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Sample records for single positive cd4

  1. Habitual physical activity levels are positively correlated with CD4 ...

    African Journals Online (AJOL)

    Habitual physical activity levels are positively correlated with CD4 counts in an ... per month) and functional independence as assessed from the responses to the ... and between CD4 cell counts and total habitual physical activity levels (p ...

  2. Task-shifting of CD4 T cell count monitoring by the touchscreen-based Muse™ Auto CD4/CD4% single-platform system for CD4 T cell numeration: Implication for decentralization in resource-constrained settings.

    Science.gov (United States)

    Kouabosso, André; Mossoro-Kpinde, Christian Diamant; Bouassa, Ralph-Sydney Mboumba; Longo, Jean De Dieu; Mbeko Simaleko, Marcel; Grésenguet, Gérard; Bélec, Laurent

    2018-04-01

    The accuracy of CD4 T cell monitoring by the recently developed flow cytometry-based CD4 T cell counting Muse™ Auto CD4/CD4% Assay analyzer (EMD Millipore Corporation, Merck Life Sciences, KGaA, Darmstadt, Germany) was evaluated in trained lay providers against laboratory technicians. After 2 days of training on the Muse™ Auto CD4/CD4% analyzer, EDTA-blood samples from 6 HIV-positive and 4 HIV-negative individuals were used for CD4 T cell counting in triplicate in parallel by 12 trained lay providers as compared to 10 lab technicians. Mean number of CD4 T cells in absolute number was 829 ± 380 cells/μl by lay providers and 794 ± 409 cells/μl by technicians (P > 0.05); and in percentage 36.2 ± 14.8%CD4 by lay providers and 36.1 ± 15.0%CD4 by laboratory technician (P > 0.05). The unweighted linear regression and Passing-Bablok regression analyses on CD4 T cell results expressed in absolute count revealed moderate correlation between CD4 T cell counts obtained by lay providers and lab technicians. The mean absolute bias measured by Bland-Altman analysis between CD4 T cell/μl obtained by lay providers and lab technicians was -3.41 cells/μl. Intra-assay coefficient of variance (CV) of Muse™ Auto CD4/CD4% in absolute number was 10.1% by lay providers and 8.5% by lab technicians (P > 0.05), and in percentage 5.5% by lay providers and 4.4% by lab technicians (P > 0.05). The inter-assay CV of Muse™ Auto CD4/CD4% in absolute number was 13.4% by lay providers and 10.3% by lab technicians (P > 0.05), and in percentage 7.8% by lay providers and 6.9% by lab technicians (P > 0.05). The study demonstrates the feasibility of CD4 T cell counting using the alternative flow cytometer Muse™ Auto CD4/CD4% analyzer by trained lay providers and therefore the practical possibility of decentralization CD4 T cell counting to health community centers. Copyright © 2018. Published by Elsevier B.V.

  3. CD4+/CD8+ double-positive T cells

    DEFF Research Database (Denmark)

    Overgaard, Nana H; Jung, Ji-Won; Steptoe, Raymond J

    2015-01-01

    CD4(+)/CD8(+) DP thymocytes are a well-described T cell developmental stage within the thymus. However, once differentiated, the CD4(+) lineage or the CD8(+) lineage is generally considered to be fixed. Nevertheless, mature CD4(+)/CD8(+) DP T cells have been described in the blood and peripheral...... cells, CD4(+)/CD8(+) T cell populations, outside of the thymus, have recently been described to express concurrently ThPOK and Runx3. Considerable heterogeneity exists within the CD4(+)/CD8(+) DP T cell pool, and the function of CD4(+)/CD8(+) T cell populations remains controversial, with conflicting...... reports describing cytotoxic or suppressive roles for these cells. In this review, we describe how transcriptional regulation, lineage of origin, heterogeneity of CD4 and CD8 expression, age, species, and specific disease settings influence the functionality of this rarely studied T cell population....

  4. cd4 changes in haart-naïve hiv positive pregnant women on haart

    African Journals Online (AJOL)

    boaz

    This study thus attempt an assessment of the pattern of immunologic (CD4) changes in naïve. HIV positive pregnant women, in the first two months of commencing HAART, with a view to possibly postulate CD4 response rate and recommend the ideal time to initiate HAARTin HIV positive pregnant patients. METHODOLOGY.

  5. Association between red blood cell indices and CD4 count in HIV-positive reproductive women

    Science.gov (United States)

    Lumbanraja, S. N.; Siregar, D. I. S.

    2018-03-01

    Red blood cell indices, hemoglobin, and hematocrit reflect rapidity of HIV disease progression. This study aims to determine red blood cell indices and CD4 count in HIV-positive reproductive women. This study was a cross sectional study conducted at AIDS outpatient clinic at Haji Adam Malik General Hospital, Medan Indonesia. All seropositive reproductive women within antiretroviral therapy consented for blood count and CD4 examination. Data were collected and analyzed with SPSS 19. In subjects with CD4≤350 mm3, mean hemoglobin was 10.95 ± 2.01, hematocrit was 31.83 ± 5.04%, MCV was 84.17 ± 11.41, MCH was 25.98 ± 2.65, and MCHC was 32.18 ± 2.17. Mean hemoglobin, hematocrit, and MCH value was significantly lower in subjects with CD4 ≤350 mm3 (p=0.014; p=0.001; p=0.01; respectively). Lower Hb, Ht, and MCH associated with thelower CD4 count.

  6. The relationship between skin manifestations and CD4 counts among hiv positive patients

    International Nuclear Information System (INIS)

    Rad, F.; Ghaderi, E.; Moradi, G.; Mafakheri, L.

    2008-01-01

    Skin manifestations are common clinical features among HIV positive patients. The aim of this study was to document skin manifestations and their relationships with CD4 cell counts among HIV positive patients in Sanandaj. This was a descriptive study. The patients were examined for skin disorders by a dermatologist and CD4 counts were obtained from the patient's medical records. Independent samples T test were used for data analysis. In this study 66 (94.3%) patients had at least one skin problem. Fungal infections were the most common cause. The eight most common types of mucocutaneous problems were gingivitis, pallor, itching, photosensitivity, seborrheic dermatitis, candidiasis, folliculitis and tinea versicolor. The most common manifestation was gingivitis. Mean CD4 cell counts were lower in individuals with viral and bacterial skin diseases (P <0.05). The results of this study indicated that skin problems were common among HIV positive patients. Patients with advanced stages of skin disorders had relatively lower CD4 counts. Therefore examination of skin is recommended for all HIV positive patients for early detection of skin disorders, as early diagnosis and management of dermatologic problems will improve the quality of life in HIV positive patients. (author)

  7. Pulmonary candidiasis and CD4 count in HIV positive patients seen ...

    African Journals Online (AJOL)

    Pulmonary candidiasis and CD4 count in HIV positive patients seen in Jos, north central Nigeria. YJ Peter, AH Isa, AS Anzaku, MI Builders. Abstract. Background: Accurate and reliable diagnosis of HIV opportunistic infections plays a central role in effective HIV intervention programmes. Pulmonary infections are the leading ...

  8. A Positive Control for Detection of Functional CD4 T Cells in PBMC: The CPI Pool.

    Science.gov (United States)

    Schiller, Annemarie; Zhang, Ting; Li, Ruliang; Duechting, Andrea; Sundararaman, Srividya; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

    2017-12-07

    Testing of peripheral blood mononuclear cells (PBMC) for immune monitoring purposes requires verification of their functionality. This is of particular concern when the PBMC have been shipped or stored for prolonged periods of time. While the CEF (Cytomegalo-, Epstein-Barr and Flu-virus) peptide pool has become the gold standard for testing CD8 cell functionality, a positive control for CD4 cells is so far lacking. The latter ideally consists of proteins so as to control for the functionality of the antigen processing and presentation compartments, as well. Aiming to generate a positive control for CD4 cells, we first selected 12 protein antigens from infectious/environmental organisms that are ubiquitous: Varicella, Influenza, Parainfluenza, Mumps, Cytomegalovirus, Streptococcus , Mycoplasma , Lactobacillus , Neisseria , Candida , Rubella, and Measles. Of these antigens, three were found to elicited interferon (IFN)-γ-producing CD4 cells in the majority of human test subjects: inactivated cytomegalo-, parainfluenza-, and influenza virions (CPI). While individually none of these three antigens triggered a recall response in all donors, the pool of the three (the 'CPI pool'), did. One hundred percent of 245 human donors tested were found to be CPI positive, including Caucasians, Asians, and African-Americans. Therefore, the CPI pool appears to be suitable to serve as universal positive control for verifying the functionality of CD4 and of antigen presenting cells.

  9. Restoring Cytokine Balance in HIV-Positive Individuals with Low CD4 T Cell Counts

    Science.gov (United States)

    Valdivia, Anddre; Ly, Judy; Gonzalez, Leslie; Hussain, Parveen; Saing, Tommy; Islamoglu, Hicret; Pearce, Daniel; Ochoa, Cesar

    2017-01-01

    Abstract HIV infects and destroys CD4+ T cells leading to a compromised immune system. In a double-blinded study, a group of HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 were given either an empty liposomal supplement or a liposomal glutathione (L-GSH) supplement to take over a 3-month period. Baseline measurements in HIV-positive subjects show a significant decrease in levels of interleukin (IL)-12, IL-2, and interferon (IFN)-γ, along with a substantial increase in the levels of IL-6, IL-10, transforming growth factor (TGF)-β, and free radicals, compared to healthy individuals. Supplementation of HIV-positive subjects with L-GSH for 3 months resulted in a notable increase in the levels of IL-12, IL-2, and IFN-γ, with a concomitant decrease in the levels of IL-6, IL-10, and free radicals, and stabilization in the levels of TGF-β, IL-1, and IL-17, compared to their placebo counterparts. Levels of free radicals in CD4+ T cells stabilized, while GSH levels increased in the treatment group. Those in the placebo group showed no significant difference throughout the study. In summary, supplementation with L-GSH in HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 can help restore redox homeostasis and cytokine balance, therefore aiding the immune system to control opportunistic infections. PMID:28398068

  10. Radiographic manifestations of Tuberculosis in HIV positive patients: Correlation with CD4+ T-cell count

    Directory of Open Access Journals (Sweden)

    Mehrdad Bakhshayesh-Karam

    2016-01-01

    Conclusion: In CD4+ cell count <500, the dominant radiographic pattern of Tuberculosis is atypical presentation. At this level of immunity, CD4+ T cell dysfunction may play a deterministic role in TB radiographic manifestation.

  11. Association of asymptomatic oral candidal carriage, oral candidiasis and CD4 lymphocyte count in HIV-positive patients in China.

    Science.gov (United States)

    Liu, X; Liu, H; Guo, Z; Luan, W

    2006-01-01

    To compare the prevalence of asymptomatic oral candidal carriage in healthy volunteers with human immunodeficiency virus (HIV)-positive patients in China, as well as to investigate the relationship between CD4+ lymphocyte count and oral candidal colonization or oral candidiasis. Oral candidal carriage and oral candidiasis were investigated in 101 patients with HIV-infection seen at Youan Hospital, Beijing, China. Two hundred and seventeen healthy volunteers were involved as a control. Culture from saliva was used to test for the presence of oral Candida. CD4+ lymphocyte count was measured by flow cytometry. All data were analyzed statistically by SAS. Asymptomatic oral candidal carriage rate (28.6%) in HIV-positive group was similar to that in the healthy group (18.0%; P = 0.07). No significant difference in CD4+ lymphocyte count was found between oral Candida carriers and non-carriers among HIV-positive subjects (P = 0.89). However, the frequency of oral candidiasis increased with the decrease in CD4+ lymphocyte count (P < 0.0001), and pseudomembranous candidiasis was predominant in HIV-positive patients with CD4+ <200 cells microl(-1) (66.7%). In HIV-positive subjects, asymptomatic oral candidal colonization is not related to CD4+ lymphocyte count of blood, and the carriage rate is similar to that in the healthy population. Oral candidiasis is more likely to be observed in HIV-positive patients who have a low CD4+ lymphocyte count.

  12. Human CD4 restores normal T cell development and function in mice deficient in murine CD4

    OpenAIRE

    1994-01-01

    The ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4-/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V beta T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positiv...

  13. Single Particle Tracking reveals two distinct environments for CD4 receptors at the surface of living T lymphocytes

    International Nuclear Information System (INIS)

    Mascalchi, Patrice; Lamort, Anne Sophie; Salomé, Laurence; Dumas, Fabrice

    2012-01-01

    Highlights: ► We studied the diffusion of single CD4 receptors on living lymphocytes. ► This study reveals that CD4 receptors have either a random or confined diffusion. ► The dynamics of unconfined CD4 receptors was accelerated by a temperature raise. ► The dynamics of confined CD4 receptors was unchanged by a temperature raise. ► Our results suggest the existence of two different environments for CD4 receptors. -- Abstract: We investigated the lateral diffusion of the HIV receptor CD4 at the surface of T lymphocytes at 20 °C and 37 °C by Single Particle Tracking using Quantum Dots. We found that the receptors presented two major distinct behaviors that were not equally affected by temperature changes. About half of the receptors showed a random diffusion with a diffusion coefficient increasing upon raising the temperature. The other half of the receptors was permanently or transiently confined with unchanged dynamics on raising the temperature. These observations suggest that two distinct subpopulations of CD4 receptors with different environments are present at the surface of living T lymphocytes.

  14. Risk factors associated with low CD4+ lymphocyte count among HIV-positive pregnant women in Nigeria.

    Science.gov (United States)

    Abimiku, Alash'le; Villalba-Diebold, Pacha; Dadik, Jelpe; Okolo, Felicia; Mang, Edwina; Charurat, Man

    2009-09-01

    To determine the risk factors for CD4+ lymphocyte counts of 200 cells/mm(3) or lower in HIV-positive pregnant women in Nigeria. A cross-sectional data analysis from a prospective cohort of 515 HIV-positive women attending a prenatal clinic. Risk of a low CD4+ count was estimated using logistic regression analysis. CD4+ lymphocyte counts of 200 cells/mm(3) or lower (280+/-182 cells/mm(3)) were recorded in 187 (36.3%) out of 515 HIV-positive pregnant women included in the study. Low CD4+ count was associated with older age (adjusted odds ratio [aOR] 10.71; 95% confidence interval [CI], 1.20-95.53), lack of condom use (aOR, 5.16; 95% CI, 1.12-23.8), history of genital ulcers (aOR, 1.78; 95% CI, 1.12-2.82), and history of vaginal discharge (aOR; 1.62; 1.06-2.48). Over 35% of the HIV-positive pregnant women had low CD4+ counts, indicating the need for treatment. The findings underscore the need to integrate prevention of mother-to-child transmission with HIV treatment and care, particularly services for sexually transmitted infections.

  15. The role of CD4 in antigen-independent activation of isolated single T lymphocytes

    DEFF Research Database (Denmark)

    Kelso, A; Owens, T

    1988-01-01

    The membrane molecule CD4 (L3T4) is thought to facilitate activation of Class II H-2-restricted T cells by binding to Ia determinants on antigen-presenting cells. Recent reports suggest that CD4 can also contribute to antigen-independent activation by anti-T cell receptor (TCR) antibodies. An ass...

  16. CD52 expression on CD4+ T cells in HIV-positive individuals on cART

    DEFF Research Database (Denmark)

    Vojdeman, Fie Juhl; Gaardbo, Julie Christine; Hartling, Hans Jakob

    2018-01-01

    BACKGROUND: Human immune defect virus (HIV) persists in a latent state in quiescent CD4+ T cells preventing eradication of HIV. CD52 is a surface molecule modulated by HIV. We aimed at examining factors related to CD52 expression on CD4+ T cells in HIV-positive individuals and the impact...... of initiation of combination antiretroviral therapy (cART). METHODS: Peripheral blood mononuclear cells (PBMC) from 18 HIV-positive individuals and 10 uninfected age and gender matched controls were examined by flow cytometry for CD38 and CD52 expression on CD4+ T cells. Stimulation assays were performed on 8...... healthy blood donors to determine a cut-off for CD52 expression. RESULTS: All examined CD4+ T cells expressed CD52. However, both CD4+ T cells with higher (CD52++) and with lower CD52 expression (CD52dim) were found in HIV-positive individuals compared to uninfected controls. Two % CD52dim cells defined...

