results show that RPE cells can be reprogrammed to pluripotency, and suggest that they often retain a memory of their previous state of differentiation.

  1. Maintenance of anti-Sm/RNP autoantibody production by plasma cells residing in ectopic lymphoid tissue and bone marrow memory B cells.

    Science.gov (United States)

    Weinstein, Jason S; Delano, Matthew J; Xu, Yuan; Kelly-Scumpia, Kindra M; Nacionales, Dina C; Li, Yi; Lee, Pui Y; Scumpia, Philip O; Yang, Lijun; Sobel, Eric; Moldawer, Lyle L; Reeves, Westley H

    2013-04-15

    Although ectopic lymphoid tissue formation is associated with many autoimmune diseases, it is unclear whether it serves a functional role in autoimmune responses. 2,6,10,14-Tetramethylpentadecane causes chronic peritoneal inflammation and lupus-like disease with autoantibody production and ectopic lymphoid tissue (lipogranuloma) formation. A novel transplantation model was used to show that transplanted lipogranulomas retain their lymphoid structure over a prolonged period in the absence of chronic peritoneal inflammation. Recipients of transplanted lipogranulomas produced anti-U1A autoantibodies derived exclusively from the donor, despite nearly complete repopulation of the transplanted lipogranulomas by host lymphocytes. The presence of ectopic lymphoid tissue alone was insufficient, as an anti-U1A response was not generated by the host in the absence of ongoing peritoneal inflammation. Donor-derived anti-U1A autoantibodies were produced for up to 2 mo by plasma cells/plasmablasts recruited to the ectopic lymphoid tissue by CXCR4. Although CD4(+) T cells were not required for autoantibody production from the transplanted lipogranulomas, de novo generation of anti-U1A plasma cells/plasmablasts was reduced following T cell depletion. Significantly, a population of memory B cells was identified in the bone marrow and spleen that did not produce anti-U1A autoantibodies unless stimulated by LPS to undergo terminal differentiation. We conclude that 2,6,10,14-tetramethylpentadecane promotes the T cell-dependent development of class-switched, autoreactive memory B cells and plasma cells/plasmablasts. The latter home to ectopic lymphoid tissue and continue to produce autoantibodies after transplantation and in the absence of peritoneal inflammation. However, peritoneal inflammation appears necessary to generate autoreactive B cells de novo.

  2. Increased expression of the CD45RO (memory) antigen on T cells in HIV-infected children.

    Science.gov (United States)

    Froebel, K S; Doherty, K V; Whitelaw, J A; Hague, R A; Mok, J Y; Bird, A G

    1991-01-01

    Expression of the CD45RO putative memory cell antigen on CD4 (helper) and CD8 (cytotoxic/suppressor) lymphocytes of children born to HIV-infected women was investigated using the UCHL1 antibody. Significantly raised numbers of CD45RO+ CD8 lymphocytes were found in all nine of the infected children compared with uninfected and control children. Expression of CD45RO on CD4 lymphocytes was variable; absolute numbers were not increased, although the percentage was increased in four out of nine infected children. All the infected children except two (who had comparatively low numbers of CD45RO+ CD8 cells) were clinically well, which suggests that an increase in CD45RO+ CD8 cells may be indicative of a functionally active immune response against HIV.

  3. Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats.

    Science.gov (United States)

    Sil, Susmita; Ghosh, Tusharkanti; Ghosh, Rupsa; Gupta, Pritha

    2017-02-15

    Intracerebroventricular (i.c.v.) injection of colchicine induces neurodegeneration, memory impairments and changes of some systemic immune responses in rats. Though the role of cox 2 in these colchicine induced changes have been evaluated, the influence of nitric oxide synthase (NOS) remains to be studied. The present study was designed to assess the role of NOS on the i.c.v. colchicine induced neurodegeneration, memory impairments and changes of some systemic immune responses by inhibiting its activity with aminoguanidine. In the present study the impairments of working and reference memories, neurodegeneration (chromatolysis and plaque formation) and changes of neuroinflammatory markers in the hippocampus (increased TNF α, IL 1β, ROS and nitrite) along with changes of serum inflammatory markers (TNF α, IL 1β, ROS and nitrite) and alteration of systemic immune responses (higher phagocytic activity of blood WBC and splenic PMN, higher cytotoxicity and lower leukocyte adhesion inhibition index of splenic MNC) were measured in the intracerebroventricular colchicine injected rats (ICIR). Administration of aminoguanidine (p.o. 30/50mg/kg body weight) to ICIR resulted in recovery of neuroinflammation and partial prevention of neurodegeneration which could be corroborated with the partial recovery of memory impairments in this model. The recovery of serum inflammatory markers and the systemic immune responses in ICIR was also observed after administration of aminoguanidine. Therefore, the present study shows that aminoguanidine can protect the colchicine induced neurodegeneration, memory impairments, and changes of systemic immune systemic responses in ICIR by inhibiting the iNOS.

  4. Priming and memory of stress responses in organisms lacking a nervous system.

    Science.gov (United States)

    Hilker, Monika; Schwachtje, Jens; Baier, Margarete; Balazadeh, Salma; Bäurle, Isabel; Geiselhardt, Sven; Hincha, Dirk K; Kunze, Reinhard; Mueller-Roeber, Bernd; Rillig, Matthias C; Rolff, Jens; Romeis, Tina; Schmülling, Thomas; Steppuhn, Anke; van Dongen, Joost; Whitcomb, Sarah J; Wurst, Susanne; Zuther, Ellen; Kopka, Joachim

    2016-11-01

    Experience and memory of environmental stimuli that indicate future stress can prepare (prime) organismic stress responses even in species lacking a nervous system. The process through which such organisms prepare their phenotype for an improved response to future stress has been termed 'priming'. However, other terms are also used for this phenomenon, especially when considering priming in different types of organisms and when referring to different stressors. Here we propose a conceptual framework for priming of stress responses in bacteria, fungi and plants which allows comparison of priming with other terms, e.g. adaptation, acclimation, induction, acquired resistance and cross protection. We address spatial and temporal aspects of priming and highlight current knowledge about the mechanisms necessary for information storage which range from epigenetic marks to the accumulation of (dormant) signalling molecules. Furthermore, we outline possible patterns of primed stress responses. Finally, we link the ability of organisms to become primed for stress responses (their 'primability') with evolutionary ecology aspects and discuss which properties of an organism and its environment may favour the evolution of priming of stress responses.

  5. Memory CD8+ T cells from naturally acquired primary dengue virus infection are highly cross-reactive.

    Science.gov (United States)

    Friberg, Heather; Burns, Lynne; Woda, Marcia; Kalayanarooj, Siripen; Endy, Timothy P; Stephens, Henry A F; Green, Sharone; Rothman, Alan L; Mathew, Anuja

    2011-01-01

    Cross-reactive memory T cells induced by primary infection with one of the four serotypes of dengue virus (DENV) are hypothesized to have an immunopathological function in secondary heterologous DENV infection. To define the T-cell response to heterologous serotypes, we isolated HLA-A(*)1101-restricted epitope-specific CD8(+) T-cell lines from primary DENV-immune donors. Cell lines exhibited marked cross-reactivity toward peptide variants representing the four DENV serotypes in tetramer binding and functional assays. Many clones responded similarly to homologous and heterologous serotypes with striking cross-reactivity between the DENV-1 and DENV-3 epitope variants. In vitro-stimulated T-cell lines consistently revealed a hierarchical induction of MIP-1β>degranulation>tumor necrosis factor α (TNFα)>interferon-γ (IFNγ), which depended on the concentration of agonistic peptide. Phosphoflow assays showed peptide dose-dependent phosphorylation of ERK1/2, which correlated with cytolysis, degranulation, and induction of TNFα and IFNγ, but not MIP-1β production. This is the first study to show significant DENV serotype-cross-reactivity of CD8(+) T cells after naturally acquired primary infection. We also show qualitatively different T-cell receptor signaling after stimulation with homologous and heterologous peptides. Our data support a model whereby the order of sequential DENV infections influences the immune response to secondary heterologous DENV infection, contributing to varying disease outcomes.

  6. 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.

  7. 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

    2008-01-01

    An experimental and numerical investigation into the static and dynamic responses of shape memory alloy hybrid composite (SMAHC) beams is performed to provide quantitative validation of a recently commercialized numerical analysis/design tool for SMAHC structures. The SMAHC beam specimens consist of a composite matrix with embedded pre-strained SMA actuators, which act against the mechanical boundaries of the structure when thermally activated to adaptively stiffen the structure. Numerical results are produced from the numerical model as implemented into the commercial finite element code ABAQUS. A rigorous experimental investigation is undertaken to acquire high fidelity measurements including infrared thermography and projection moire interferometry for full-field temperature and displacement measurements, respectively. High fidelity numerical results are also obtained from the numerical model and include measured parameters, such as geometric imperfection and thermal load. 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.

  8. 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.

  9. 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.

  10. 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

  11. The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk

    Directory of Open Access Journals (Sweden)

    Sara Gabrielli

    2016-01-01

    Full Text Available Although NK cells are considered part of the innate immune system, a series of evidences has demonstrated that they possess characteristics typical of the adaptive immune system. These NK adaptive features, in particular their memory-like functions, are discussed from an ontogenetic and evolutionary point of view.

  12. Maturation, reactivity and therapy induced changes of memory T-cells in rheumatic autoimmune diseases

    NARCIS (Netherlands)

    Fritsch, R.D.E.

    2014-01-01

    This thesis covers different aspects of CD4+T-cells (maturational pathway, auto-reactive potential and differential reaction to glucocorticoid-therapy) in two auto-immune diseases: systemic lupus erythematosus (SLE) and Rheumatoid arthritis (RA). Immunological memory is important for an adequate res

  13. Constitutive CD40L expression on B cells prematurely terminates germinal center response and leads to augmented plasma cell production in T cell areas.

    Science.gov (United States)

    Bolduc, Anna; Long, Eugene; Stapler, Dale; Cascalho, Marilia; Tsubata, Takeshi; Koni, Pandelakis A; Shimoda, Michiko

    2010-07-01

    CD40/CD40L engagement is essential to T cell-dependent B cell proliferation and differentiation. However, the precise role of CD40 signaling through cognate T-B interaction in the generation of germinal center and memory B cells is still incompletely understood. To address this issue, a B cell-specific CD40L transgene (CD40LBTg) was introduced into mice with B cell-restricted MHC class II deficiency. Using this mouse model, we show that constitutive CD40L expression on B cells alone could not induce germinal center differentiation of MHC class II-deficient B cells after immunization with T cell-dependent Ag. Thus, some other MHC class II-dependent T cell-derived signals are essential for the generation of germinal center B cells in response to T cell-dependent Ag. In fact, CD40LBTg mice generated a complex Ag-specific IgG1 response, which was greatly enhanced in early, but reduced in late, primary response compared with control mice. We also found that the frequency of Ag-specific germinal center B cells in CD40LBTg mice was abruptly reduced 1 wk after immunization. As a result, the numbers of Ag-specific IgG1 long-lived plasma cells and memory B cells were reduced. By histology, large numbers of Ag-specific plasma cells were found in T cell areas adjacent to Ag-specific germinal centers of CD40LBTg mice, temporarily during the second week of primary response. These results indicate that CD40L expression on B cells prematurely terminated their ongoing germinal center response and produced plasma cells. Our results support the notion that CD40 signaling is an active termination signal for germinal center reaction.

  14. Effect of IL-7 therapy on naïve 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.

    2015-01-01

    Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naïve T cells (TN) associated with decline in thymic output and export of new cells into the peripheral T cell pool. Since 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 years) and old (>20 years) 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 non-responsiveness. 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 didn't 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

  15. The first dose of a Haemophilus influenzae type b conjugate vaccine reactivates memory B cells: evidence for extensive clonal selection, intraclonal affinity maturation, and multiple isotype switches to IgA2

    DEFF Research Database (Denmark)

    Hougs, L; Juul, L; Ditzel, H J

    1999-01-01

    selected, and expanded population of cells existing before vaccination, i.e., memory B cells. The dominating heavy and light chains of the response were combined in a Fab that bound HibCP. It was shown that the shared heavy and light chain mutations increased the affinity for HibCP considerably, indicating...... that the clonal selection had been driven by affinity. Pre-existing memory cells in unvaccinated adults may explain several features of Ab responses to polysaccharide vaccines and may play a role in acquiring the ability to respond to pure polysaccharides during infancy....

  16. Acetyl CoA Carboxylase 2 Is Dispensable for CD8+ T Cell Responses.

    Directory of Open Access Journals (Sweden)

    Jang Eun Lee

    Full Text Available Differentiation of T cells is closely associated with dynamic changes in nutrient and energy metabolism. However, the extent to which specific metabolic pathways and molecular components are determinative of CD8+ T cell fate remains unclear. It has been previously established in various tissues that acetyl CoA carboxylase 2 (ACC2 regulates fatty acid oxidation (FAO by inhibiting carnitine palmitoyltransferase 1 (CPT1, a rate-limiting enzyme of FAO in mitochondria. Here, we explore the cell-intrinsic role of ACC2 in T cell immunity in response to infections. We report here that ACC2 deficiency results in a marginal increase of cellular FAO in CD8+ T cells, but does not appear to influence antigen-specific effector and memory CD8+ T cell responses during infection with listeria or lymphocytic choriomeningitis virus. These results suggest that ACC2 is dispensable for CD8+ T cell responses.