  17. Seroprevalence of Epstein-Barr virus among HIV positive patients moreover and its association with CD4 positive lymphocyte count.

    Directory of Open Access Journals (Sweden)

    Alireza Abdollahi

    2014-12-01

    Full Text Available Opportunistic infections are the leading cause of hospitalization and morbidity in human immunodeficiency virus (HIV positive patients and are the most common cause of death between them. We aimed to measure IgG antibody against EBV viral capsid antigen (EBV-VCA IgG to determine the seroprevalence of this infection in HIV-positive population. A case-control study between September 2011 and October 2012 was conducted in a teaching hospital enrolling 114 HIV-positive patients as case group and 114 healthy individuals as control with similar age and sex. Enzyme-linked immunosurbant assay (ELISA technique was used for determination of EBV-VAC IgG in obtained samples. Of 114 serum samples obtained from HIV-positive patients, 103 (90.4% samples were found positive for EBV-VCA IgG antibody. There was no significant difference in seroprevalence of EBV VCA IgG antibody between patients received antiretroviral therapy and naive patients (91.5% vs. 87.5%, P>0.05. There was no statistically significant difference in EBV-VCA IgG seroprevalence between three groups of CD4+ in HIV positive group. In conclusion current study showed that seroprevalence of EBV in HIV-positive patients is higher than HIV-negative healthy participants; however, administration of HAART and CD4+ lymphocyte count did not reveal a significant effect in seroprevalence of EBV. Due to the significance of this virus in mortality and morbidity and causing certain malignancies in patients with AIDS, these patients are strongly recommended to be tested for this virus.

  18. Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

    Science.gov (United States)

    Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

    2016-06-01

    TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  19. Primary Cutaneous CD4-Positive Small/Medium Pleomorphic T-cell Lymphoma – A Case Report

    Directory of Open Access Journals (Sweden)

    Micković Milena

    2016-12-01

    Full Text Available Primary cutaneous CD4-positive small- to medium-sized pleomorphic T-cell lymphoma is a provisional entity in the 2005 WHO-EORTC classification for cutaneous lymphomas. It is a rare condition and, in most cases, it has a favorable clinical course and prognosis. Primary cutaneous CD4-positive small/medium pleomorphic T-cell lymphoma (PCSM-TCL is defined as a cutaneous T-cell lymphoma with predominantly small- to medium-sized CD4-positive pleomorphic T-cells without a history of patches and plaques typical of mycosis fungoides. PCSM-TCL usually presents as a solitary plaque or tumor on the head, neck, trunk or upper extremities and it is considered to have indolent clinical behavior. Histologically, it is characterized by a dense infiltration of small/medium-sized pleomorphic T-cells that involves the entire dermal thickness, often with nodular extension into the hypodermis. Using immunohistochemical staining, the majority of the reported cases proved to be CD3, CD4 positive and CD8, CD30 negative. However, due to the rarity and heterogeneity of the PCSM-TCL, precise clinicopathologic characteristics of PCSM-TCL have not been well characterized and the optimal treatment for this group of lymphomas is yet to be defined. Dermatologists and pathologists should be aware of this entity in order to avoid unnecessary aggressive treatments.

  20. Factors influencing CD4 cell count in HIV-positive pregnant women in a secondary health center in Lagos, Nigeria

    Directory of Open Access Journals (Sweden)

    Akinbami AA

    2015-04-01

    Full Text Available Akinsegun A Akinbami,1 Abidoye Gbadegesin,2 Sarah O Ajibola,3 Ebele I Uche,1 Adedoyin O Dosunmu,1 Adewumi Adediran,4 Adekunle Sobande2 1Department of Haematology and Blood Transfusion, 2Department Of Obstetrics and Gynaecology, College of Medicine, Lagos State University, Ikeja, Lagos, Nigeria; 3Department of Haematology and Immunology, Ben-Carson School of Medicine, Babcock University, Ilisan, Ogun State, Nigeria; 4Department of Haematology and Blood Transfusion, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria Background: Immunity in pregnancy is physiologically compromised, and this may affect CD4 count levels. It is well-established that several factors affect CD4 count level in pregnancy. This study aimed to determine the mean and reference range of CD4 count in human immunodeficiency virus (HIV-positive pregnant women in Lagos, Nigeria. Methods: A retrospective study was carried out at antenatal clinics of the Maternal and Child Center of a secondary health center in Lagos State, Nigeria. Records of HIV-positive pregnant women at various gestational ages, including CD4+ cell count at booking, packed cell volume (PCV at booking and labor, gestational age at delivery, and infant weight and sex were retrieved. The descriptive data was given as mean ± standard deviation (SD. Pearson's chi-squared test and correlation were used for analytical assessment. Results: Data were retrieved for a total of 143 patients. The mean age was 31.15±3.78 years. The mean PCV was 31.01%±3.79% at booking and 30.49%±4.80% during labor. The mean CD4 count was 413.87±212.09 cells/µL, with a range of 40 to 1,252 cells/µL. The mean infant weight was 3.05±0.45 kg, with a range of 2 to 5 kg. Age of the mother, gestational age, and PCV at booking were not statistically significantly associated with CD4 count. Conclusion: Maternal age, gestational age, and PCV at booking had no significant effects on CD4+ cell count levels in

  1. Secondary syphilis in HIV positive individuals: correlation with histopathologic findings, CD4 counts, and quantity of treponemes in microscopic sections.

    Science.gov (United States)

    Rosa, Gabriela; Procop, Gary W; Schold, Jesse D; Piliang, Melissa P

    2016-10-01

    Although syphilis is uncommon, infection rates are much higher in HIV-infected individuals than the general population. A proposed explanation is impaired cellular immunity with HIV infection. A search of one institution yielded 10 patients with a diagnosis of secondary syphilis on skin biopsy, positive syphilis serology and available CD4 counts. We evaluated 11 biopsies from the 10 patients. We correlated the patients' CD4 counts with the histologic findings and with the number of treponemes on skin biopsies, highlighted by immunohistochemistry (IHC). We also compared the detection of spirochetes in silver stained sections (e.g. Warthin-Starry) with T. pallidum IHC. All biopsies were assessed for various histologic features. The sensitivity of IHC to detect treponemes was 64% and of silver stain was 9% (p-value 0.04). The number of treponemes on the biopsies was determined by IHC. High numbers of spirochetes (i.e. >100 per 10 hpf) were only seen in patients with CD4 counts less than 250 cells/ml. The most consistent histologic finding was a moderate to severe lymphoplasmacytic infiltrate. Although the study is small, it appears that a higher number of spirochetes is associated with CD4 counts less than 250 cell/ml. The T. pallidum IHC stain was vastly superior to the Warthin-Starry stain. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Factors influencing utilization of postpartum CD4 count testing by HIV-positive women not yet eligible for antiretroviral treatment.

    Science.gov (United States)

    Gilles, Kate P; Zimba, Chifundo; Mofolo, Innocent; Bobrow, Emily; Hamela, Gloria; Martinson, Francis; Hoffman, Irving; Hosseinipour, Mina

    2011-03-01

    Delayed antiretroviral initiation is associated with increased mortality, but individuals frequently delay seeking treatment. To increase early antiretroviral therapy (ART) enrollment of HIV-positive women, antenatal clinics are implementing regular, postpartum CD4 count testing. We examined factors influencing women's utilization of extended CD4 count testing. About 53 in-depth interviews were conducted with nurses, patients, social support persons, and government health officials at three antenatal clinics in Lilongwe, Malawi. Counseling and positive interactions with staff emerged as facilitating factors. Women wanted to know their CD4 count, but didn't understand the importance of early ART initiation. Support from husbands facilitated women's return to the clinic. Reminders were perceived as helpful but ineffectively employed. Staff identified lack of communication, difficulty in tracking, and referring women as barriers. Counseling messages should emphasize the importance of starting ART early. Clinics should focus on male partner involvement, case management, staff communication, and appointment reminders. Follow-up should be offered at multiple service points.

  3. Protection of xenografts by a combination of immunoisolation and a single dose of anti-CD4 antibody.

    Science.gov (United States)

    Mckenzie, A W; Georgiou, H M; Zhan, Y; Brady, J L; Lew, A M

    2001-01-01

    Immunoisolation is the separation of transplanted cells from cells of the immune system using a semipermeable membrane. Using one such immunoisolation capsule-the TheraCyte device-we have assessed the survival of encapsulated xenogeneic tissue in vivo as well as the contribution of CD4+ve T cells to encapsulated xenograft rejection. The foreign body reaction to the TheraCyte capsule in vivo was assessed by transplanting empty capsules into normal mice. These capsules elicit a foreign body response by the host animal. Encapsulated CHO, NIT-1, and PK-15 cells were placed in culture and in immunodeficient mice to investigate their growth characteristics in the TheraCyte device. These cell lines survive both in culture and in immunodeficient SCID mice. Xenogeneic PK cells were also transplanted into normal C57BL/6 mice. These cells do not survive in normal mice despite the absence of direct contact between infiltrating and encapsulated cells. In addition, the survival of encapsulated cells in mice treated with a single dose of anti-CD4 antibody was examined. This was assessed using two systems: 1) histological analysis of capsule sections; 2) a quantitative luciferase reporter system using PK cells transfected to express luciferase. In both cases, anti-CD4 antibody contributed to prolonged encapsulated xenogeneic cell survival. Encapsulated xenogeneic cells survive in immunodeficient mice but not normal mice. Treatment of normal mice with anti-CD4 antibody results in prolonged survival of xenogeneic cells that can be measured using a luciferase reporter system. These results highlight the contribution of CD4+ve T cells to encapsulated xenograft rejection.

  4. lon-beam analysis of plasma of HIV-Aids positive individual patients and comparison to CD4 counts

    International Nuclear Information System (INIS)

    Mars, J.A.; Kunsevi-Kilola, C.; Maqutu, M.L.; Kunsevi-Kilola, C; Mohammed, A.; Tarr, S.

    2013-01-01

    Full text: HIV-Aids related diseases have claimed the lives of many individuals, especially those that are economically active. This economic burden has crippled many economies since many of the lives claimed are those of individuals with special skills. However, the pathogenesis of human immuno-deficiency virus (HIV) infection is until present not fully understood. Elements such as Ca, Mg, Fe, Cu, Zn and Se are incorporated into the structure of many enzymes and are therefore essential to the enzyme function. The focus of this study is the correlation of trace element concentrations, determined by IBA, and the CD4 count. Blood obtained from 100 HIV sero-positive males and females attending clinics at the National Health Training College in Maseru metropolis, Lesotho. The CD4 cells of the samples were determined by flow cytometry (Cytoflow SL - S using CD4/CD45 monoclonal antibody and SSC/F12 getting strategy). Afterwards the plasma specimens were freeze dried and then pulverized into palettes. The palettes were coated with carbon and then irradiated with a proton beam of 3 MeV energy. X-ray emission and backscattering data were obtained and then quantified with various computational software. (author)

  5. lon-beam analysis of plasma of HIV-Aids positive individual patients and comparison to CD4 counts

    Energy Technology Data Exchange (ETDEWEB)

    Mars, J.A.; Kunsevi-Kilola, C. [Department of Biomedical Sciences, Cape Peninsula University of Technology, PO Box 1906. Bellville, 7535 (South Africa); Maqutu, M.L.; Kunsevi-Kilola, C; Mohammed, A. [HIV-Aids Unit, Cape Peninsula Universily of Technology, PO Box 1906, Bellville, 7535, (South Africa); Tarr, S. [National Health Training College, Private Bag A18, Maseru, Lesotho (South Africa)

    2013-07-01

    Full text: HIV-Aids related diseases have claimed the lives of many individuals, especially those that are economically active. This economic burden has crippled many economies since many of the lives claimed are those of individuals with special skills. However, the pathogenesis of human immuno-deficiency virus (HIV) infection is until present not fully understood. Elements such as Ca, Mg, Fe, Cu, Zn and Se are incorporated into the structure of many enzymes and are therefore essential to the enzyme function. The focus of this study is the correlation of trace element concentrations, determined by IBA, and the CD4 count. Blood obtained from 100 HIV sero-positive males and females attending clinics at the National Health Training College in Maseru metropolis, Lesotho. The CD4 cells of the samples were determined by flow cytometry (Cytoflow SL - S using CD4/CD45 monoclonal antibody and SSC/F12 getting strategy). Afterwards the plasma specimens were freeze dried and then pulverized into palettes. The palettes were coated with carbon and then irradiated with a proton beam of 3 MeV energy. X-ray emission and backscattering data were obtained and then quantified with various computational software. (author)

  6. The association between detected drug resistance mutations and CD4(+) T-cell decline in HIV-positive individuals maintained on a failing treatment regimen

    DEFF Research Database (Denmark)

    Schultze, Anna; Paredes, Roger; Sabin, Caroline

    2018-01-01

    BACKGROUND: To analyse the effect of drug resistance mutations (DRM) on CD4 cell trends in HIV-positive people maintained on virologically failing antiretroviral therapy (ART). METHODS: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with >1 CD4...

  7. Assessment of metabolic and mitochondrial dynamics in CD4+ and CD8+ T cells in virologically suppressed HIV-positive individuals on combination antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Jesse J R Masson

    Full Text Available Metabolism plays a fundamental role in supporting the growth, proliferation and effector functions of T cells. We investigated the impact of HIV infection on key processes that regulate glucose uptake and mitochondrial biogenesis in subpopulations of CD4+ and CD8+ T cells from 18 virologically-suppressed HIV-positive individuals on combination antiretroviral therapy (cART; median CD4+ cell count: 728 cells/μl and 13 HIV seronegative controls. Mitochondrial membrane potential (MMP and reactive oxygen species (ROS production were also analysed in total CD4+ and CD8+ T cells. Among HIV+/cART individuals, expression of glucose transporter (Glut1 and mitochondrial density were highest within central memory and naïve CD4+ T cells, and lowest among effector memory and transitional memory T cells, with similar trends in HIV-negative controls. Compared to HIV-negative controls, there was a trend towards higher percentage of circulating CD4+Glut1+ T cells in HIV+/cART participants. There were no significant differences in mitochondrial dynamics between subject groups. Glut1 expression was positively correlated with mitochondrial density and MMP in total CD4+ T cells, while MMP was also positively correlated with ROS production in both CD4+ and CD8+ T cells. Our study characterizes specific metabolic features of CD4+ and CD8+ T cells in HIV-negative and HIV+/cART individuals and will invite future studies to explore the immunometabolic consequences of HIV infection.

  8. Association between oral candidiasis and low CD4+ count among HIV positive patients in Hoima Regional Referral Hospital.

    Science.gov (United States)

    Nanteza, Martina; Tusiime, Jayne B; Kalyango, Joan; Kasangaki, Arabat

    2014-11-28

    The aim of this study was to determine the prevalence of Human Immune Virus (HIV) related oral lesions and their association with Cluster of Differentiation 4 (CD4+) count among treatment naïve HIV positive patients. This was a descriptive and analytical cross sectional study. Participants were 346 treatment naïve HIV positive adult patients. These were consecutively recruited from Hoima Regional Referral hospital between March and April 2012. Data collection involved interviews, oral examinations and laboratory analysis. A total of 168(48.6%) participants had oral lesions. The four commonest lesions were oral candidiasis (24.9%, CI = 20.6-29.7%), melanotic hyperpigmentation (17.3%, CI = 13.7-21.7%), kaposi sarcoma (9.3%, CI = 6.6-12.8%) and Oral Hairy Leukoplakia (OHL) (5.5%, CI = 3.5-8.4%). There was significant association between oral candidiasis and immunosuppression measured as CD4+ less than 350 cells/mm3 (OR = 2.69, CI = 1.608-4.502, p Oral candidiasis was the only oral lesion significantly predictive of immunosuppression (OR = 2.56, CI = 1.52-4.30, p Oral candidiasis can be considered as a marker for immunesuppression, making routine oral examinations essential in the management of HIV positive patients.

  9. A single CD4 test with 250 cells/mm3 threshold predicts viral suppression in HIV-infected adults failing first-line therapy by clinical criteria.

    Directory of Open Access Journals (Sweden)

    Charles F Gilks

    Full Text Available In low-income countries, viral load (VL monitoring of antiretroviral therapy (ART is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable.3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4<100 cells/mm(3 were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55% participants.Overall, 265/361 (73% LCM participants failed with CD4<100 cells/mm(3; only 7 (2% switched with CD4≥250 cells/mm(3, four switches triggered by WHO events. Without CD4 monitoring, 207/314 (66% CDM participants failed with WHO 4 events, and 77(25%/30(10% with single/multiple WHO 3 events. Failure/switching with single WHO 3 events was more likely with CD4≥250 cells/mm(3 (28/77; 36% (p = 0.0002. CD4 monitoring reduced switching with viral suppression: 23/187 (12% LCM versus 49/181 (27% CDM had VL<400 copies/ml at failure/switch (p<0.0001. Amongst CDM participants with CD4<250 cells/mm(3 only 11/133 (8% had VL<400 copies/ml, compared with 38/48 (79% with CD4≥250 cells/mm(3 (p<0.0001.Multiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold 'tiebreaker' of ≥250 cells/mm(3 for clinically-monitored patients failing first-line could identify ∼80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 'clinical failures' would particularly avoid premature, costly

  10. Second site escape of a T20-dependent HIV-1 variant by a single amino acid change in the CD4 binding region of the envelope glycoprotein

    Directory of Open Access Journals (Sweden)

    Berkhout Ben

    2006-11-01

    Full Text Available Abstract Background We previously described the selection of a T20-dependent human immunodeficiency virus type-1 (HIV-1 variant in a patient on T20 therapy. The fusion inhibitor T20 targets the viral envelope (Env protein by blocking a conformational switch that is critical for viral entry into the host cell. T20-dependent viral entry is the result of 2 mutations in Env (GIA-SKY, creating a protein that undergoes a premature conformational switch, and the presence of T20 prevents this premature switch and rescues viral entry. In the present study, we performed 6 independent evolution experiments with the T20-dependent HIV-1 variant in the absence of T20, with the aim to identify second site compensatory changes, which may provide new mechanistic insights into Env function and the T20-dependence mechanism. Results Escape variants with improved replication capacity appeared within 42 days in 5 evolution cultures. Strikingly, 3 cultures revealed the same single amino acid change in the CD4 binding region of Env (glycine at position 431 substituted for arginine: G431R. This mutation was sufficient to abolish the T20-dependence phenotype and restore viral replication in the absence of T20. The GIA-SKY-G431R escape variant produces an Env protein that exhibits reduced syncytia formation and reduced cell-cell fusion activity. The escape variant was more sensitive to an antibody acting on an early gp41 intermediate, suggesting that the G431R mutation helps preserve a pre-fusion Env conformation, similar to T20 action. The escape variant was also less sensitive to soluble CD4, suggesting a reduced CD4 receptor affinity. Conclusion The forced evolution experiments indicate that the premature conformational switch of the T20-dependent HIV-1 Env variant (GIA-SKY can be corrected by a second site mutation in Env (GIA-SKY-G431R that affects the interaction with the CD4 receptor.

  11. The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer

    International Nuclear Information System (INIS)

    Hoffman, Rex; Welton, Mark L.; Klencke, Barbara; Weinberg, Vivian; Krieg, Richard

    1999-01-01

    Purpose: To assess the outcome and tolerance of HIV-positive patients with anal cancer to standard therapy based on their pretreatment CD4 count. Methods and Materials: Between 1991 and 1997, 17 HIV-positive patients with anal cancer and documented pretreatment CD4 counts were treated at the University of California, San Francisco or its affiliated hospitals with either concurrent chemotherapy and radiation or radiation alone. The outcome and complications of treatment were correlated with the patients' pretreatment CD4 count. Results: Disease for all 9 patients with pretreatment CD4 counts ≥ 200 was controlled with chemoradiation. Although four required a treatment break of 2 weeks because of toxicity, none required hospitalization. Of the 8 patients with pretreatment CD4 counts < 200, 4 experienced decreased counts, intractable diarrhea, or moist desquamation requiring hospitalization. Additionally, 4 of these 8 ultimately required a colostomy either for a therapy-related complication or for salvage. Nevertheless, 6/7 in this group who received concurrent chemotherapy and radiation had their disease controlled, whereas the patient treated with radiation alone failed and required a colostomy for salvage. Conclusion: Patients with CD4 ≥ 200 had excellent disease control with acceptable morbidity. Patients with CD4 < 200 had markedly increased morbidity; however, disease was ultimately controlled in 7/8 patients

  12. Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

    DEFF Research Database (Denmark)

    Engsig, Frederik N; Zangerle, Robert; Katsarou, Olga

    2014-01-01

    BACKGROUND: Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after 3 years...... of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality. RESULTS: Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/µL after 3 years of suppression. Increasing...... age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998, and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving a CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after 3...

  13. Regulation and Gene Expression Profiling of NKG2D Positive Human Cytomegalovirus-Primed CD4+ T-Cells

    Science.gov (United States)

    Jensen, Helle; Folkersen, Lasse; Skov, Søren

    2012-01-01

    NKG2D is a stimulatory receptor expressed by natural killer (NK) cells, CD8+ T-cells, and γδ T-cells. NKG2D expression is normally absent from CD4+ T-cells, however recently a subset of NKG2D+ CD4+ T-cells has been found, which is specific for human cytomegalovirus (HCMV). This particular subset of HCMV-specific NKG2D+ CD4+ T-cells possesses effector-like functions, thus resembling the subsets of NKG2D+ CD4+ T-cells found in other chronic inflammations. However, the precise mechanism leading to NKG2D expression on HCMV-specific CD4+ T-cells is currently not known. In this study we used genome-wide analysis of individual genes and gene set enrichment analysis (GSEA) to investigate the gene expression profile of NKG2D+ CD4+ T-cells, generated from HCMV-primed CD4+ T-cells. We show that the HCMV-primed NKG2D+ CD4+ T-cells possess a higher differentiated phenotype than the NKG2D– CD4+ T-cells, both at the gene expression profile and cytokine profile. The ability to express NKG2D at the cell surface was primarily determined by the activation or differentiation status of the CD4+ T-cells and not by the antigen presenting cells. We observed a correlation between CD94 and NKG2D expression in the CD4+ T-cells following HCMV stimulation. However, knock-down of CD94 did not affect NKG2D cell surface expression or signaling. In addition, we show that NKG2D is recycled at the cell surface of activated CD4+ T-cells, whereas it is produced de novo in resting CD4+ T-cells. These findings provide novel information about the gene expression profile of HCMV-primed NKG2D+ CD4+ T-cells, as well as the mechanisms regulating NKG2D cell surface expression. PMID:22870231

  14. Regulation and gene expression profiling of NKG2D positive human cytomegalovirus-primed CD4+ T-cells.

    Directory of Open Access Journals (Sweden)

    Helle Jensen

    Full Text Available NKG2D is a stimulatory receptor expressed by natural killer (NK cells, CD8(+ T-cells, and γδ T-cells. NKG2D expression is normally absent from CD4(+ T-cells, however recently a subset of NKG2D(+ CD4(+ T-cells has been found, which is specific for human cytomegalovirus (HCMV. This particular subset of HCMV-specific NKG2D(+ CD4(+ T-cells possesses effector-like functions, thus resembling the subsets of NKG2D(+ CD4(+ T-cells found in other chronic inflammations. However, the precise mechanism leading to NKG2D expression on HCMV-specific CD4(+ T-cells is currently not known. In this study we used genome-wide analysis of individual genes and gene set enrichment analysis (GSEA to investigate the gene expression profile of NKG2D(+ CD4(+ T-cells, generated from HCMV-primed CD4(+ T-cells. We show that the HCMV-primed NKG2D(+ CD4(+ T-cells possess a higher differentiated phenotype than the NKG2D(- CD4(+ T-cells, both at the gene expression profile and cytokine profile. The ability to express NKG2D at the cell surface was primarily determined by the activation or differentiation status of the CD4(+ T-cells and not by the antigen presenting cells. We observed a correlation between CD94 and NKG2D expression in the CD4(+ T-cells following HCMV stimulation. However, knock-down of CD94 did not affect NKG2D cell surface expression or signaling. In addition, we show that NKG2D is recycled at the cell surface of activated CD4(+ T-cells, whereas it is produced de novo in resting CD4(+ T-cells. These findings provide novel information about the gene expression profile of HCMV-primed NKG2D(+ CD4(+ T-cells, as well as the mechanisms regulating NKG2D cell surface expression.

  15. Double positive CD4+CD8+ T cells: key suppressive role in the production of autoantibodies in systemic lupus erythematosus

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    Yongkang Wu

    2014-01-01

    Full Text Available Background & objectives: The presence of CD4+CD8+ (double positive T cells (DPT in the target organs of several autoimmune diseases has been reported. The aim of this study was to investigate the pathogenic role of DPT in systemic lupus erythematosus (SLE. Methods: A total of 175 SLE cases and 125 matched healthy controls were investigated for CD3+, CD4+, CD8+ lymphocytes and DPT by flow cytometry. Serum samples from SLE patients and controls were tested for antinuclear antibody (ANA, anti-double strain deoxyribonucleic acid (anti-dsDNA, anti-U1 ribonucleoprotein (anti-U1 RNP, anti-sjogren syndrome A (anti-SSA, anti-ribosomal P protein (anti-rib-P, anti-Smith (anti-Sm, anti-Sjogren syndrome B (anti-SSB, complement 3 (C3 and complement 4 (C4. Results: The DPT median and 5-95 per cent range of SLE cases and healthy controls were 0.50 [0.10-2.60] and 0.80 [0.20-2.74] respectively (P<0.001. SLE patients were divided into a ≥1:1000 subgroup and a <1:1000 subgroup according to the ANA titre. The DPT of the former subgroup was significantly lower than that of the latter (P=0.032. The DPT medians of positive subgroups with anti-dsDNA (P<0.001, anti-U1RNP (P=0.018, anti-SSA (P=0.021 or anti-rib-P (P=0.039 were also significantly lower than the negative subgroups. Likewise, DPT was significantly lower in SLE subgroups with low concentration of C3 or C4 than those with high concentration (P<0.006. Interpretation & conclusions: Our findings show that the DPT cells may play a key suppressive role in the production of autoantibodies in SLE. Direct evidence that DPT regulates the pathogenesis of SLE needs to be investigated in future work.

  16. Impact of ART on TB case fatality stratified by CD4 count for HIV-positive TB patients in Cape Town, South Africa (2009-2011).

    Science.gov (United States)

    Kaplan, Richard; Caldwell, Judy; Middelkoop, Keren; Bekker, Linda-Gail; Wood, Robin

    2014-08-15

    To identify determinants of tuberculosis (TB) case fatality including the impact of antiretroviral therapy (ART) at different CD4 thresholds for HIV-positive adult and adolescent TB patients. Through a retrospective analysis of the electronic TB database, we identified the HIV status of newly registered patients aged ≥15 years. Multivariable Cox proportional hazard models were used to determine the risk factors for TB case fatality in these patients. In 2009, 2010, and 2011, 25,841, 26,104, and 25,554 newly registered adult TB patients were treated in primary health care clinics in Cape Town, of whom 49.7%, 50.4%, and 50.9% were HIV positive. ART uptake increased over 3 years from 43% to 64.9%, and case fatality of the HIV-positive patients decreased from 7.0% to 5.8% (P ART had a substantial decrease in case fatality. The difference in case fatality between patients on ART and not on ART was most pronounced at low CD4 counts with the positive influence of ART noted up to a CD4 count threshold of 350 cells per cubic millimeter (P ART uptake, in 2011, 21% of the patients with CD4 counts ART during TB treatment. This study showed a relatively poor uptake of ART among severely immune-compromised TB patients. Patients with CD4 counts ART during TB treatment, and ART initiation should be prioritized for this category of patients.

  17. A single CD4 test with 250 cells/mm3 threshold predicts viral suppression in HIV-infected adults failing first-line therapy by clinical criteria.

    Science.gov (United States)

    Gilks, Charles F; Walker, A Sarah; Munderi, Paula; Kityo, Cissy; Reid, Andrew; Katabira, Elly; Goodall, Ruth L; Grosskurth, Heiner; Mugyenyi, Peter; Hakim, James; Gibb, Diana M

    2013-01-01

    In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable. 3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4tiebreaker' of ≥250 cells/mm(3) for clinically-monitored patients failing first-line could identify ∼80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 'clinical failures' would particularly avoid premature, costly switch to second-line ART.

  18. Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

    DEFF Research Database (Denmark)

    Nielsen, S. D.; Jeppesen, D. L.; Kolte, L.

    2001-01-01

    and fetal thymic organ cultures (FTOCs). Lower naive CD4 counts (459.3 +/- 68.9 vs 1128.9 +/- 146.8 cells/microL, P mothers were found (frequency of CD4(+) cells with TRECs was 3.6% +/- 0.7% compared with 14.3% +/- 2.2% in controls, P ...). In combination with lower red blood cell counts in infants of HIV-positive mothers, this finding suggested impairment of progenitor cell function. Indeed, progenitors from infants of HIV-positive mothers had decreased cloning efficiency (15.7% +/- 2.6% vs 55.8% +/- 15.9%, P =.009) and seemed to generate fewer T...... cells in FTOCs. In conclusion, lower numbers of naive CD4(+) cells and reduced thymic output in HIV-negative infants of HIV-positive mothers may be due to impaired progenitor cell function....

  19. Radiosensitivity of CD4 and CD8 positive human T lymphocytes by an in vitro colony formation assay

    International Nuclear Information System (INIS)

    Nakamura, Nori; Kusunoki, Yoichiro; Akiyama, Mitoshi.

    1989-12-01

    The recent development of an in vitro lymphocyte colony assay provides a new opportunity to examine possible variations in human radiosensitivity using peripheral blood lymphocytes (PBL) in place of the hitherto used skin fibroblast assay. Our recent study showed that most of the colonies consisted of lymphocytes bearing CD4 or CD8 antigens. Since the fraction of CD4 + and CD8 + cells in PBL differs among individuals, it was suspected that individual radiosensitivity might be biased by the different subset frequencies if the dose-survival curves of the CD4 + and CD8 + cells differed. In the present study, CD4 + lymphocytes (helper/inducer T cells) and CD8 + lymphocytes (suppressor/cytotoxic T cells) were isolated from PBL and their dose-survival curves were determined. The results showed that the D 10 (the dose required to reduce the surviving fraction to 10 %) was quite similar for these two types of cells (3.13 ± 0.10 Gy [mean ±SD] for CD4 + , 3.34 ± 0.50 Gy for CD8 + and 3.07 ± 0.05 Gy for the unsorted cells), supporting the use of a whole PBL population for screening of individuals with altered radiosensitivity. (author)

  20. EOMES-positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers.

    Science.gov (United States)

    Chemin, Karine; Ramsköld, Daniel; Diaz-Gallo, Lina-Marcela; Herrath, Jessica; Houtman, Miranda; Tandre, Karolina; Rönnblom, Lars; Catrina, Anca; Malmström, Vivianne

    2018-04-01

    The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve human CD4 + T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation. Moreover, the protein expression of the T-box transcription factor Eomesodermin (EOMES) was increased in T cells from healthy donors homozygous for the PTPN22 risk allele and correlated with a decreased number of naïve CD4 + T cells. There was no difference in the frequency of other CD4 + T-cell subsets (Th1, Th17, Tfh, Treg). Finally, an accumulation of EOMES + CD4 + T cells was observed in synovial fluid of RA patients with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, we propose a novel mechanism of action of PTPN22 risk allele through the generation of cytotoxic CD4 + T cells and identify EOMES + CD4 + T cells as a relevant T-cell subset in RA pathogenesis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Morbidity and mortality according to latest CD4+ cell count among HIV positive individuals in South Africa who enrolled in project Phidisa.