  17. 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

  18. 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.

  19. 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....

  20. A dendritic cell-based assay for measuring memory T cells specific to dengue envelope proteins in human peripheral blood.

    Science.gov (United States)

    Sun, Peifang; Beckett, Charmagne; Danko, Janine; Burgess, Timothy; Liang, Zhaodong; Kochel, Tadeusz; Porter, Kevin

    2011-05-01

    Dengue envelope (E) protein is a dominant immune inducer and E protein-based vaccines elicited partial to complete protection in non-human primates. To study the immunogenicity of these vaccines in humans, an enzyme linked immunospot (ELISPOT) assay for measuring interferon gamma (IFN-γ) production was developed. Cells from two subject groups, based on dengue-exposure, were selected for assay development. The unique feature of the IFN-γ ELISPOT assay is the utilization of dendritic cells pulsed with E proteins as antigen presenting cells. IFN-γ production, ranging from 53-513 spot forming units per million peripheral blood mononuclear cells (PBMCs), was observed in dengue-exposed subjects as compared to 0-45 IFN-γ spot forming units in dengue-unexposed subjects. Further, both CD4(+) and CD8(+) T cells, and cells bearing CD45RO memory marker, were the major sources of IFN-γ production. The assay allowed quantification of E-specific IFN-γ-secreting memory T cells in subjects 9 years after exposure to a live-attenuated virus vaccine and live-virus challenge. Results suggested that the dendritic cell-based IFN-γ assay is a useful tool for assessing immunological memory for clinical research.

  1. Mitigation of Memory Effects in Beta Scintillation Cells for Radioactive Gas Detection

    Energy Technology Data Exchange (ETDEWEB)

    Seifert, Carolyn E; McIntyre, Justin I; Antolick, Kathryn C; Carman, April J; Cooper, Matthew W; Hayes, James C; Heimbigner, Tom R; Hubbard, C W; Litke, Kevin E; Ripplinger, Mike D; Suarez, Reynold

    2005-08-31

    The Automated Radioxenon Sampler/Analyzer (ARSA) developed at PNNL measures the relative concentrations of xenon isotopes using a coincidence system. Previous tests of the ARSA system have shown that latent radioactivity remains in the plastic cells after evacuation of the gases, leading to a “memory effect” in which the background count rate is dependent on the sample history. The increased background results in lower detection sensitivity. Two possible solutions to the memory effect are explored in this work: depositing a thin layer of metal on the plastic cell (“metallization”), and using an inorganic scintillating cell composed of yttrium aluminum perovskite (YAP). In both cases, the presence of inorganic material at the surface is intended to inhibit the diffusion of gases into the cell walls.

  2. Programming power reduction in confined phase change memory cells with titanium dioxide clad layer

    Science.gov (United States)

    Chen, Liangliang; Zhang, Zhonghua; Song, Sannian; Song, Zhitang; Zheng, Qianqian; Zhang, Xin; Zhang, Juan; Zheng, Wanting; Shao, Hehong; Zhu, Xiuwei; Yu, Wenlei

    2017-01-01

    A confined structure phase change memory (PCM) cell has been fabricated based on the focused-ion beam technique. Furthermore, the titanium dioxide clad layer was proposed for promoting the temperature rise in the Ge0.61Sb2Te layer that causes the reduction in the reset voltage and current compared to the phase change memory cell without clad layer. Theoretical thermal simulation and calculation for the reset process are conducted to analyze the thermal effect of the titanium dioxide heating layer. The improved performance of the PCM cell with dioxide clad layer can be attributed to the fact that the buffer layer not only acted as heating layer but also efficiently reduced the cell dissipated power.

  3. 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.

  4. Natural suppression of human immunodeficiency virus type 1 replication is mediated by transitional memory CD8+ T cells.

    Science.gov (United States)

    Killian, M Scott; Johnson, Carl; Teque, Fernando; Fujimura, Sue; Levy, Jay A

    2011-02-01

    HIV replication is suppressed in vitro by a CD8(+) cell noncytotoxic antiviral response (CNAR). This activity directly correlates with an asymptomatic clinical state. The objective of this study was to identify the phenotype of CD8(+) cell subsets having strong CNAR activity. CD8(+) cell subset frequencies and CNAR levels were measured for human immunodeficiency virus (HIV)-uninfected individuals and three groups of HIV type 1 (HIV-1)-infected individuals: asymptomatic individuals with low-level viremia (vHIV), antiretroviral-drug-treated subjects with undetectable virus levels (TxHIV), and therapy-naïve aviremic elite controllers (EC). CD8(+) cells from the vHIV individuals exhibited the highest HIV-suppressing activity and had elevated frequencies of CD45RA(-) CD27(+) and PD-1(+) (CD279(+)) cells. Functional assessments of CD8(+) cells sorted into distinct subsets established that maximal CNAR activity was mediated by CD45RA(-) CCR7(-) CD27(+) and PD-1(+) CD8(+) cells. T cell receptor (TCR) repertoire profiles of CD8(+) cell subsets having strong CNAR activity exhibited increased perturbations in comparison to those of inactive subsets. Together, these studies suggest that CNAR is driven by HIV replication and that this antiviral activity is associated with oligoclonally expanded activated CD8(+) cells expressing PD-1 and having a transitional memory cell phenotype. The findings better describe the identity of CD8(+) cells showing CNAR and should facilitate the evaluation of this important immune response in studies of HIV pathogenesis, resistance to infection, and vaccine development.

  5. Effects of environmental enrichment on anxiety responses, spatial memory and cytochrome c oxidase activity in adult rats.

    Science.gov (United States)

    Sampedro-Piquero, P; Zancada-Menendez, C; Begega, A; Rubio, S; Arias, J L

    2013-09-01

    We have studied the effect of an environmental enrichment (EE) protocol in adult Wistar rats on the activity in the elevated zero-maze (EZM), performance in the radial-arm water maze (RAWM) and we have also examined the changes in the neuronal metabolic activity of several brain regions related to anxiety response and spatial memory through cytochrome c oxidase histochemistry (COx). Our EE protocol had anxiolytic effect in the EZM; the animals spent more time and made more entries into the open quadrants, they had lower latency to enter into the open quadrant and lower levels of defecation. Also, the EE group showed fewer working memory and reference memory errors, as well as lesser distance travelled in the first day of the spatial training. In relation to the neuronal metabolic activity, EE reduced the COx activity in brain regions related to anxiety response, such as the infralimbic cortex, the paraventricular thalamic and hypothalamic nucleus, the basolateral amygdala, and the ventral hippocampus. Interestingly, there were no significant differences between groups in the dorsal hippocampus, more related to spatial cognition. These results suggest a beneficial effect of EE on spatial memory as a result of reducing anxiety levels and the COx activity in brain regions involved in anxiety response. We also found a differential pattern of activation inside the hippocampus, suggesting that the dorsal hippocampus has a preferential involvement in spatial learning and memory, whereas the ventral hippocampus has a role in anxiety response.