    Directory of Open Access Journals (Sweden)

    Patrick H Maduna

    Full Text Available Short-term morbidity and mortality rates for HIV positive soldiers in the South African National Defence Force (SANDF would inform decisions about deployment and HIV disease management. Risks were determined according to the latest CD4+ cell count and use of antiretroviral therapy (ART for HIV positive individuals in the SANDF and their dependents.A total of 7,114 participants were enrolled and followed for mortality over a median of 4.7 years (IQR: 1.9, 7.1 years. For a planned subset (5,976, progression of disease (POD and grade 4, potentially life-threatening events were also ascertained. CD4+ count and viral load were measured every 3 to 6 months. Poisson regression was used to compare event rates by latest CD4+ count (<50, 50-99, 100-199, 200-349, 350-499, 500+ with a focus on upper three strata, and to estimate relative risks (RRs (ART/no ART. Median entry CD4+ was 207 cells/mm3. During follow-up over 70% were prescribed ART. Over follow-up 1,226 participants died; rates ranged from 57.6 (< 50 cells to 0.8 (500+ cells per 100 person years (py. Compared to those with latest CD4+ 200-349 (2.2/100 py, death rates were significantly lower (p<0.001, as expected, for those with 350-499 (0.9/100 py and with 500+ cells (0.8/100 py. The composite outcome of death, POD or grade 4 events occurred in 2,302 participants (4,045 events; rates were similar in higher CD4+ count strata (9.4 for 350-499 and 7.9 for 500+ cells and lower than those with counts 200-349 cells (13.5 (p<0.001. For those with latest CD4+ 350+ cells, 63% of the composite outcomes (680 of 1,074 were grade 4 events.Rates of morbidity and mortality are lowest among those with CD4+ count of 350 or higher and rates do not differ for those with counts of 350-499 versus 500+ cells. Grade 4 events are the predominant morbidity for participants with CD4+ counts of 350+ cells.

  2. Cd4As2Br3

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    Mohammed Kars

    2014-03-01

    Full Text Available Single crystals of Cd4As2Br3 (tetracadmium biarsenide tribromide were grown by a chemical transport reaction. The structure is isotypic with the members of the cadmium and mercury pnictidohalides family with general formula M4A2X3 (M = Cd, Hg; A = P, As, Sb; X = Cl, Br, I and contains two independent As atoms on special positions with site symmetry -3 and two independent Cd atoms, of which one is on a special position with site symmetry -3. The Cd4As2Br3 structure consists of AsCd4 tetrahedra sharing vertices with isolated As2Cd6 octahedra that contain As–As dumbbells in the centre of the octahedron. The Br atoms are located in the voids of this three-dimensional arrangement and bridge the different polyhedra through Cd...Br contacts.

  3. A Single HIV-1 Cluster and a Skewed Immune Homeostasis Drive the Early Spread of HIV among Resting CD4+ Cell Subsets within One Month Post-Infection

    Science.gov (United States)

    Avettand-Fenoël, Véronique; Nembot, Georges; Mélard, Adeline; Blanc, Catherine; Lascoux-Combe, Caroline; Slama, Laurence; Allegre, Thierry; Allavena, Clotilde; Yazdanpanah, Yazdan; Duvivier, Claudine; Katlama, Christine; Goujard, Cécile; Seksik, Bao Chau Phung; Leplatois, Anne; Molina, Jean-Michel; Meyer, Laurence; Autran, Brigitte; Rouzioux, Christine

    2013-01-01

    Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3−CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that

  4. A single HIV-1 cluster and a skewed immune homeostasis drive the early spread of HIV among resting CD4+ cell subsets within one month post-infection.

    Directory of Open Access Journals (Sweden)

    Charline Bacchus

    Full Text Available Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI. We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM] and short-lived (transitional-memory [TTM] and effector-memory cells [TEM] resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells, although 10-fold less (p = 0.0005 than in equally infected TCM (4.5, TTM (4.7 and TEM (4.6 cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells, unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells. The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility

  5. Novel teleost CD4-bearing cell populations provide insights into the evolutionary origins and primordial roles of CD4+ lymphocytes and CD4+ macrophages

    OpenAIRE

    Takizawa, Fumio; Magadan, Susana; Parra, David; Xu, Zhen; Koryt����, Tom����; Boudinot, Pierre; Sunyer, J. Oriol

    2016-01-01

    Tetrapods contain a single CD4 co-receptor with four immunoglobulin domains that likely arose from a primordial two-domain ancestor. Notably, teleost fish contain two CD4 genes. Like tetrapod CD4, CD4-1 of rainbow trout includes four immunoglobulin domains while CD4-2 contains only two. Since CD4-2 is reminiscent of the prototypic two-domain CD4 co-receptor, we hypothesized that by characterizing the cell types bearing CD4-1 and CD4-2, we would shed light into the evolution and primordial rol...

  6. Expansion of PD-1-positive effector CD4 T cells in an experimental model of SLE: contribution to the self-organized criticality theory.

    Science.gov (United States)

    Miyazaki, Yumi; Tsumiyama, Ken; Yamane, Takashi; Ito, Mitsuhiro; Shiozawa, Shunichi

    2013-04-18

    We have developed a systems biology concept to explain the origin of systemic autoimmunity. From our studies of systemic lupus erythematosus (SLE) we have concluded that this disease is the inevitable consequence of over-stimulating the host's immune system by repeated exposure to antigen to levels that surpass a critical threshold, which we term the system's "self-organized criticality". We observed that overstimulation of CD4 T cells in mice led to the development of autoantibody-inducing CD4 T cells (aiCD4 T) capable of generating various autoantibodies and pathological lesions identical to those observed in SLE. We show here that this is accompanied by the significant expansion of a novel population of effector T cells characterized by expression of programmed death-1 (PD-1)-positive, CD27(low), CD127(low), CCR7(low) and CD44(high)CD62L(low) markers, as well as increased production of IL-2 and IL-6. In addition, repeated immunization caused the expansion of CD8 T cells into fully-matured cytotoxic T lymphocytes (CTL) that express Ly6C(high)CD122(high) effector and memory markers. Thus, overstimulation with antigen leads to the expansion of a novel effector CD4 T cell population that expresses an unusual memory marker, PD-1, and that may contribute to the pathogenesis of SLE.

  7. Impact on ART initiation of point-of-care CD4 testing at HIV diagnosis among HIV-positive youth in Khayelitsha, South Africa.

    Science.gov (United States)

    Patten, Gabriela E M; Wilkinson, Lynne; Conradie, Karien; Isaakidis, Petros; Harries, Anthony D; Edginton, Mary E; De Azevedo, Virginia; van Cutsem, Gilles

    2013-07-04

    Despite the rapid expansion of antiretroviral therapy (ART) programmes in developing countries, pre-treatment losses from care remain a challenge to improving access to treatment. Youth and adolescents have been identified as a particularly vulnerable group, at greater risk of loss from both pre-ART and ART care. Point-of-care (POC) CD4 testing has shown promising results in improving linkage to ART care. In Khayelitsha township, South Africa, POC CD4 testing was implemented at a clinic designated for youth aged 12-25 years. We assessed whether there was an associated reduction in attrition between HIV testing, assessment for eligibility and ART initiation. A before-and-after observational study was conducted using routinely collected data. These were collected on patients from May 2010 to April 2011 (Group A) when baseline CD4 count testing was performed in a laboratory and results were returned to the clinic within two weeks. Same-day POC CD4 testing was implemented in June 2011, and data were collected on patients from August 2011 to July 2012 (Group B). A total of 272 and 304 youth tested HIV-positive in Group A and Group B, respectively. Group B patients were twice as likely to have their ART eligibility assessed compared to Group A patients: 275 (90%) vs. 183 (67%) [relative risk (RR)=2.4, 95% CI: 1.8-3.4, pART was 50% and 44% (p=0.6) in Groups B and A, respectively; and 50% and 43% (p=0.5) when restricted to patients with baseline CD4 count≤250 cells/µL. Time between HIV-testing and ART initiation was reduced from 36 to 28 days (p=0.6). POC CD4 testing significantly improved assessment for ART eligibility. The improvement in the proportion initiating ART and the reduction in time to initiation was not significant due to sample size limitations. POC CD4 testing reduced attrition between HIV-testing and assessment of ART eligibility. Strategies to improve uptake of ART are needed, possibly by improving patient support for HIV-positive youth immediately

  8. Prevalence of orofacial manifestations in HIV-positive South Indian children and the co-relation with CD4 counts

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    Rachna Kaul

    2009-01-01

    Full Text Available Objectives : Orofacial manifestations (OFMs are seen early in the course of HIV disease in children and can also act as indicators for the presence of the disease. The objective of the study were to find the prevalence of OFMs of HIV in infected children, co-relate them with their CD4 counts and establish whether OFMs could be used as markers for disease progression. Materials and Methods : Using the diagnostic criteria recommended by the European Collaborative Clearinghouse (ECC on oral problems related to HIV infection and WHO Collaborating Centre on oral manifestations of the HIV, 48 HIV-infected children were examined at the baseline and their CD4 counts were obtained. A follow-up was conducted 6 months later. Chi-Square test was used to analyse the data obtained. Results : OFM showed a high prevalence in HIV-infected children. The degree of immunosuppression was found to co-relate with the presence of OFMs. But, it could not be established that the presence of OFMs could be a marker for HIV disease progression. Conclusion : The results of our study indicated a high prevalence of OFMs in HIV-infected South Indian children. A decline in CD4 counts was found to be associated with more number of OFMs. However, we were unable to establish OFMs as markers for HIV disease progression. The sample size in our study being about 48 patients and the variability in the initiation and duration of HAART therapy, use of other drugs not being considered, may have an influence on the result of our study. Larger population groups, with parameters such as nutritional status and HAART initiation included, can probably give a more conclusive result..

  9. Corrected Lymphocyte Percentages Reduce the Differences in Absolute CD4+ T Lymphocyte Counts between Dual-Platform and Single-Platform Flow Cytometric Approaches.

    Science.gov (United States)

    Noulsri, Egarit; Abudaya, Dinar; Lerdwana, Surada; Pattanapanyasat, Kovit

    2018-03-13

    To determine whether a corrected lymphocyte percentage could reduce bias in the absolute cluster of differentiation (CD)4+ T lymphocyte counts obtained via dual-platform (DP) vs standard single-platform (SP) flow cytometry. The correction factor (CF) for the lymphocyte percentages was calculated at 6 laboratories. The absolute CD4+ T lymphocyte counts in 300 blood specimens infected with human immunodeficiency virus (HIV) were determined using the DP and SP methods. Applying the CFs revealed that 4 sites showed a decrease in the mean bias of absolute CD4+ T lymphocyte counts determined via DP vs standard SP (-109 vs -84 cells/μL, -80 vs -58 cells/μL, -52 vs -45 cells/μL, and -32 vs 1 cells/μL). However, 2 participating laboratories revealed an increase in the difference of the mean bias (-42 vs -49 cells/μL and -20 vs -69 cells/μL). Use of the corrected lymphocyte percentage shows potential for decreasing the difference in CD4 counts between DP and the standard SP method.

  10. Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry

    International Nuclear Information System (INIS)

    Pham, Son; Tabarin, Thibault; Garvey, Megan; Pade, Corinna; Rossy, Jérémie; Monaghan, Paul; Hyatt, Alex; Böcking, Till; Leis, Andrew; Gaus, Katharina; Mak, Johnson

    2015-01-01

    Viruses are often thought to have static structure, and they only remodel after the viruses have entered target cells. Here, we detected a size expansion of virus particles prior to viral entry using cryo-electron microscopy (cryo-EM) and single molecule fluorescence imaging. HIV expanded both under cell-free conditions with soluble receptor CD4 (sCD4) targeting the CD4 binding site on the HIV-1 envelope protein (Env) and when HIV binds to receptor on cellular membrane. We have shown that the HIV Env is needed to facilitate receptor induced virus size expansions, showing that the ‘lynchpin’ for size expansion is highly specific. We demonstrate that the size expansion required maturation of HIV and an internal capsid core with wild type stability, suggesting that different HIV compartments are linked and are involved in remodelling. Our work reveals a previously unknown event in HIV entry, and we propose that this pre-entry priming process enables HIV particles to facilitate the subsequent steps in infection. - Highlights: • Cell free viruses are able to receive external trigger that leads to apparent size expansion. • Virus envelope and CD4 receptor engagement is the lynchpin of virus size expansion. • Internal capsid organisation can influence receptor mediated virus size expansion. • Pre-existing virus-associated lipid membrane in cell free virus can accommodate the receptor mediated virus size expansion.

  11. Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry

    Energy Technology Data Exchange (ETDEWEB)

    Pham, Son [Deakin University, Victoria 3216 (Australia); CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Tabarin, Thibault [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Garvey, Megan; Pade, Corinna [Deakin University, Victoria 3216 (Australia); CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Rossy, Jérémie [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Monaghan, Paul; Hyatt, Alex [CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Böcking, Till [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Leis, Andrew [CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Gaus, Katharina, E-mail: k.gaus@unsw.edu.au [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Mak, Johnson, E-mail: j.mak@deakin.edu.au [Deakin University, Victoria 3216 (Australia); CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia)

    2015-12-15

    Viruses are often thought to have static structure, and they only remodel after the viruses have entered target cells. Here, we detected a size expansion of virus particles prior to viral entry using cryo-electron microscopy (cryo-EM) and single molecule fluorescence imaging. HIV expanded both under cell-free conditions with soluble receptor CD4 (sCD4) targeting the CD4 binding site on the HIV-1 envelope protein (Env) and when HIV binds to receptor on cellular membrane. We have shown that the HIV Env is needed to facilitate receptor induced virus size expansions, showing that the ‘lynchpin’ for size expansion is highly specific. We demonstrate that the size expansion required maturation of HIV and an internal capsid core with wild type stability, suggesting that different HIV compartments are linked and are involved in remodelling. Our work reveals a previously unknown event in HIV entry, and we propose that this pre-entry priming process enables HIV particles to facilitate the subsequent steps in infection. - Highlights: • Cell free viruses are able to receive external trigger that leads to apparent size expansion. • Virus envelope and CD4 receptor engagement is the lynchpin of virus size expansion. • Internal capsid organisation can influence receptor mediated virus size expansion. • Pre-existing virus-associated lipid membrane in cell free virus can accommodate the receptor mediated virus size expansion.

  12. Trends in baseline CD4 cell counts and risk factors for late antiretroviral therapy initiation among HIV-positive patients in Shanghai, a retrospective cross-sectional study.

    Science.gov (United States)

    Sun, Jianjun; Liu, Li; Shen, Jiayin; Chen, Panpan; Lu, Hongzhou

    2017-04-19

    There are few studies focus on the factors underlying the late initiation of ART in China. We analyzed the trends in the median CD4 cell counts among different patient groups over time and the risk factors for the late initiation of ART in Shanghai, China. A retrospective cross-sectional survey was made in the Department of Infectious Disease of Shanghai Public Health Clinical Center which is a designated diagnosis and treatment center for HIV-positive patients in Shanghai during the period of January 1st, 2008--June 30th, 2014. Late ART initiation was defined as a CD4 cell count 30 years) (p HIV exposure who are male, older even heterosexual orientation should be given more opportunities to receive frequently screening, earlier diagnoses and timely treatment.

  13. Urinary Tract Infections among HIV-Positive Pregnant Women in Mwanza City, Tanzania, Are High and Predicted by Low CD4+ Count

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    Tito Chaula

    2017-01-01

    Full Text Available Introduction. Urinary tract infection (UTI among pregnant women can lead to adverse maternal and foetal outcomes. UTI has been widely studied in the general obstetric population in Tanzania; the present study evaluated the magnitude, antimicrobial resistance, and predictors of UTI among HIV-positive pregnant women. Methods. Between March and May 2016 midstream urine samples from 234 women attending prevention of mother to child transmission of HIV (PMTCT clinics were analyzed using standard methods. Data was analyzed by STATA version 11.0. Results. The prevalence of UTI was 21.4%, 50/234 [95% CI: 16.1–26.6]. The asymptomatically significant bacteriuria was higher than symptomatically significant bacteriuria (16.6% versus 4.7%, p<0.001. On multivariable logistic regression analysis, single marital status (OR: 2.6, 95% CI: 1.1–6.1, and p=0.026, low CD4+ counts of <200/μL (OR: 2.9, 95% CI: 1.1–7.7, and p=0.031, and having UTI symptoms (OR: 2.5, 95% CI: 1.1–6.0, and p=0.03 were independent predictors of UTI. Escherichia coli predominated (57.7% and exhibited a low prevalence of resistance to nitrofurantoin (16.7%, gentamicin (10.0%, and ceftriaxone (13.3%. Four (13.3% of these were extended-spectrum beta-lactamase producers. Conclusions. A considerable proportion of HIV-positive pregnant women in Mwanza have significant bacteriuria which calls for the need to introduce routine UTI screening at PMTCT clinics to guide specific treatment and prevent associated complications.

  14. Some hematological parameters and the prognostic values of CD4, CD8 and total lymphocyte counts and CD4/CD8 cell count ratio in healthy HIV sero-negative, healthy HIV sero-positive and AIDS subjects in Port Harcourt, Nigeria

    Directory of Open Access Journals (Sweden)

    Blessing Didia

    2008-12-01

    Full Text Available OBJECTIVE: The present study attempts to determine normal values of CD4, CD8, CD4/CD8 ratio, total WBC and differential counts, hematocrit and total lymphocyte count (TLC in healthy HIV sero-negative and sero-positive subjects, and to assess the prognostic significance of these parameters in these subjects as compared to AIDS subjects.METHODS: A total of 300 subjects (147 M, 153 F aged between 17 and 71 years were recruited into the study. Subjects were separated according to sex and divided into three groups: Group A: healthy HIV sero-negative subjects; Group B: healthy HIV sero-positive newly diagnosed ART-naïve subjects; and Group C: AIDS subjects. CD4 and CD8 counts were determined by flow cytometry; hematocrit was determined using Hawksley micro-capillary tubes; total WBC and differential counts were determined manually with the improved Neubauer counting chamber; and TLC was obtained by multiplying the percentage of lymphocytes by the total WBC count.RESULTS: For male subjects, significant differences were found in CD4 count, CD4/CD8 count ratio, hematocrit, total WBC and TLC, whereas for female subjects, significant differences were found only in CD4 and CD4/CD8 count ratio in the three groups of subjects. In both sexes, however, these parameters were found to be highest in healthy HIV sero-negative subjects and lowest in AIDS subjects, with HIV sero-positive subjects having intermediate values. CONCLUSION: The results confirm previous reports that the CD4 count and CD4/CD8 count ratio are fairly reliable indicators of the progression of HIV infection. In addition, the results also apparently suggest that the prognostic value of CD8 count is limited and that of TLC possibly sex-dependent. The results could be of importance in our environment since previous reports have been relatively scarce.

  15. A single amino-acid change in a highly conserved motif of gp41 elicits HIV-1 neutralization and protects against CD4 depletion.

    Science.gov (United States)

    Petitdemange, Caroline; Achour, Abla; Dispinseri, Stefania; Malet, Isabelle; Sennepin, Alexis; Ho Tsong Fang, Raphaël; Crouzet, Joël; Marcelin, Anne-Geneviève; Calvez, Vincent; Scarlatti, Gabriella; Debré, Patrice; Vieillard, Vincent

    2013-09-01

    The induction of neutralizing antibodies against conserved regions of the human immunodeficiency virus type 1 (HIV-1) envelope protein is a major goal of vaccine strategies. We previously identified 3S, a critical conserved motif of gp41 that induces the NKp44L ligand of an activating NK receptor. In vivo, anti-3S antibodies protect against the natural killer (NK) cell-mediated CD4 depletion that occurs without efficient viral neutralization. Specific substitutions within the 3S peptide motif were prepared by directed mutagenesis. Virus production was monitored by measuring the p24 production. Neutralization assays were performed with immune-purified antibodies from immunized mice and a cohort of HIV-infected patients. Expression of NKp44L on CD4(+) T cells and degranulation assay on activating NK cells were both performed by flow cytometry. Here, we show that specific substitutions in the 3S motif reduce viral infection without affecting gp41 production, while decreasing both its capacity to induce NKp44L expression on CD4(+) T cells and its sensitivity to autologous NK cells. Generation of antibodies in mice against the W614 specific position in the 3S motif elicited a capacity to neutralize cross-clade viruses, notable in its magnitude, breadth, and durability. Antibodies against this 3S variant were also detected in sera from some HIV-1-infected patients, demonstrating both neutralization activity and protection against CD4 depletion. These findings suggest that a specific substitution in a 3S-based immunogen might allow the generation of specific antibodies, providing a foundation for a rational vaccine that combine a capacity to neutralize HIV-1 and to protect CD4(+) T cells.

  16. Coexpresión de CD4 y CD8 en linfocitos de sangre periférica en pacientes positivos para VIH Peripheral blood lymphocyte CD4 and CD8 co-expression in HIV positive patients

    Directory of Open Access Journals (Sweden)

    Alberto Gómez

    2008-12-01

    Full Text Available Objetivo. La coexpresión en membrana de las moléculas CD4 y CD8 en leucocitos de sangre periférica se halla generalmente restringida a casos de leucemias agudas T prolinfocíticas o de leucemias T del adulto y no representa más de 3% a 5% de los linfocitos T periféricos. En este trabajo buscamos establecer la frecuencia de elevación de los linfocitos CD4+CD8+ de la totalidad de las muestras de pacientes remitidos para tipificación al Instituto de Referencia Andino en el año 2007. Diseño. Se hizo la tipificación de 1.883 subpoblaciones de linfocitos T de individuos diferentes y, luego, se procedió a la revisión retrospectiva de los resultados que correspondían a la totalidad de los análisis del 2007 en nuestro instituto. Además, se tabularon 142 muestras recibidas en enero de 2008 con el fin de determinar valores de referencia para la población estudiada. Metodología. Las muestras de sangre total se marcaron con anticuerpos monoclonales fluorescentes utilizando el reactivo Cyto-Stat® triCHROME™ CD8-FITC/CD4-RD1/CD3-PC5 y, luego, se procesaron en un citómetro Epics XL-MCL. Resultados. El análisis de los pacientes tipificados en 2007 reveló la existencia de dos individuos (0,11% en los que se presentó el fenómeno de aumento de la coexpresión en membrana de las moléculas CD4 y CD8. Conclusiones. El hallazgo de este fenotipo linfocitario en sangre periférica de pacientes no leucémicos debe alertar a los laboratorios que tipifican aisladamente los linfocitos CD4+ sin evaluar los marcadores CD3 y CD8, puesto que podrían estar sobreestimando los recuentos y porcentajes reales de células CD4+CD8 en la sangre periférica de sus pacientes y subestimando una subpoblación de linfocitos que es infrecuente, pero que se ha reportado como funcional y diferenciada en una variedad de infecciones y modelos experimentales.Objective: Membrane co-expression of CD4 and CD8 molecules in peripheral blood leukocytes is usually restricted to

  17. CD4dullCD8bright double-positive T-lymphocytes have a phenotype of granzyme Bpos CD8pos memory T-lymphocytes

    NARCIS (Netherlands)

    Rentenaar, R. J.; Wever, P. C.; van Diepen, F. N.; Schellekens, P. T.; Wertheim, P. M.; ten Berge, I. J.

    1999-01-01

    BACKGROUND: T-lymphocytes that co-express CD4 and CD8 antigens may be found in small percentages in the peripheral blood of healthy individuals, and have a CD4brightCD8dull phenotype. CD4dullCD8bright T-lymphocytes have been found only in temporal association with some viral infections. METHODS:

  18. Trends in CD4 cell count response to first-line antiretroviral treatment in HIV-positive patients from Asia, 2003-2013: TREAT Asia HIV Observational Database Low Intensity Transfer.

    Science.gov (United States)

    De La Mata, Nicole L; Ly, Penh S; Ng, Oon T; Nguyen, Kinh V; Merati, Tuti P; Pham, Thuy T; Lee, Man P; Choi, Jun Y; Sohn, Annette H; Law, Matthew G; Kumarasamy, Nagalingeswaran

    2017-11-01

    Antiretroviral treatment (ART) guidelines have changed over the past decade, recommending earlier initiation and more tolerable regimens. The study objective was to examine the CD4 response to ART, depending on the year of ART initiation, in HIV-positive patients in the Asia-Pacific. We included HIV-positive adult patients who initiated ART between 2003 and 2013 in our regional cohort from eight urban referral centres in seven countries within Asia. We used mixed-effects linear regression models to evaluate differences in CD4 response by year of ART initiation during 36 months of follow-up, adjusted a priori for other covariates. Overall, 16,962 patients were included. Patients initiating in 2006-9 and 2010-13 had an estimated mean CD4 cell count increase of 8 and 15 cells/µl, respectively, at any given time during the 36-month follow-up, compared to those in 2003-5. The median CD4 cell count at ART initiation also increased from 96 cells/µl in 2003-5 to 173 cells/µl in 2010-13. Our results suggest that the CD4 response to ART is modestly higher for those initiating ART in more recent years. Moreover, fewer patients are presenting with lower absolute CD4 cell counts over time. This is likely to reduce their risk of opportunistic infections and future non-AIDS defining cancers.

  19. CD98 Heavy Chain Is a Potent Positive Regulator of CD4+ T Cell Proliferation and Interferon-γ Production In Vivo.

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    Takeshi Kurihara

    Full Text Available Upon their recognition of antigens presented by the MHC, T cell proliferation is vital for clonal expansion and the acquisition of effector functions, which are essential for mounting adaptive immune responses. The CD98 heavy chain (CD98hc, Slc3a2 plays a crucial role in the proliferation of both CD4+ and CD8+ T cells, although it is unclear if CD98hc directly regulates the T cell effector functions that are not linked with T cell proliferation in vivo. Here, we demonstrate that CD98hc is required for both CD4+ T cell proliferation and Th1 functional differentiation. T cell-specific deletion of CD98hc did not affect T cell development in the thymus. CD98hc-deficient CD4+ T cells proliferated in vivo more slowly as compared with control T cells. C57BL/6 mice lacking CD98hc in their CD4+ T cells could not control Leishmania major infections due to lowered IFN-γ production, even with massive CD4+ T cell proliferation. CD98hc-deficient CD4+ T cells exhibited lower IFN-γ production compared with wild-type T cells, even when comparing IFN-γ expression in cells that underwent the same number of cell divisions. Therefore, these data indicate that CD98hc is required for CD4+ T cell expansion and functional Th1 differentiation in vivo, and suggest that CD98hc might be a good target for treating Th1-mediated immune disorders.

  20. Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study

    NARCIS (Netherlands)

    Caniglia, Ellen C.; Cain, Lauren E.; Sabin, Caroline A.; Robins, James M.; Logan, Roger; Abgrall, Sophie; Mugavero, Michael J.; Hernández-Díaz, Sonia; Meyer, Laurence; Seng, Remonie; Drozd, Daniel R.; Seage, George R.; Bonnet, Fabrice; Dabis, Francois; Moore, Richard D.; Reiss, Peter; van Sighem, Ard; Mathews, William C.; del Amo, Julia; Moreno, Santiago; Deeks, Steven G.; Muga, Roberto; Boswell, Stephen L.; Ferrer, Elena; Eron, Joseph J.; Napravnik, Sonia; Jose, Sophie; Phillips, Andrew; Justice, Amy C.; Tate, Janet P.; Gill, John; Pacheco, Antonio; Veloso, Valdilea G.; Bucher, Heiner C.; Egger, Matthias; Furrer, Hansjakob; Porter, Kholoud; Touloumi, Giota; Crane, Heidi; Miro, Jose M.; Sterne, Jonathan A.; Costagliola, Dominique; Saag, Michael; Hernán, Miguel A.

    2017-01-01

    Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. In this observational study, we used data from prospective

  1. CD4+ T cell-mediated rejection of MHC class II-positive tumor cells is dependent on antigen secretion and indirect presentation on host APCs.

    Science.gov (United States)

    Haabeth, Ole Audun Werner; Fauskanger, Marte; Manzke, Melanie; Lundin, Katrin U; Corthay, Alexandre; Bogen, Bjarne; Tveita, Anders Aune

    2018-05-11

    Tumor-specific CD4+ T cells have been shown to mediate efficient anti-tumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)-expressing tumor cells or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4+ T cells reactive against an epitope within the Ig light chain variable region of a murine B cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II-restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II-expressing tumor cells was essential both for the priming and effector phase of CD4+ T cell-driven anti-tumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen-specific CD4+ T cells in vivo. These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4+ T cell-mediated rejection, and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4+ T cells. Copyright ©2018, American Association for Cancer Research.

  2. Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Weizao, E-mail: chenw3@mail.nih.gov [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Feng, Yang [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Wang, Yanping [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); The Basic Research Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Zhu, Zhongyu; Dimitrov, Dimiter S. [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibit decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.

  3. Quasi-Poisson versus negative binomial regression models in identifying factors affecting initial CD4 cell count change due to antiretroviral therapy administered to HIV-positive adults in North-West Ethiopia (Amhara region).