  6. Externalizing psychopathology and behavioral disinhibition: working memory mediates signal discriminability and reinforcement moderates response bias in approach-avoidance learning.

    Science.gov (United States)

    Endres, Michael J; Rickert, Martin E; Bogg, Tim; Lucas, Jesolyn; Finn, Peter R

    2011-05-01

    Research has suggested that reduced working memory capacity plays a key role in disinhibited patterns of behavior associated with externalizing psychopathology. In this study, participants (N = 365) completed 2 versions of a go/no-go mixed-incentive learning task that differed in the relative frequency of monetary rewards and punishments for correct and incorrect active-approach responses, respectively. Using separate structural equation models for conventional (hit and false alarm rates) and signal detection theory (signal discriminability and response bias) performance indices, distinct roles for working memory capacity and changes in payoff structure were found. Specifically, results showed that (a) working memory capacity mediated the effects of externalizing psychopathology on false alarms and discriminability of go versus no-go signals; (b) these effects were not moderated by the relative frequency of monetary rewards and punishments; (c) the relative frequency of monetary rewards and punishments moderated the effects of externalizing psychopathology on hits and response bias for go versus no-go responses; and (d) these effects were not mediated by working memory capacity. The findings implicate distinct roles for reduced working memory capacity and poorly modulated active approach and passive avoidance in the link between externalizing psychopathology and behavioral disinhibition.

  7. Dynamic NMDAR-mediated properties of place cells during the object place memory task.

    Science.gov (United States)

    Faust, Thomas W; Robbiati, Sergio; Huerta, Tomás S; Huerta, Patricio T

    2013-01-01

    N-methyl-D-aspartate receptors (NMDAR) in the hippocampus participate in encoding and recalling the location of objects in the environment, but the ensemble mechanisms by which NMDARs mediate these processes have not been completely elucidated. To address this issue, we examined the firing patterns of place cells in the dorsal CA1 area of the hippocampus of mice (n = 7) that performed an object place memory (OPM) task, consisting of familiarization (T1), sample (T2), and choice (T3) trials, after systemic injection of 3-[(±)2-carboxypiperazin-4yl]propyl-1-phosphate (CPP), a specific NMDAR antagonist. Place cell properties under CPP (CPP-PCs) were compared to those after control saline injection (SAL-PCs) in the same mice. We analyzed place cells across the OPM task to determine whether they signaled the introduction or movement of objects by NMDAR-mediated changes of their spatial coding. On T2, when two objects were first introduced to a familiar chamber, CPP-PCs and SAL-PCs showed stable, vanishing or moving place fields in addition to changes in spatial information (SI). These metrics were comparable between groups. Remarkably, previously inactive CPP-PCs (with place fields emerging de novo on T2) had significantly weaker SI increases than SAL-PCs. On T3, when one object was moved, CPP-PCs showed reduced center-of-mass (COM) shift of their place fields. Indeed, a subset of SAL-PCs with large COM shifts (>7 cm) was largely absent in the CPP condition. Notably, for SAL-PCs that exhibited COM shifts, those initially close to the moving object followed the trajectory of the object, whereas those far from the object did the opposite. Our results strongly suggest that the SI changes and COM shifts of place fields that occur during the OPM task reflect key dynamic properties that are mediated by NMDARs and might be responsible for binding object identity with location.

  8. Dynamic NMDAR-mediated properties of place cells during the object place memory task

    Directory of Open Access Journals (Sweden)

    Thomas William Faust

    2013-12-01

    Full Text Available N-methyl-D-aspartate receptors (NMDAR in the hippocampus participate in encoding and recalling the location of objects in the environment, but the ensemble mechanisms by which NMDARs mediate these processes have not been completely elucidated. To address this issue, we examined the firing patterns of place cells in the dorsal CA1 area of the hippocampus of mice (n = 7 that performed an object place memory (OPM task, consisting of familiarization (T1, sample (T2 and choice (T3 trials, after systemic injection of 3-((±2-carboxypiperazin-4ylpropyl-1-phosphate (CPP, a specific NMDAR antagonist. Place cell properties under CPP (CPP–PCs were compared to those after control saline injection (SAL–PCs in the same mice. We analyzed place cells across the OPM task to determine whether they signaled the introduction or movement of objects by NMDAR-mediated changes of their spatial coding. On T2, when two objects were first introduced to a familiar chamber, CPP–PCs and SAL–PCs showed stable, vanishing or moving place fields in addition to changes in spatial information (SI. These metrics were comparable between groups. Remarkably, previously inactive CPP–PCs (with place fields emerging de novo on T2 had significantly weaker SI increases than SAL–PCs. On T3, when one object was moved, CPP–PCs showed reduced center-of-mass (COM shift of their place fields. Indeed, a subset of SAL–PCs with large COM shifts (>7 cm was largely absent in the CPP condition. Notably, for SAL–PCs that exhibited COM shifts, those initially close to the moving object followed the trajectory of the object, whereas those far from the object did the opposite. Our results strongly suggest that the SI changes and COM shifts of place fields that occur during the OPM task reflect key dynamic properties that are mediated by NMDARs and might be responsible for binding object identity with location.

  9. Thermo-mechanical Response and Damping Behavior of Shape Memory Alloy-MAX Phase Composites

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    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.

  10. IL-10 promotes homeostatic proliferation of human CD8(+) memorycells and, when produced by CD1c(+) DCs, shapes naive CD8(+) T-cell priming.

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    Nizzoli, Giulia; Larghi, Paola; Paroni, Moira; Crosti, Maria Cristina; Moro, Monica; Neddermann, Petra; Caprioli, Flavio; Pagani, Massimiliano; De Francesco, Raffaele; Abrignani, Sergio; Geginat, Jens

    2016-07-01

    IL-10 is an anti-inflammatory cytokine that inhibits maturation and cytokine production of dendritic cells (DCs). Although mature DCs have the unique capacity to prime CD8(+) CTL, IL-10 can promote CTL responses. To understand these paradoxic findings, we analyzed the role of IL-10 produced by human APC subsets in T-cell responses. IL-10 production was restricted to CD1c(+) DCs and CD14(+) monocytes. Interestingly, it was differentially regulated, since R848 induced IL-10 in DCs, but inhibited IL-10 in monocytes. Autocrine IL-10 had only a weak inhibitory effect on DC maturation, cytokine production, and CTL priming with high-affinity peptides. Nevertheless, it completely blocked cross-priming and priming with low-affinity peptides of a self/tumor-antigen. IL-10 also inhibited CD1c(+) DC-induced CD4(+) T-cell priming and enhanced Foxp3 induction, but was insufficient to induce T-cell IL-10 production. CD1c(+) DC-derived IL-10 had also no effect on DC-induced secondary expansions of memory CTL. However, IL-15-driven, TCR-independent proliferation of memory CTL was enhanced by IL-10. We conclude that DC-derived IL-10 selects high-affinity CTL upon priming. Moreover, IL-10 preserves established CTL memory by enhancing IL-15-dependent homeostatic proliferation. These combined effects on CTL priming and memory maintenance provide a plausible mechanism how IL-10 promotes CTL responses in humans.