    Science.gov (United States)

    Seyoum, Awoke; Ndlovu, Principal; Zewotir, Temesgen

    2016-01-01

    CD4 cells are a type of white blood cells that plays a significant role in protecting humans from infectious diseases. Lack of information on associated factors on CD4 cell count reduction is an obstacle for improvement of cells in HIV positive adults. Therefore, the main objective of this study was to investigate baseline factors that could affect initial CD4 cell count change after highly active antiretroviral therapy had been given to adult patients in North West Ethiopia. A retrospective cross-sectional study was conducted among 792 HIV positive adult patients who already started antiretroviral therapy for 1 month of therapy. A Chi square test of association was used to assess of predictor covariates on the variable of interest. Data was secondary source and modeled using generalized linear models, especially Quasi-Poisson regression. The patients' CD4 cell count changed within a month ranged from 0 to 109 cells/mm 3 with a mean of 15.9 cells/mm 3 and standard deviation 18.44 cells/mm 3 . The first month CD4 cell count change was significantly affected by poor adherence to highly active antiretroviral therapy (aRR = 0.506, P value = 2e -16 ), fair adherence (aRR = 0.592, P value = 0.0120), initial CD4 cell count (aRR = 1.0212, P value = 1.54e -15 ), low household income (aRR = 0.63, P value = 0.671e -14 ), middle income (aRR = 0.74, P value = 0.629e -12 ), patients without cell phone (aRR = 0.67, P value = 0.615e -16 ), WHO stage 2 (aRR = 0.91, P value = 0.0078), WHO stage 3 (aRR = 0.91, P value = 0.0058), WHO stage 4 (0876, P value = 0.0214), age (aRR = 0.987, P value = 0.000) and weight (aRR = 1.0216, P value = 3.98e -14 ). Adherence to antiretroviral therapy, initial CD4 cell count, household income, WHO stages, age, weight and owner of cell phone played a major role for the variation of CD4 cell count in our data. Hence, we recommend a close follow-up of patients to adhere the prescribed medication for

  4. Efectos de la vacunación antigripal sobre el porcentaje de linfocitos T CD4 positivos en pacientes VIH 1/2 positivos: estudio de una cohorte Effects of influenza vaccination on the percentage of CD4+ T lymphocytes in HIV 1/2 positive patients: a cohort study

    Directory of Open Access Journals (Sweden)

    Leslie Barrionuevo Rosas

    2009-08-01

    Full Text Available Objetivo: Determinar la incidencia del cambio inmunitario del porcentaje de linfocitos T CD4+ en pacientes VIH 1/2 positivos en el primer trimestre posvacunación antigripal (P-CIR y secundariamente comparar las características demográficas y clínicas relacionadas con dicho cambio. Métodos: Se estudiaron 105 pacientes con VIH-sida de una cohorte retrospectiva hospitalaria entre 2001 y 2006. Se consideró P-CIR una disminución >3% del porcentaje de CD4+ prevacunal, y su asociación cruda y ajustada (sexo, edad, terapia antirretroviral, estabilidad clínica, carga viral prevacunal, CD4 total prevacunal fue evaluada por regresión logística (odds ratio [OR] con intervalo de confianza del 95% [IC95%]. Resultados: La incidencia del P-CIR fue del 33,3%, y fue persistente en un 31,4% durante los siete meses posvacunación independientemente de una viremia alta prevacunal. Asimismo, las variables demográficas y clínicas estudiadas no se relacionaron con la presencia de P-CIR, con una OR cruda de 0,90 (0,17-4,8 y una OR ajustada de 1,09 (0,17-6,8. Conclusiones: Los datos encontrados reflejan que el cambio relevante del estado inmunitario no fue despreciable en la posvacunación, aunque mayoritariamente resultó transitorio.Objective: To determine the incidence of immunologic change in the percentage of CD4+ T lymphocytes in HIV 1/2 positive patients in the first quarter after influenza vaccination (P-CIR and to compare the demographic and clinical characteristics associated with this change. Methods: We studied 105 patients with HIV/AIDS in a retrospective hospital cohort between 2001-2006. P-CIR was considered as a decrease of >3% in the prevaccination CD4+ percentage. Crude and adjusted OR (sex, age, antiretroviral therapy, clinical stability, prevaccination viremia and prevaccination total CD4 were evaluated by logistic regression (95%CI. Results: The incidence of P-CIR was 33.3%. P-CIR was persistent in 31.4% for 7 months after vaccination

  5. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes

    DEFF Research Database (Denmark)

    Ledergerber, Bruno; Lundgren, Jens D; Walker, A Sarah

    2014-01-01

    Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure....

  6. World Health Organization guidelines should not change the CD4 ...

    African Journals Online (AJOL)

    2013-03-02

    Mar 2, 2013 ... The World Health Organization (WHO) currently recommends that HIV-positive adults start antiretroviral therapy (ART) at. CD4 counts <350 cells/µl. Several countries have changed their guidelines to recommend ART irrespective of CD4 count or at a threshold of 500 CD4 cells/µl. Consequently, WHO is ...

  7. World Health Organization guidelines should not change the CD4 ...

    African Journals Online (AJOL)

    The World Health Organization (WHO) currently recommends that HIV-positive adults start antiretroviral therapy (ART) at CD4 counts <350 cells/μl. Several countries have changed their guidelines to recommend ART irrespective of CD4 count or at a threshold of 500 CD4 cells/μl. Consequently, WHO is currently revising its ...

  8. CD4+CD8β+ double-positive T cells in skin-draining lymph nodes respond to inflammatory signals from the skin

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr; Cruz, Jazmina L.; Bridge, Jennifer A.

    2017-01-01

    CD4+CD8+ double-positive (DP), mature, peripheral T cells are readily detectable in a variety of species and tissues. Despite a common association with autoimmune and malignant skin disorders, however, little is understood about their role or function. Herein, we show that DP T cells are readily ...

  9. HuMax-CD4

    DEFF Research Database (Denmark)

    Skov, Lone; Kragballe, Knud; Zachariae, Claus

    2003-01-01

    BACKGROUND: Psoriasis is characterized by infiltration with mononuclear cells. Especially activated memory CD4+ T cells are critical in the pathogenesis. Interaction between the CD4 receptor and the major histocompatibility complex class II molecule is important for T-cell activation. OBJECTIVE......: To test safety and efficacy of a fully human monoclonal anti-CD4 antibody (HuMax-CD4) in the treatment of psoriasis. DESIGN: Multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients Eighty-five patients with moderate to severe psoriasis. INTERVENTIONS: Subcutaneous infusions...... dose level, 6 (38%) of 16 patients obtained more than 25% reduction of PASI and 3 (19%) obtained more than 50% reduction of PASI. A dose-dependent decrease in total lymphocyte count was seen and was parallel to a dose-dependent decrease in CD4+ T cells. This decrease was due to a decrease in the memory...

  10. Phenotypical and functional characterization of double-negative (CD4-CD8-) alpha beta T-cell receptor positive cells from an immunodeficient patient

    DEFF Research Database (Denmark)

    Illum, N; Ralfkiaer, E; Pallesen, G

    1991-01-01

    We have characterized CD4-CD8- double-negative (DN) alpha beta TCR+ T cells from a patient with immunodeficiency, lymphocytosis, lymphadenopathy, and hepatosplenomegaly. The majority of peripheral blood lymphocytes were DN alpha beta TCR+ T cells as evaluated by FACS and biochemical analysis...... (MoAbs) indicated a polyclonal T-cell expansion. Thymic biopsy showed normal histology, whereas lymph node biopsy samples showed altered histological and immunohistological patterns with markedly expanded paracortical areas containing the DN T cells of the same phenotype as found in peripheral blood T...

  11. Deregulation of calcium fluxes in HTLV-I infected CD4-positive T-cells plays a major role in malignant transformation.

    Science.gov (United States)

    Akl, Haidar; Badran, Bassam; El Zein, Nabil; Dobirta, Gratiela; Burny, Arsene; Martiat, Philippe

    2009-01-01

    The CD4+ T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-I) infection and termed; Adult T-cell Leukemia lymphoma (ATLL), is caused by defects in the mechanisms underlying cell proliferation and cell death. In the CD4+ T-cells, calcium ions are central for both phenomena. ATLL is associated with a marked hypercalcemia in many patients. The consequence of a defect in the Ca2+ signaling pathway for lymphocyte activation is characterized by an impaired NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defense. Fresh ATLL cells lack the TCR/CD3 and CD7 molecules on their surface. Whereas CD7 is a calcium transporter, reduction in calcium influx in response to T-cell activation was reported as a functional consequence of TCR/CD3 expression deficiency. Understanding these changes and identifying the molecular players involved might provide further insights on how to improve ATLL treatment.

  12. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice

    International Nuclear Information System (INIS)

    Hanna, Zaher; Priceputu, Elena; Hu, Chunyan; Vincent, Patrick; Jolicoeur, Paul

    2006-01-01

    HIV-1 Nef has the ability to downmodulate CD4 cell surface expression. Several studies have shown that CD4 downregulation is required for efficient virus replication and high infectivity. However, the pathophysiological relevance of this phenomenon in vivo, independently of its role in sustaining high virus loads, remains unclear. We studied the impact of the CD4 downregulation function of Nef on its pathogenesis in vivo, in the absence of viral replication, in the CD4C/HIV transgenic (Tg) mouse model. Two independent Nef mutants (RD35/36AA and D174K), known to abrogate CD4 downregulation, were tested in Tg mice. Flow cytometry analysis showed that downregulation of murine CD4 was severely decreased or abrogated on Tg T cells expressing respectively Nef RD35/36AA and Nef D174K . Similarly, the severe depletion of double-positive CD4 + CD8 + and of single-positive CD4 + CD8 - thymocytes, usually observed with Nef Wt , was not detected in Nef RD35/36AA and Nef D174K Tg mice. However, both mutant Tg mice showed a partial depletion of peripheral CD4 + T cells. This was accompanied, as previously reported for Net Wt Tg mice, by the presence of an activated/memory-like phenotype (CD69 + , CD25 + , CD44 + , CD45RB Low , CD62 Low ) of CD4 + T cells expressing Nef RD35/36AA and to a lesser extent Nef D174K . In addition, both mutants retained the ability to block CD4 + T cell proliferation in vitro after anti-CD3 stimulation, but not to enhance apoptosis/death of CD4 + T cells. Therefore, it appears that Nef-mediated CD4 downregulation is associated with thymic defects, but segregates independently of the activated/memory-like phenotype, of the partial depletion and of the impaired in vitro proliferation of peripheral CD4 + T cells. Histopathological assessment revealed the total absence of or decrease severity and frequency of organ AIDS-like diseases (lung, heart and kidney pathologies) in respectively Nef RD35/36AA and Nef D174K Tg mice, relative to those developing in

  13. Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

    DEFF Research Database (Denmark)

    Kristiansen, O P; Karlsen, A E; Larsen, Z M

    2004-01-01

    screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes...... promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP...

  14. Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study

    NARCIS (Netherlands)

    Lodi, Sara; Phillips, Andrew; Logan, Roger; Olson, Ashley; Costagliola, Dominique; Abgrall, Sophie; van Sighem, Ard; Reiss, Peter; Miró, José M.; Ferrer, Elena; Justice, Amy; Gandhi, Neel; Bucher, Heiner C.; Furrer, Hansjakob; Moreno, Santiago; Monge, Susana; Touloumi, Giota; Pantazis, Nikos; Sterne, Jonathan; Young, Jessica G.; Meyer, Laurence; Seng, Rémonie; Dabis, Francois; Vandehende, Marie-Anne; Pérez-Hoyos, Santiago; Jarrín, Inma; Jose, Sophie; Sabin, Caroline; Hernán, Miguel A.; Ainsworth, J.; Anderson, J.; Babiker, A.; Delpech, V.; Dunn, D.; Easterbrook, P.; Fisher, M.; Gazzard, B.; Gilson, R.; Gompels, M.; Hill, T.; Johnson, M.; Leen, C.; Orkin, C.; Phillips, A.; Pillay, D.; Porter, K.; Sabin, C.; Walsh, J.; Glabay, A.; Thomas, R.; Jones, K.; Perry, N.; Pullin, A.; Churchill, D.; Bulbeck, S.; Mandalia, S.; Clarke, J.; Munshi, S.; Post, F.; Khan, Y.; Patel, P.; Karim, F.; Duffell, S.; Williams, I.; Dooley, D.; Schwenk, A.; Youle, M.; Lampe, F.; Chaloner, C.; Puradiredja, D. Ismajani; Bansi, L.; Weber, J.; Kemble, C.; Mackie, N.; Winston, A.; Wilson, A.; Bezemer, D. O.; Kesselring, A. M.; van Sighem, A. I.; Smit, C.; Zaheri, S.; Kortmann, W.; Prins, J. M.; Kuijpers, T. W.; Godfried, M. H.; Pajkrt, D.; Bos, J. C.; van der Valk, M.; Grijsen, M. L.; Wiersinga, W. J.; Vrouwe, Lieve; Brinkman, K.; Blok, W. L.; Ziekenhuis, Andreas; Veenstra, J.; Lettinga, K. D.; Mulder, J. W.; Lauw, F. N.; van Agtmael, M. A.; Perenboom, R. M.; Bomers, M.; Richter, C.; van der Berg, J. P.; Gisolf, E. H.; Schippers, E. F.; van Elzakker, E. P.; Bravenboer, B.; Kootstra, G. J.; Sprenger, H. G.; Doedens, R.; van Assen, S.; Gasthuis, Kennemer; Soetekouw, R.; Kroon, F. P.; van Dissel, J. T.; Arend, S. M.; Jolink, H.; Bauer, M. P.; Weijer, S.; Lowe, S.; Lashof, A. Oude; Posthouwer, D.; Koopmans, P. P.; Warris, A.; van Crevel, R.; Nouwen, J. L.; Nispen, M. H.; Verbon, A.; Hassing, R. J.; Hartwig, N. G.; Ziekenhuis, Maasstad; Pogany, K.; Ziekenhuis, Sint Elisabeth; Juttmann, J. R.; van Kasteren, M. E. E.; Mudrikova, T.; Ellerbroek, P. M.; Oosterheert, J. J.; Barth, R. E.; Kinderziekenhuis, Wilhelmina; Bont, L. J.; de Ruyter Ziekenhuis, Admiraal; Stegeman, A.; Alleman, M. A.; Bouwhuis, J. W.; Abgrall, S.; Barin, F.; Bentata, M.; Billaud, E.; Boué, F.; Burty, C.; Cabié, A.; de Truchis, P.; Duval, X.; Duvivier, C.; Enel, P.; Fredouille-Heripret, L.; Gasnault, J.; Gaud, C.; Katlama, C.; Khuong, M. A.; Lang, J. M.; Lascaux, A. S.; Launay, O.; Mahamat, A.; Mary-Krause, M.; Meynard, J. L.; Pavie, J.; Pialoux, G.; Pilorgé, F.; Poizot-Martin, I.; Pradier, C.; Reynes, J.; Rouveix, E.; Simon, A.; Tissot-Dupont, H.; Viard, J. P.; Viget, N.; Jacquemet, N.; Costagliola, D.; Grabar, S.; Guiguet, M.; Lanoy, E.; Lièvre, L.; Lacombe, J. M.; Potard, V.; Pitié, G. H.; Bricaire, F.; Herson, S.; Desplanque, N.; Meyohas, M. C.; Picard, O.; Cadranel, J.; Mayaud, C.; Clauvel, J. P.; Decazes, J. M.; Gerard, L.; Molina, J. M.; Lariboisière-Fernand, G. H.; Honoré, P.; Jeantils, V.; Tassi, S.; Mechali, D.; Taverne, B.; Bouvet, E.; Ecobichon, J. L.; Matheron, S.; Picard-Dahan, C.; Yeni, P.; Dupont, C.; Chandemerle, C.; Mortier, E.; Tisne-Dessus, D.; Weiss, L.; Tarnier-Cochin, G. H.; Auperin, I.; Gilquin, J.; Roudière, L.; Fior, R.; Delfraissy, J. F.; Goujard, C.; Jung, C.; Vittecoq, D.; Fraisse, P.; Beck-Wirth, G.; Stahl, J. P.; Lecercq, P.; Gourdon, F.; Laurichesse, H.; Fresard, A.; Basse-Normandie, Corevih; Bazin, C.; Verdon, R.; Bourgogne, Corevih; Bretagne, Corevih; Arvieux, C.; Michelet, C.; Goudeau, A.; Maître, M. F.; Hoen, B.; Faller, J. P.; Haute-Normandie, Corevih; Borsa-Lebas, F.; Caron, F.; Daures, J. P.; Lorraine, Corevih; May, T.; Rabaud, C.; Berger, J. L.; Rémy, G.; Arlet-Suau, E.; Cuzin, L.; Massip, P.; Legrand, M. F. Thiercelin; Pontonnier, G.; de Calais, Corevih Nord-Pas; Yasdanpanah, Y.; Dellamonica, P.; Pugliese, P.; Quinsat, D.; Ravaux, I.; Tissot, H.; Delmont, J. P.; Moreau, J.; Gastaut, J. A.; Retornaz, F.; Soubeyrand, J.; Galinier, A.; Ruiz, J. M.; Allegre, T.; Blanc, P. A.; Bonnet, D.; Lepeu, G.; Granet-Brunello, P.; Esterni, J. P.; Cohen-Valensi, R.; Nezri, M.; Chadapaud, S.; Laffeuillade, A.; Raffi, F.; Boibieux, A.; Peyramond, D.; Livrozet, J. M.; Touraine, J. L.; Strobel, M.; Saint-Martin, C. H.; Bissuel, F.; Pradinaud, R.; Sobesky, M.; Martinique, Corevih; Guyon, Félix; Contant, M.; HC, Bucher; CA, Fux; HH, Hirsch; de Tejada B, Martinez; Casabona, J.; Miró, Jose M.; de Barcelona-Idibaps, Clínic; Gallois, A.; Esteve, A.; Podzamczer, D.; Murillas, J.; Gatell, J. M.; Manzardo, C.; Tural, C.; Clotet, B.; Ferrer, E.; Riera, M.; Segura, F.; Navarro, G.; Vilaró, J.; Masabeu, A.; García, I.; Guadarrama, M.; Cifuentes, C.; Dalmau, D.; Agustí, C.; Montoliu, A.; Pérez, I.; Gargoulas, Freyra; Blanco, J. L.; Garcia-Alcaide, F.; Martínez, E.; García-Goez, J. F.; Sirera, G.; Negredo, E.; Miranda, C.; Capitan, M. C.; Saumoy, M.; Imaz, A.; Tiraboschi, J. M.; Murillo, O.; Bolao, F.; Peña, C.; Cabellos, C.; Vila, A.; Sala, M.; Cervantes, M.; Amengual, Jose; Navarro, M.; Barrufet, P.; Molina, J.; Alvaro, M.; Mercadal, J.; Fernández, Juanse; Ospina, Jesús E.; Berenguer, J.; García, F.; Gutiérrez, F.; Labarga, P.; Moreno, S.; Caro-Murillo, A. M.; Sobrino, P.; Jarrín, I.; Sirvent, J. L. Gómez; Rodríguez, P.; Alemán, M. R.; Alonso, M. M.; López, A. M.; Hernández, M. I.; Soriano, V.; Barreiro, P.; Medrano, J.; Rivas, P.; Herrero, D.; Blanco, F.; Vispo, M. E.; Martín, L.; Ramírez, G.; Rubio, R.; Pulido, F.; Moreno, V.; Cepeda, C.; Iribarren, J. A.; Camino, X.; Rodríguez-Arrondo, F.; von Wichmann, M. A.; Pascual, L.; Goenaga, M. A.; Masiá, M.; Ramos, J. M.; Padilla, S.; Sánchez-Hellín, V.; Bernal, E.; Montolio, F.; Peral, Y.; Marañón, Gregorio; López, J. C.; Miralles, P.; Cosín, J.; Sánchez, M.; Gutiérrez, I.; Ramírez, M.; Padilla, B.; Vidal, F.; Veloso, S.; Viladés, C.; López-Dupla, M.; Olona, M.; Vargas, M.; Lacruz, J.; Salavert, M.; Montero, M.; Cuéllar, S.; Sanz, J.; Oteo, J. A.; Blanco, J. R.; Ibarra, V.; Metola, L.; Sanz, M.; Pérez-Martínez, L.; Sola, J.; Uriz, J.; Castiello, J.; Reparaz, J.; Arriaza, M. J.; Irigoyen, C.; Antela, A.; Casado, J. L.; Dronda, F.; Moreno, A.; Pérez, M. J.; López, D.; Gutiérrez, C.; Martí, P.; García, L.; Page, C.; Hernández, J.; Peña, A.; Muñoz, L.; Parra, J.; Viciana, P.; Leal, M.; López-Cortés, L. F.; Mata, R.; Justice, A. C.; Rimland, D.; Jones-Taylor, C.; Oursler, K. A.; Brown, S.; Garrison, S.; Rodriguez-Barradas, M.; Masozera, N.; Goetz, M.; Leaf, D.; Simberkoff, M.; Blumenthal, D.; Leung, J.; Peck, R.; Mattocks, K.; Braithwaite, S.; Cook, R.; Conigliaro, J.; Crothers, K.; Chang, J.; Crystal, S.; Day, N.; Erdos, J.; Freiberg, M.; Kozal, M.; Gerschenson, M.; Good, B.; Gordon, A.; Goulet, J. L.; Hernán, M. A.; Kraemer, K.; Lim, J.; Maisto, S.; O'Connor, P.; Papas, R.; Robins, J. M.; Rinaldo, C.; Roberts, M.; Samet, J.; Tierney, B.; Whittle, J.; Brettle, R.; Fidler, S.; Goldberg, D.; Hawkins, D.; Jaffe, H.; Johnson, A.; McLean, K.; Porter, Kholoud; Ewings, Fiona; Fairbrother, Keith; Gnatiuc, Louisa; Murphy, Brendan; Douglas, G.; Kennedy, N.; Pritchard, J.; Andrady, U.; Gwynedd, Ysbyty; Rajda, N.; Maw, R.; McKernan, S.; Drake, S.; Gilleran, G.; White, D.; Ross, J.; Toomer, S.; Hewart, R.; Wilding, H.; Woodward, R.; Dean, G.; Heald, L.; Horner, P.; Glover, S.; Bansaal, D.; Carne, C.; Browing, M.; Stanley, B.; O'Mahony, C.; Fraser, P.; Hayman, B.; Joshi, U.; Ralph, S.; Wade, A.; Mette, R.; Lalik, J.; Summerfield, H.; El-Dalil, A.; France, A. J.; White, C.; Robertson, R.; Gordon, S.; Lean, C.; Morris, S.; Vithayathil, K.; McLean, L.; Winter, A.; Gale, D.; Jacobs, S.; Tayal, S.; Short, L.; Williams, G.; Minton, J.; Dhar, J.; Nye, F.; DeSouza, C. B.; Isaksen, A.; McDonald, L.; Franca, A.; William, L.; Peters, B.; El, S.; Easterbrook, P. J.; Mazhude, C.; Johnstone, R.; Fakoya, A.; Mchale, J.; Waters, A.; Kegg, S.; Mitchell, S.; Byrne, P.; Rice, P.; Mullaney, S. A.; McCormack, S.; David, D.; Melville, R.; Phillip, K.; Balachandran, T.; Mabey, S.; Sukthankar, A.; Murphy, C.; Wilkins, E.; Ahmad, S.; Cook, James; Haynes, J.; Keynes, Milton; Evans, E.; Ong, E.; Das, R.; Grey, R.; Meaden, J.; Bignell, C.; Loay, D.; Peacock, K.; Eliot, George; Girgis, M. R.; Morgan, B.; Palfreeman, A.; Wilcox, J.; Tobin, J.; Tucker, L.; Saeed, A. M.; Williams, O.; Clwyd, Glan; Lacey, H.; Herman, S.; Kinghorn, D.; Devendra, S. V.; Wither, J.; Dawson, S.; Rowen, D.; Harvey, J.; Chauhan, M.; Kellock, D.; Young, S.; Dannino, S.; Kathir, Y.; Rooney, G.; Currie, J.; Fitzgerald, M.; Devendra, S.; Keane, F.; Booth, G.; Arumainayyagam, J.; Chandramani, S.; Robinson, T.; Curless, E.; Gokhale, R.; Tariq, A.; Luzzi, G.; Fairley, I.; Wallis, F.; Smit, E.; Ward, F.; Loze, B.; Morlat, P.; Bonarek, M.; Bonnet, F.; Nouts, C.; Louis, I.; Reliquet, V.; Sauser, F.; Biron, C.; Mounoury, O.; Hue, H.; Brosseau, D.; Ghosn, J.; Rannou, M. T.; Bergmann, J. F.; Badsi, E.; Rami, A.; Girard, P. M.; Samanon-Bollens, D.; Campa, P.; Tourneur, M.; Desplanques, N.; Jeanblanc, F.; Chiarello, P.; Makhloufi, D.; Herriot, E.; Blanc, A. P.; Allègre, T.; Baillat, V.; Lemoing, V.; de Boever, C. Merle; Tramoni, C.; Sobesky, G.; Abel, S.; Beaujolais, V.; Slama, L.; Fournier, I.; Gerbe, J.; Trepo, C.; Koffi, K.; Miailhes, P.; Thoirain, V.; Brochier, C.; Souala, F.; Ratajczak, M.; Beytoux, J.; Jacomet, C.; Montpied, G.; Olivier, C.; Paré, A.; Lortholary, O.; Dupont, B.; Maignan, A.; Raymond, I.; Leport, C.; Jadand, C.; Jestin, C.; Longuet, P.; Boucherit, S.; Sereni, D.; Lascoux, C.; Prevoteau, F.; Sobel, A.; Levy, Y.; Lelièvre, J. D.; Mondor, H.; Aumaître, H.; Delmas, B.; Saada, M.; Medus, M.; Salmon, D.; Tahi, T.; Yazdanpanah, Y.; Pavel, S.; Marien, M. C.; Dron, C. H.; Beck, C.; Benomar, M.; Muller, E.; Tubiana, R.; Mohand, H. Ait; Touam, F.; Folzer, A.; Obadia, M.; Prudhomme, L.; Bonnet, E.; Balzarin, F.; Pichard, E.; Chennebault, J. M.; Fialaire, P.; Loison, J.; Galanaud, P.; Bornarel, D.; Six, M.; Ferret, P.; Batisse, D.; Devidas, A.; Chevojon, P.; Turpault, I.; Philip, G.; Morel, P.; Timsit, J.; Amirat, N.; Cabane, J.; Tredup, J.; Chavanet, C.; Buisson, M.; Treuvetot, S.; Choutet, P.; Bastides, F.; Boyer, L.; Wassoumbou, S.; Oksenhendeler, E.; Gérard, L.; Bernard, L.; Berthé, H.; Poincaré, R.; Domart, Y.; Merrien, D.; Belan, A. Greder; Mignot, A.; Gayraud, M.; Bodard, L.; Meudec, A.; Pape, E.; Vinceneux, P.; Simonpoli, A. M.; Zeng, A.; Mourier, L.; Fournier, L.; Jacquet, M.; Fuzibet, J. G.; Sohn, C.; Rosenthal, E.; Quaranta, M.; Sabah, M.; Audhuy, B.; Schieber, A.; Pasteur, L.; Moreau, P.; Vaillant, O.; Huchon, G.; Compagnucci, A.; de Lacroix Szmania, I.; Lamaury, I.; Saint-Dizier, F.; Garipuy, D.; Drogoul, M. P.; Martin, I. Poizot; Fabre, G.; Lambert, G.; Lagarde, P.; David, F.; Roche-Sicot, J.; Saraux, J. L.; Leprêtre, A.; Veil, S.; Fampin, B.; Uludag, A.; Morin, A. S.; Bletry, O.; Zucman, D.; Regnier, A.; Girard, J. J.; Quinsat, D. T.; Heripret, L.; Grihon, F.; Houlbert, D.; Ruel, M.; Chemlal, K.; Debab, Y.; Nicolle, C.; Perronne, V.; Quesnay, F.; Slama, B.; Duffaut, H.; Perré, P.; Miodovski, C.; Guermonprez, G.; Dulioust, A.; Ballanger, R.; Patey, O.; Semaille, C.; Deville, J.; Beclere, Antoine; Boue, F.; Chambrin, V.; Pignon, C.; Estocq, G. A.; Levy, A.; Bicetre, Le Kremlin; Duracinsky, M.; Bras, P. Le; Ngussan, M. S.; Lambert, T.; Segeral, O.; Lezeau, P.; Laurian, Y.; Piketty, C.; Karmochkine, M.; Eliaszewitch, M.; Jayle, D.; Tisne, D.; Colasante, U.; Vilde, J. L.; Bollens, D.; Binet, D.; Diallo, B.; Lagneau, J. L.; Pietrie, M. P.; Sicard, D.; Stieltjes, N.; Michot, J.; Bourdillon, F.; Obenga, G.; Escaut, L.; Bolliot, C.; Schneider, L.; Iguertsira, M.; Stein, A.; Tomei, C.; Dhiver, C.; Gallais, J.; Gallais, H.; Durant, J.; Mondain, V.; Perbost, I.; Cassuto, J. P.; Karsenti, J. M.; Ceppi, C.; Krivitsky, J. A.; Honore, P.; Delgado, J.; Rouzioux, C.; Burgard, M.; Boufassa, L.; Peynet, J.; Pérez-Hoyos, S.; Schiaffino, A.; Monge, D. Alvarez S.; Pujol, I.; Muga, R.; Sanvisens, A.; Tor, J.; Rivas, I.; Vallecillo, G.; del Romero, J.; Raposo, P.; Rodríguez, C.; Vera, M.; Alastrue, E. Fernandez I.; Tasa, C. Santos T.; Juan, A.; Trullen, J.; de Olalla, P. Garcia; Cayla, J.; Sambeat, M. A.; Guerrero, R.; Rivera, E.; Marco, A.; Quintana, M.; Gonzalez, C.; Castilla, J.; Guevara, M.; de Mendoza, C.; Zahonero, N.; Ortíz, M.; G, Daikos; T, Kordossis; G, Panos; H, Sambatakou; M, Chini; Nelson, M.; Asboe, D.; Man, S.-L.; Smith, C.; Grabowska, H.; Gras, L. A. J.; Branger, J.; Scherpbier, H. J.; van der Meer, J. T. M.; Wit, F. W. M. N.; van der Poll, T.; Nellen, F. J. B.; Lange, J. M. A.; Geerlings, S. E.; van Vugt, M.; Frissen, P. H. J.; Schouten, W. E. M.; van den Berk, G. E. L.; Vrouenraets, S. M. E.; van Eeden, A.; Verhagen, D. W. M.; Claessen, F. A. P.; Peters, E. J. G.; van Nieuwkoop, C.; Leyten, E. M. S.; Gelinck, L. B. S.; Ziekenhuis, Catharina; Pronk, M. J. H.; Delsing, C. E.; Scholvinck, E. H.; Bierman, W. F. W.; ten Kate, R. W.; de Boer, M. G. J.; ter Vollaard, H. J. M.; Zuiderzee, M. C.; Schreij, G.; Keuter, M.; van der Ven, A. J. A. M.; ter Hofstede, H. J. M.; Dofferhoff, A. S. M.; van der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; Schurink, C. A. M.; Rijnders, B. J. A.; van Gorp, E. C. M.; Smeulders, A. W. M.; den Hollander, J. G.; Hoepelman, A. I. M.; Schneider, M. M. E.; Jaspers, C. A. J. J.; Arends, J. E.; Wassenberg, M. W. M.; Geelen, S. P. M.; Wolfs, T. F. W.; Cotte, L.; Tattevin, P.; Selinger-Leneman, H.; Diemer, M.; Sellier, P.; Crickx, B.; Lesprit, Ph; Rey, D.; Lucht, F.; Chavanet, P.; Eglinger, P.; Aleksandrowicz, K.; Pelissier, L.; Aubert, V.; Barth, J.; Battegay, M.; Bernasconi, E.; Böni, J.; Burton-Jeangros, C.; Calmy, A.; Cavassini, M.; Egger, M.; Elzi, L.; Fehr, J.; Fellay, J.; Furrer, H.; Gorgievski, M.; Günthard, H.; Hasse, B.; Hösli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Klimkait, T.; Kovari, H.; Ledergerber, B.; Martinetti, G.; Metzner, K.; Müller, N.; Nadal, D.; Pantaleo, G.; Rauch, A.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schmid, P.; Schultze, D.; Schöni-Affolter, F.; Schüpbach, J.; Speck, R.; Taffé, P.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Yerly, S.; Force, L.; Mallolas, J.; López-Dieguez, M.; Romeu, J.; Jou, A.; Masó, M.; Bejarano, G.; del Amo, J.; Muñoz, M. A.; Arrizabalaga, A. J.; Aramburu, M. J.; Escolano, C.; Sanjuan, M.; Peraire, J.; Aldeguer, J. L.; Blanes, M.; de los Santos, I.; Hernández, B.; Pumares, M.; Trastoy, M.; Fiellin, D. A.; Titanji, R.; Butt, A.; Brandt, C.; Bryant, K.; Gandhi, N.; Gaziano, M.; Miller, P.; Mole, L.; Darbyshire, J.; Cursley, Adam; Eduards, S.; Estreich, S.; Magdy, A.; Jebakumar, S. P. R.; McMillan, S.; Green, S.; Sivakumar, K.; Monteiro, E.; Jendrulek, I.; Deheragada, A.; Rajamanoharan, S.; Parrinello, M.; Chakvetadze, C.; Berrebi, V.; Augustin-Normand, C.; Morelon, S.; Ragnaud, J. M.; Dominguez, S.; Dumont, C.; Drenou, B.; Drobacheff, C.; Gonzales-Canali, A.; Cheret, A.; Brancion, C.; Ravault, I.; Nau, P.; Beuscart, C.; Daniel, C.; Chaillou, S.; Niault, M.; Richier, L.; Abraham, B.; Perino, C.; Tremollieres, F.; Boudon, P.; Malbec, D.; Remy, G.; Béguinot, I.; Peretti, D.; Medintzeff, N.; Kazatchkine, M.; Fonquernie, L.; Lelievre, J. D.; Tissot Dupont, H.; Vallon, A.; Venti, H.; Bouchaud, O.; Hurtado, I.; Belda, J.; Gargalianos-Kakolyris, P.; Katsarou, O.; Lazanas, M.; Paparizos, V.; Paraskevis, D.; Skoutelis, A.; Touloumi, G.; Pantazis, N.; Bakoyannis, G.; Gioukari, V.; Antoniadou, A.; Papadopoulos, A.; Petrikkos, G.; Daikos, G.; Psichogiou, M.; Xylomenos, G.; Kouramba, A.; Ioannidou, P.; Kordossis, T.; Kontos, A.; Tsogas, N.; Leuow, K.; Kourkounti, S.; Sambatakou, H.; Mariolis, I.; Papastamopoulos, V.; Baraboutis, I.