  11. CD40 signaling drives B lymphocytes into an intermediate memory-like state, poised between naïve and plasma cells.

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    Upadhyay, Mala; Priya, G Krishna; Ramesh, P; Madhavi, M B; Rath, Satyajit; Bal, Vineeta; George, Anna; Vaidya, Tushar

    2014-10-01

    Immunological memory comprising of antigen-specific B and T cells contributes to the acquisition of long-term resistance to pathogens. Interactions between CD40 on B cells and CD40L on T cells are responsible for several aspects of acquired immune responses including generation of memory B cells. In order to gain insights into events leading to memory B cell formation, we analyzed the genome-wide expression profile of murine naive B cells stimulated in the presence of anti-CD40. We have identified over 8,000 genes whose expression is altered minimally 1.5-fold at least at one time point over a 3-day time course. The array analysis indicates that changes in expression level of maximum number of these genes occur within 24 h of anti-CD40 treatment. In parallel, we have studied the events following CD40 ligation by examining the expression of known regulators of naive B cell to plasma cell transition, including Pax5 and BLIMP1. The expression profile of these regulatory genes indicates firstly, that CD40 signaling activates naïve B cells to a phenotype that is intermediate between the naive and plasma cell stages of the B cell differentiation. Secondly, the major known regulator of plasma cell differentiation, BLIMP1, gets irreversibly downregulated upon anti-CD40 treatment. Additionally, our data reveal that CD40 signaling mediated BLIMP1 downregulation occurs by non-Pax5/non-Bcl6 dependent mechanisms, indicating novel mechanisms at work that add to the complexity of understanding of B cell master regulatory molecules like BLIMP1 and Pax5.

  12. 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.

  13. 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.

  14. Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates.

    Science.gov (United States)

    Cicin-Sain, Luka; Smyk-Pearson, Susan; Smyk-Paerson, Sue; Currier, Noreen; Byrd, Laura; Koudelka, Caroline; Robinson, Tammie; Swarbrick, Gwendolyn; Tackitt, Shane; Legasse, Alfred; Fischer, Miranda; Nikolich-Zugich, Dragana; Park, Byung; Hobbs, Theodore; Doane, Cynthia J; Mori, Motomi; Axthelm, Michael K; Axthelm, Michael T; Lewinsohn, Deborah A; Nikolich-Zugich, Janko

    2010-06-15

    Aging is usually accompanied by diminished immune protection upon infection or vaccination. Although aging results in well-characterized changes in the T cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary Ag responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naive T cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of TCR repertoire limit the Ag responses in aging primates. We show in this study that aging rhesus monkeys (Macaca mulatta) exhibit poor CD8 T cell and B cell responses in the blood and poor CD8 responses in the lungs upon vaccination with the modified vaccinia strain Ankara. The function of APCs appeared to be maintained in aging monkeys, suggesting that the poor response was likely intrinsic to lymphocytes. We found that the loss of naive CD4 and CD8 T cells, and the appearance of persisting T cell clonal expansions predicted poor CD8 responses in individual monkeys. There was strong correlation between early CD8 responses in the transitory CD28+ CD62L- CD8+ T cell compartment and the peak Ab titers upon boost in individual animals, as well as a correlation of both parameters of immune response to the frequency of naive CD8+ T cells in old but not in adult monkeys. Therefore, our results argue that T cell repertoire constriction and naive cell loss have prognostic value for global immune function in aging primates.

  15. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells

    Science.gov (United States)

    Li, Chen Xi; Talele, Nilesh P.; Boo, Stellar; Koehler, Anne; Knee-Walden, Ericka; Balestrini, Jenna L.; Speight, Pam; Kapus, Andras; Hinz, Boris

    2016-10-01

    Expansion on stiff culture substrates activates pro-fibrotic cell programs that are retained by mechanical memory. Here, we show that priming on physiologically soft silicone substrates suppresses fibrogenesis and desensitizes mesenchymal stem cells (MSCs) against subsequent mechanical activation in vitro and in vivo, and identify the microRNA miR-21 as a long-term memory keeper of the fibrogenic program in MSCs. During stiff priming, miR-21 levels were gradually increased by continued regulation through the acutely mechanosensitive myocardin-related transcription factor-A (MRTF-A/MLK-1) and remained high over 2 weeks after removal of the mechanical stimulus. Knocking down miR-21 once by the end of the stiff-priming period was sufficient to erase the mechanical memory and sensitize MSCs to subsequent exposure to soft substrates. Soft priming and erasing mechanical memory following cell culture expansion protects MSCs from fibrogenesis in the host wound environment and increases the chances for success of MSC therapy in tissue-repair applications.

  16. Visual short-term memory load reduces retinotopic cortex response to contrast.

    Science.gov (United States)

    Konstantinou, Nikos; Bahrami, Bahador; Rees, Geraint; Lavie, Nilli

    2012-11-01

    Load Theory of attention suggests that high perceptual load in a task leads to reduced sensory visual cortex response to task-unrelated stimuli resulting in "load-induced blindness" [e.g., Lavie, N. Attention, distraction and cognitive control under load. Current Directions in Psychological Science, 19, 143-148, 2010; Lavie, N. Distracted and confused?: Selective attention under load. Trends in Cognitive Sciences, 9, 75-82, 2005]. Consideration of the findings that visual STM (VSTM) involves sensory recruitment [e.g., Pasternak, T., & Greenlee, M. Working memory in primate sensory systems. Nature Reviews Neuroscience, 6, 97-107, 2005] within Load Theory led us to a new hypothesis regarding the effects of VSTM load on visual processing. If VSTM load draws on sensory visual capacity, then similar to perceptual load, high VSTM load should also reduce visual cortex response to incoming stimuli leading to a failure to detect them. We tested this hypothesis with fMRI and behavioral measures of visual detection sensitivity. Participants detected the presence of a contrast increment during the maintenance delay in a VSTM task requiring maintenance of color and position. Increased VSTM load (manipulated by increased set size) led to reduced retinotopic visual cortex (V1-V3) responses to contrast as well as reduced detection sensitivity, as we predicted. Additional visual detection experiments established a clear tradeoff between the amount of information maintained in VSTM and detection sensitivity, while ruling out alternative accounts for the effects of VSTM load in terms of differential spatial allocation strategies or task difficulty. These findings extend Load Theory to demonstrate a new form of competitive interactions between early visual cortex processing and visual representations held in memory under load and provide a novel line of support for the sensory recruitment hypothesis of VSTM.

  17. 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.

  18. A SPICE model for a phase-change memory cell based on the analytical conductivity model

    Science.gov (United States)

    Yiqun, Wei; Xinnan, Lin; Yuchao, Jia; Xiaole, Cui; Jin, He; Xing, Zhang

    2012-11-01

    By way of periphery circuit design of the phase-change memory, it is necessary to present an accurate compact model of a phase-change memory cell for the circuit simulation. Compared with the present model, the model presented in this work includes an analytical conductivity model, which is deduced by means of the carrier transport theory instead of the fitting model based on the measurement. In addition, this model includes an analytical temperature model based on the 1D heat-transfer equation and the phase-transition dynamic model based on the JMA equation to simulate the phase-change process. The above models for phase-change memory are integrated by using Verilog-A language, and results show that this model is able to simulate the I-V characteristics and the programming characteristics accurately.

  19. 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.

  20. 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.

  1. Leishmania braziliensis-reactive T cells are down-regulated in long-term cured cutaneous Leishmaniasis, but the renewal capacity of T effector memory compartments is preserved.

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    Regina Pereira-Carvalho

    Full Text Available Leishmania (Viannia braziliensis control and tissue damage relate to the effector immune response, which in turn affects clinical outcome. Leishmania reactive CD4(+ and CD8(+ T cells are expanded in long-term healed cutaneous leishmaniasis (hCL patients but their functional characteristics remain to be determined. This study investigates antigen-specific recall in long-term healed CL caused by L. braziliensis infection. Healed CL subjects were grouped according to the time elapsed since the end of therapy: less than two years and two to five years. Activation phenotype (CD69(+ or CD25(+ and subpopulations of memory T cell phenotypes [central memory (Tcm: CD45RO(+ CCR7(+ or effector memory (Tem: CD45RO(+ CCR7(-] were quantified in ex vivo blood mononuclear cells and after Leishmania antigens stimuli. A reduction in the percentage of activated Leishmania-responder CD4(+ and CD8(+ T cells in hCL was associated with the time elapsed since clinical cure. Percentage of CD69(+ in TCD4(+ and TCD8(+ cells were negatively correlated with IL-10 levels. Ex vivo analyses showed contracted Tem CD4(+ and Tem CD8(+ compartments from hCL with long time elapsed since clinical cure, although renewal of these compartments was observed following in vitro exposure to leishmanial stimuli. Our results show that healed L. braziliensis infected patients exhibit a recall response to Leishmania antigens with evident expansion of effector memory T cells. Regulated leishmanial-specific response seems to emerge only about two years after initial contact with the parasite antigens.

  2. Collective cell migration during inflammatory response

    Science.gov (United States)

    Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

  3. Cell mechanics: integrating cell responses to mechanical stimuli.

    Science.gov (United States)

    Janmey, Paul A; McCulloch, Christopher A

    2007-01-01

    Forces are increasingly recognized as major regulators of cell structure and function, and the mechanical properties of cells are essential to the mechanisms by which cells sense forces, transmit them to the cell interior or to other cells, and transduce them into chemical signals that impact a spectrum of cellular responses. Comparison of the mechanical properties of intact cells with those of the purified cytoskeletal biopolymers that are thought to dominate their elasticity reveal the extent to which the studies of purified systems can account for the mechanical properties of the much more heterogeneous and complex cell. This review summarizes selected aspects of current work on cell mechanics with an emphasis on the structures that are activated in cell-cell contacts, that regulate ion flow across the plasma membrane, and that may sense fluid flow that produces low levels of shear stress.

  4. An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage.

    Science.gov (United States)

    Southcombe, J H; Mounce, G; McGee, K; Elghajiji, A; Brosens, J; Quenby, S; Child, T; Granne, I

    2017-01-23

    When trying to conceive 1% of couples have recurrent miscarriages, defined as three or more consecutive pregnancy losses. This is not accounted for by the known incidence of chromosomal aneuploidy in miscarriage, and it has been suggested that there is an immunological aetiology. The endometrial mucosa is populated by a variety of immune cells which in addition to providing host pathogen immunity must facilitate pregnancy. Here we characterise the endometrial CD8-T cell population during the embryonic window of implantation and find that the majority of cells are tissue resident memory T cells with high levels of CD69 and CD103 expression, proteins that prevent cells egress. We demonstrate that unexplained recurrent miscarriage is associated with significantly decreased expression of the T-cell co-receptor CD8 and tissue residency marker CD69. These cells differ from those found in control women, with less expression of CD127 indicating a lack of homeostatic cell control through IL-7 signalling. Nevertheless this population is resident in the endometrium of women who have RM, more than three months after the last miscarriage, indicating that the memory CD8-T cell population is altered in RM patients. This is the first evidence of a differing pre-pregnancy phenotype in endometrial immune cells in RM.

  5. Antigen-specific B cells reactivate an effective cytotoxic T cell response against phagocytosed Salmonella through cross-presentation.

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    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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Reduced Number of Transitional and Naive B Cells in Addition to Decreased BAFF Levels in Response to the T Cell Independent Immunogen Pneumovax®23.

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    Alena Roth

    Full Text Available 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.

  11. 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.

  12. Divergent CD4+ T memory stem cell dynamics in pathogenic and nonpathogenic simian immunodeficiency virus infections.

    Science.gov (United States)

    Cartwright, Emily K; McGary, Colleen S; Cervasi, Barbara; Micci, Luca; Lawson, Benton; Elliott, Sarah T C; Collman, Ronald G; Bosinger, Steven E; Paiardini, Mirko; Vanderford, Thomas H; Chahroudi, Ann; Silvestri, Guido

    2014-05-15

    Recent studies have identified a subset of memory T cells with stem cell-like properties (T(SCM)) that include increased longevity and proliferative potential. In this study, we examined the dynamics of CD4(+) T(SCM) during pathogenic SIV infection of rhesus macaques (RM) and nonpathogenic SIV infection of sooty mangabeys (SM). Whereas SIV-infected RM show selective numeric preservation of CD4(+) T(SCM), SIV infection induced a complex perturbation of these cells defined by depletion of CD4(+)CCR5(+) T(SCM), increased rates of CD4(+) T(SCM) proliferation, and high levels of direct virus infection. The increased rates of CD4(+) T(SCM) proliferation in SIV-infected RM correlated inversely with the levels of central memory CD4(+) T cells. In contrast, nonpathogenic SIV infection of SM evidenced preservation of both CD4(+) T(SCM) and CD4(+) central memory T cells, with normal levels of CD4(+) T(SCM) proliferation, and lack of selective depletion of CD4(+)CCR5(+) T(SCM). Importantly, SIV DNA was below the detectable limit in CD4(+) T(SCM) from 8 of 10 SIV-infected SM. We propose that increased proliferation and infection of CD4(+) T(SCM) may contribute to the pathogenesis of SIV infection in RM.

  13. Compartmentalization of Total and Virus-Specific Tissue-Resident Memory CD8+ T Cells in Human Lymphoid Organs.

    Science.gov (United States)

    Woon, Heng Giap; Braun, Asolina; Li, Jane; Smith, Corey; Edwards, Jarem; Sierro, Frederic; Feng, Carl G; Khanna, Rajiv; Elliot, Michael; Bell, Andrew; Hislop, Andrew D; Tangye, Stuart G; Rickinson, Alan B; Gebhardt, Thomas; Britton, Warwick J; Palendira, Umaimainthan

    2016-08-01

    Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103-, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections.

  14. In vivo response to an implanted shape memory polyurethane foam in a porcine aneurysm model.

    Science.gov (United States)

    Rodriguez, Jennifer N; Clubb, Fred J; Wilson, Thomas S; Miller, Matthew W; Fossum, Theresa W; Hartman, Jonathan; Tuzun, Egemen; Singhal, Pooja; Maitland, Duncan J

    2014-05-01

    Cerebral aneurysms treated by traditional endovascular methods using platinum coils have a tendency to be unstable, either due to chronic inflammation, compaction of coils, or growth of the aneurysm. We propose to use alternate filling methods for the treatment of intracranial aneurysms using polyurethane-based shape memory polymer (SMP) foams. SMP polyurethane foams were surgically implanted in a porcine aneurysm model to determine biocompatibility, localized thrombogenicity, and their ability to serve as a stable filler material within an aneurysm. The degree of healing was evaluated via gross observation, histopathology, and low vacuum scanning electron microscopy imaging after 0, 30, and 90 days. Clotting was initiated within the SMP foam at time 0 (<1 h exposure to blood before euthanization), partial healing was observed at 30 days, and almost complete healing had occurred at 90 days in vivo, with minimal inflammatory response.

  15. Structural Acoustic Response of a Shape Memory Alloy Hybrid Composite Panel (Lessons Learned)

    Science.gov (United States)

    Turner, Travis L.

    2002-01-01

    This study presents results from an effort to fabricate a shape memory alloy hybrid composite (SMAHC) panel specimen and test the structure for dynamic response and noise transmission characteristics under the action of thermal and random acoustic loads. A method for fabricating a SMAHC laminate with bi-directional SMA reinforcement is described. Glass-epoxy unidirectional prepreg tape and Nitinol ribbon comprise the material system. Thermal activation of the Nitinol actuators was achieved through resistive heating. The experimental hardware required for mechanical support of the panel/actuators and for establishing convenient electrical connectivity to the actuators is presented. Other experimental apparatus necessary for controlling the panel temperature and acquiring structural acoustic data are also described. Deficiency in the thermal control system was discovered in the process of performing the elevated temperature tests. Discussion of the experimental results focuses on determining the causes for the deficiency and establishing means for rectifying the problem.

  16. 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.

  17. The Emotional Response to Everyday Involuntary and Voluntary Memories in Dysphoria and Non-Dysphoria

    DEFF Research Database (Denmark)

    del Palacio Gonzalez, Adriana; Watson, Lynn; Berntsen, Dorthe

    -depressed individuals completed a structured memory diary where the intensity of fear, sadness, happiness, and anger, as well as the employment of emotion regulation strategies (brooding, memory suppression, emotional suppression, and reflection) was recorded upon the retrieval of everyday autobiographical memories...

  18. 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.

  19. CROSSREACTIVE ANTIBODIES AND MEMORY T CELLS TO HUMAN AND ZOONOTIC INFLUENZA A VIRUSES IN VOLUNTEERS

    Directory of Open Access Journals (Sweden)

    I. V. Losev

    2015-01-01

    Full Text Available There exists a real hazard of transferring zoonotic influenza A viruses, either swine, or avian, into human population. In such case, severity of such pandemics depends on the pathogen-specific immunity in the population. Virtual absence of such immunity in humans was declared in the literature. In this work, we assessed systemic, local, and T-cell immunity to potentially pandemic H3N2sw, H5N1, H5N2, H7N3, H7N9 and H2N2 influenza A viruses in a group of healthy adults of different age. Our results indicate that these subjects develop the following immune reactions: (i local (i.e., nasal IgA and cellular (CD4+ and CD8v memory T cells heterosubtypic immunity, in absence of detectable virus-specific serum antibodies to avian influenza A viruses; (ii Local immune responses (as nasal IgA to human A (H2N2 virus which circulated in 1957-1968 were detected both in subjects who could be primed at that time, but also in subjects born after 1968; (iii full-scale systemic and local immunity to potentially pandemic А (H3N2sw swine virus was found in the group. Conclusion. In order of proper epidemiological forecasts and planning appropriate preventive measures for potentially pandemic Influenza A viruses, a regular monitoring of collective immunity should be performed using different adaptive markers. In this respect, any conclusion based on molecular analysis only could lead to considerable mistakes, and should be accomplished by the mentioned immunological studies.

  20. Metabolomic Responses of Guard Cells and Mesophyll Cells to Bicarbonate.

    Science.gov (United States)

    Misra, Biswapriya B; de Armas, Evaldo; Tong, Zhaohui; Chen, Sixue

    2015-01-01

    Anthropogenic CO2 presently at 400 ppm is expected to reach 550 ppm in 2050, an increment expected to affect plant growth and productivity. Paired stomatal guard cells (GCs) are the gate-way for water, CO2, and pathogen, while mesophyll cells (MCs) represent the bulk cell-type of green leaves mainly for photosynthesis. We used the two different cell types, i.e., GCs and MCs from canola (Brassica napus) to profile metabolomic changes upon increased CO2 through supplementation with bicarbonate (HCO3-). Two metabolomics platforms enabled quantification of 268 metabolites in a time-course study to reveal short-term responses. The HCO3- responsive metabolomes of the cell types differed in their responsiveness. The MCs demonstrated increased amino acids, phenylpropanoids, redox metabolites, auxins and cytokinins, all of which were decreased in GCs in response to HCO3-. In addition, the GCs showed differential increases of primary C-metabolites, N-metabolites (e.g., purines and amino acids), and defense-responsive pathways (e.g., alkaloids, phenolics, and flavonoids) as compared to the MCs, indicating differential C/N homeostasis in the cell-types. The metabolomics results provide insights into plant responses and crop productivity under future climatic changes where elevated CO2 conditions are to take center-stage.

  1. Metabolomic Responses of Guard Cells and Mesophyll Cells to Bicarbonate.

    Directory of Open Access Journals (Sweden)

    Biswapriya B Misra

    Full Text Available Anthropogenic CO2 presently at 400 ppm is expected to reach 550 ppm in 2050, an increment expected to affect plant growth and productivity. Paired stomatal guard cells (GCs are the gate-way for water, CO2, and pathogen, while mesophyll cells (MCs represent the bulk cell-type of green leaves mainly for photosynthesis. We used the two different cell types, i.e., GCs and MCs from canola (Brassica napus to profile metabolomic changes upon increased CO2 through supplementation with bicarbonate (HCO3-. Two metabolomics platforms enabled quantification of 268 metabolites in a time-course study to reveal short-term responses. The HCO3- responsive metabolomes of the cell types differed in their responsiveness. The MCs demonstrated increased amino acids, phenylpropanoids, redox metabolites, auxins and cytokinins, all of which were decreased in GCs in response to HCO3-. In addition, the GCs showed differential increases of primary C-metabolites, N-metabolites (e.g., purines and amino acids, and defense-responsive pathways (e.g., alkaloids, phenolics, and flavonoids as compared to the MCs, indicating differential C/N homeostasis in the cell-types. The metabolomics results provide insights into plant responses and crop productivity under future climatic changes where elevated CO2 conditions are to take center-stage.

  2. Influence of prior influenza vaccination on antibody and B-cell responses.

    Directory of Open Access Journals (Sweden)

    Sanae Sasaki

    Full Text Available Currently two vaccines, trivalent inactivated influenza vaccine (TIV and live attenuated influenza vaccine (LAIV, are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7-9 and 21-35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination.

  3. 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.

  4. Memory processes in delayed spatial discriminations: response intentions or response mediation?

    Science.gov (United States)

    Urcuioli, P J; DeMarse, T B

    1997-05-01

    Pigeons were trained on a pair-comparison task in which left versus right choices were reinforced following different sequences of two center-key stimuli. Choice accuracy was higher when retention intervals occurred after the entire sequence than when they separated the two stimuli comprising it, and this effect occurred independently of whether the initial and terminal stimuli came from the same or different dimensions. The initial stimulus from the prior trial was a source of proactive interference only in groups for which the retention interval separated the two sequence stimuli. By contrast, differential delay-interval behavior was observed only in groups for which the retention interval followed presentation of the entire sequence. These results indicate that coding processes in delayed discriminations are influenced by the location of the retention interval, and that response mediation affects retention performances if the reinforced choice can be determined prior to the interval.

  5. Expression of the memory marker CD45RO on helper T cells in macaques.

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    Michael Valentine

    Full Text Available 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 studying HIV pathogenesis and testing new therapies. There is now a major effort to eradicate HIV reservoirs and cure the infection. One approach is to eliminate subsets of cells housing the latent reservoir, using UCHL1 to target these cells. So that such studies may be performed in macaques, it is essential to determine expression of CD45RO. METHODS: We have used immunofluorescence and flow cytometry to study cell surface expression of CD45RO on lymphocytes from PBMC, lymphoid, and GI organs of rhesus, pigtailed, and cynomolgus macaques. Both direct and indirect immunofluorescence experiments were performed. FINDINGS: CD45RO is expressed on a subset of CD4+ lymphocytes of all pigtailed, a fraction of rhesus, and neither of the cynomolgus macaques studied. The binding of UCHL1 to macaque cells was of lower avidity than to human cells. This could be overcome by forming UCHL1 multimers. Directly conjugating fluors to UCHL1 can inhibit UCHL1 binding to macaque cells. Patterns of UCHL1 expression differ somewhat in macaques and humans, and from that of other memory markers often used in macaques. CONCLUSIONS: CD45RO, defined with mAb UCHL1, is well expressed on CD4+ cells in pigtailed macaques. Using tissues recovered from latently infected pigtailed macaques we are determining whether UCHL1, or other memory markers, can define the cellular locus of the reservoir. The low avidity of this interaction could limit the utility of UCHL1, in its conventional form, to eliminate cells in vivo and test this approach in macaque models of HIV infection.

  6. Indentation response of a NiTi shape memory alloy: modeling and experiments

    Directory of Open Access Journals (Sweden)

    C. Maletta

    2012-07-01

    Full Text Available The indentation response of a pseudoelastic nickel-titanium based shape memory alloy (SMA has been analyzed. Indentation tests have been carried out at room temperature using a spherical diamond tip and indentation loads in the range 50-500 mN in order to promote a large stress-induced transformation zone in the indentation region and, consequently, to avoid local effects due to microstructural variations. The measured load-displacement data have been analyzed to obtain information on the pseudoelastic response of the alloy. To aid this analysis numerical simulations were performed, by using a commercial finite element (FE software code and a special constitutive model for SMAs, so as to understand better the microstructural evolution occurring during the indentation process. Finally, the FE model has been used to analyze the effects of temperature on the indentation response of the alloy. This analysis revealed a marked variation of both the maximum and residual penetration depths with increasing test temperature.

  7. GA-based optimum design of a shape memory alloy device for seismic response mitigation

    Science.gov (United States)

    Ozbulut, O. E.; Roschke, P. N.; Y Lin, P.; Loh, C. H.

    2010-06-01

    Damping systems discussed in this work are optimized so that a three-story steel frame structure and its shape memory alloy (SMA) bracing system minimize response metrics due to a custom-tailored earthquake excitation. Multiple-objective numerical optimization that simultaneously minimizes displacements and accelerations of the structure is carried out with a genetic algorithm (GA) in order to optimize SMA bracing elements within the structure. After design of an optimal SMA damping system is complete, full-scale experimental shake table tests are conducted on a large-scale steel frame that is equipped with the optimal SMA devices. A fuzzy inference system is developed from data collected during the testing to simulate the dynamic material response of the SMA bracing subcomponents. Finally, nonlinear analyses of a three-story braced frame are carried out to evaluate the performance of comparable SMA and commonly used steel braces under dynamic loading conditions and to assess the effectiveness of GA-optimized SMA bracing design as compared to alternative designs of SMA braces. It is shown that peak displacement of a structure can be reduced without causing significant acceleration response amplification through a judicious selection of physical characteristics of the SMA devices. Also, SMA devices provide a recentering mechanism for the structure to return to its original position after a seismic event.

  8. 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

  9. 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.

  10. 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.