    2015-01-01

    Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation,

  15. Urinary Tract Infections among HIV-Positive Pregnant Women in Mwanza City, Tanzania, Are High and Predicted by Low CD4+ Count

    Science.gov (United States)

    Chaula, Tito; Ng'walida, Nhandi; Kajura, Alphaxaid; Mirambo, Mariam M.; DeVinney, Rebekah

    2017-01-01

    Introduction. Urinary tract infection (UTI) among pregnant women can lead to adverse maternal and foetal outcomes. UTI has been widely studied in the general obstetric population in Tanzania; the present study evaluated the magnitude, antimicrobial resistance, and predictors of UTI among HIV-positive pregnant women. Methods. Between March and May 2016 midstream urine samples from 234 women attending prevention of mother to child transmission of HIV (PMTCT) clinics were analyzed using standard methods. Data was analyzed by STATA version 11.0. Results. The prevalence of UTI was 21.4%, 50/234 [95% CI: 16.1–26.6]. The asymptomatically significant bacteriuria was higher than symptomatically significant bacteriuria (16.6% versus 4.7%, p pregnant women in Mwanza have significant bacteriuria which calls for the need to introduce routine UTI screening at PMTCT clinics to guide specific treatment and prevent associated complications. PMID:28255302

  16. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus.

    Directory of Open Access Journals (Sweden)

    Jie Dong

    Full Text Available After a tightly regulated developmental program in the thymus, "mature" single positive (SP thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4(+ pre-RTEs, a population of CD4(+ SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4(+ pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs' better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+ pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4(+ pre-RTEs is independent of MHC class II and Aire molecules.

  17. CD4 cell levels during treatment for tuberculosis (TB in Ethiopian adults and clinical markers associated with CD4 lymphocytopenia.

    Directory of Open Access Journals (Sweden)

    Sten Skogmar

    Full Text Available BACKGROUND: The clinical correlations and significance of subnormal CD4 levels in HIV-negative patients with TB are unclear. We have determined CD4 cell levels longitudinally during anti-tuberculosis treatment (ATT in patients, with and without HIV co-infection, and their associations with clinical variables. METHOD: Adults diagnosed with TB (maximum duration of ATT for 2 weeks, and with no history of antiretroviral therapy (ART in HIV-positive subjects were included consecutively in eight out-patient clinics in Ethiopia. Healthy individuals were recruited for comparison at one of the study health centers. Data on patient characteristics and physical findings were collected by trained nurses following a structured questionnaire at inclusion and on follow-up visits at 2 and 6 months. In parallel, peripheral blood CD4 cell levels were determined. The evolution of CD4 cell levels during ATT was assessed, and the association between clinical characteristics and low CD4 cell levels at baseline was investigated using regression analysis. RESULTS: In total, 1116 TB patients were included (307 HIV-infected. Among 809 HIV-negative patients, 200 (25% had subnormal CD4 cell counts (<500 cells/mm(3, with <350 cells/mm(3 in 82 (10% individuals. CD4 cell levels increased significantly during the course of ATT in both HIV+ and HIV- TB-patients, but did not reach the levels in healthy subjects (median 896 cells/mm(3. Sputum smear status, signs of wasting (low mid upper arm circumference (MUAC, and bedridden state were significantly associated with low CD4 cell counts. CONCLUSION: A high proportion of Ethiopian TB patients have subnormal CD4 cell counts before starting treatment. Low CD4 cell levels are associated with smear positive disease and signs of wasting. The continuous increase of CD4 cell counts during the course of ATT suggest a reversible impact of active TB on CD4 cell homeostasis, which may be considered in interpretation of CD4 cell counts in HIV

  18. Distinct and overlapping effector functions of expanded human CD4+, CD8α+ and CD4-CD8α- invariant natural killer T cells.

    Directory of Open Access Journals (Sweden)

    Vincent O'Reilly

    Full Text Available CD1d-restricted invariant natural killer T (iNKT cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4(+, CD8α(+ and CD4(-CD8α(- double-negative (DN subsets. CD4(+ iNKT cells expanded more readily than CD8α(+ and DN iNKT cells upon mitogen stimulation. CD8α(+ and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d(+ cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α and Th2 (IL-4, IL-5 and IL-13 cytokines. Relative amounts followed a CD8α>DN>CD4 pattern for Th1 and CD4>DN>CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4(+ and CD8α(+ fractions, respectively. Only CD4(+ iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α(+, DN or CD4(+ iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.

  19. Applying machine learning to predict patient-specific current CD 4 ...

    African Journals Online (AJOL)

    This work shows the application of machine learning to predict current CD4 cell count of an HIV-positive patient using genome sequences, viral load and time. A regression model predicting actual CD4 cell counts and a classification model predicting if a patient's CD4 cell count is less than 200 was built using a support ...

  20. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study

    DEFF Research Database (Denmark)

    Lodwick, Rebecca K; Sabin, Caroline A; Porter, Kholoud

    2010-01-01

    Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries.......Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries....

  1. Enteric parasitic infections in HIV-infected patients with low CD4 counts in Toto, Nigeria

    International Nuclear Information System (INIS)

    Abaver, D.T.; Nwobegahay, J.M.; Goon, D.T.; Khoza, L.B

    2012-01-01

    Objectives: Enteric parasites are a major cause of diarrhoea in HIV/AIDS patients with low CD4 counts. Parasitic infections in HIV-infected individuals can reduce their quality of life and life span, especially those who are severely immunosuppressed with a CD4 T-lymphocyte count 0.05). Conclusions: Low CD4 counts in HIV-infected patients can lead to enteric infections. This information strengthens the importance of monitoring CD4 counts and intestinal parasites. Routine CD4 testing will greatly improve the prognosis of HIV positive patients. (author)

  2. CD4-regulatory cells in COPD patients

    DEFF Research Database (Denmark)

    Smyth, Lucy J C; Starkey, Cerys; Vestbo, Jørgen

    2007-01-01

    BACKGROUND: The numbers of airway CD8 and B lymphocytes are increased in COPD patients, suggesting an autoimmune process. CD4-regulatory T cells control autoimmunity but have not been studied in patients with COPD. OBJECTIVE: To compare T-regulatory cell numbers in the BAL from COPD patients......, smokers with normal lung function, and healthy nonsmokers (HNS). METHODS: BAL and peripheral blood mononuclear cell (PBMC) samples were obtained from 26 COPD patients, 19 smokers, and 8 HNS. Flow cytometry was performed for regulatory phenotypic markers. RESULTS: COPD patients had increased BAL CD8...... numbers compared to smokers and HNS. CD4 numbers were similar between groups. There was increased BAL CD4CD25(bright) expression in smokers (median 28.8%) and COPD patients (median 23.1%) compared to HNS (median 0%). Increased FoxP3 expression was confirmed in BAL CD4CD25(bright) cells. BAL CD4CD25 cells...

  3. [CD4 lymphocytopenia in systemic lupus erythematosus].

    Science.gov (United States)

    Ferreira, Sofia; Vasconcelos, Júlia; Marinho, António; Farinha, Fátima; Almeida, Isabel; Correia, João; Barbosa, Paulo; Mendonça, Teresa; Vasconcelos, Carlos

    2009-01-01

    Systemic Lupus Erythematosus (SLE) is an inflammatory chronic disease characterized by the presence of autoantibodies, immunocomplex production and organ injury. Several alterations of the immune system have been described, namely of CD4 T cells, with particular focus on regulatory subgroup. Quantify peripheral CD4 T cells in a population of patients with SLE and correlate it with lupus activity, affected organs, therapeutics and infections. Retrospective study involving all SLE patients seen in the clinical immunology outpatient clinic of the Hospital Geral Santo António, Porto that has done some peripheral blood flow cytometry study. Twenty-nine patients have been evaluated, 16 were taking glucocorticoids and six immunossupressors. The mean SLEDAI at the study time was nine and the ECLAM was three. Thirty-one percent of the patients had leukopenia, 76% lymphocytopenia and the same number CD4 depletion. Fifty-five percent of the patients had CD4 levels lower than 500/mm3, 31% lower than 200/mm3. All patients with SLEDAI > or = 20 and ECLAM > or = 4 had CD4 counts inferior to 500/mm3 and all patients with inactive disease had CD4 superior to 500/mm3. There have been three opportunistic infections: cryptococcal meningitis, pulmonary aspergilosis, Pneumocystis jirovecii pneumonia, all in patients with CD4 counts lower than 500/mm3. Decreased CD4 T cells counts have been very common in this study population. There is an inverse relation between CD4 cells counts and disease activity. Opportunistic infections occurred in patients with severe CD4 depletion.

  4. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study

    DEFF Research Database (Denmark)

    Lodwick, Rebecca K; Sabin, Caroline A; Porter, Kholoud

    2010-01-01

    Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries....

  5. A general approach for controlling transcription and probing epigenetic mechanisms: application to the CD4 locus.

    Science.gov (United States)

    Wan, Mimi; Kaundal, Ravinder; Huang, Haichang; Zhao, Jiugang; Yang, Xiaojun; Chaiyachati, Barbara H; Li, Sicong; Chi, Tian

    2013-01-15

    Synthetic regulatory proteins such as tetracycline (tet)-controlled transcription factors are potentially useful for repression as well as ectopic activation of endogenous genes and also for probing their regulatory mechanisms, which would offer a versatile genetic tool advantageous over conventional gene targeting methods. In this study, we provide evidence supporting this concept using Cd4 as a model. CD4 is expressed in double-positive and CD4 cells but irreversibly silenced in CD8 cells. The silencing is mediated by heterochromatin established during CD8 lineage development via transient action of the Cd4 silencer; once established, the heterochromatin becomes self-perpetuating independently of the Cd4 silencer. Using a tet-sensitive Cd4 allele harboring a removable Cd4 silencer, we found that a tet-controlled repressor recapitulated the phenotype of Cd4-deficient mice, inhibited Cd4 expression in a reversible and dose-dependent manner, and could surprisingly replace the Cd4 silencer to induce irreversible Cd4 silencing in CD8 cells, thus suggesting the Cd4 silencer is not the (only) determinant of heterochromatin formation. In contrast, a tet-controlled activator reversibly disrupted Cd4 silencing in CD8 cells. The Cd4 silencer impeded this disruption but was not essential for its reversal, which revealed a continuous role of the silencer in mature CD8 cells while exposing a remarkable intrinsic self-regenerative ability of heterochromatin after forced disruption. These data demonstrate an effective approach for gene manipulation and provide insights into the epigenetic Cd4 regulatory mechanisms that are otherwise difficult to obtain.

  6. In vitro separation and expansion of CD4 lymphocytes from HIV-infected individuals without activation of HIV infection

    DEFF Research Database (Denmark)

    Nielsen, S D; Nielsen, Jens Ole; Hansen, J E

    1997-01-01

    In order to offer a gene therapy-based treatment against AIDS, it is likely to be necessary to harvest and culture CD4 cells from HIV-positive patients without activating the HIV infection. We have used a magnetic cell sorting (MACS) system to enrich CD4 cells. Using positive selection, CD4 cells...

  7. A Prospective Longitudinal Study on Implant Prosthetic Rehabilitation in Controlled HIV-Positive Patients with 1-Year Follow-Up: The Role of CD4+ Level, Smoking Habits, and Oral Hygiene.

    Science.gov (United States)

    Gherlone, Enrico F; Capparé, Paolo; Tecco, Simona; Polizzi, Elisabetta; Pantaleo, Giuseppe; Gastaldi, Giorgio; Grusovin, Maria Gabriella

    2016-10-01

    A recent study showed that implant-prosthetic rehabilitation in well-controlled HIV patients gave slightly worse results than in an healthy population, and failures were all linked to infection. The aim of this study was to examine the associations between the success of implant-prosthetic treatment and systemic CD4+ level, smoking habits, and oral hygiene. This mono-centric study included HIV patients with a stable disease and good oral hygiene requiring implant rehabilitation. Each patient received at least one dental implant. Prosthesis were delivered after 90 days in the upper jaw and 60 days in the lower jaw. Primary outcome measures were prosthetic failures, implant failures, peri-implant marginal bone level changes, and biological complications (peri-implantitis, pus, pain, paresthesia). The possible association with CD4 count, smoking habits, and oral hygiene was analyzed. Sixty-eight patients received 194 implants, and 66 patients (190 implants) were followed for 1 year. No significant associations were found between CD4+ count, oral hygiene-associated variables, and any of the outcome measures. If compared with nonsmoking/light smoking patients, patients who smoked >10 cigarettes/day suffered a statistically significant greater number of implant failures (p ≤ .005), presented a comparatively higher number of peri-implantitis (p 10 cigarettes/day) demonstrated an increased risk of early implant failure, peri-implantitis, episodes of pus, and self-reported pain. © 2015 Wiley Periodicals, Inc.

  8. CD4 T cells mediate both positive and negative regulation of the immune response to HIV infection: complex role of T follicular helper cells and Regulatory T cells in pathogenesis

    Directory of Open Access Journals (Sweden)

    Chansavath ePhetsouphanh

    2015-01-01

    Full Text Available HIV-1 infection results in chronic activation of cells in lymphoid tissue, including T cells, B cells and myeloid lineage cells. The resulting characteristic hyperplasia is an amalgam of proliferating host immune cells in the adaptive response, increased concentrations of innate response mediators due to viral and bacterial products, and homeostatic responses to inflammation. While it is generally thought that CD4 T cells are greatly depleted, in fact, two types of CD4 T cells appear to be increased, namely regulatory T cells (Tregs and T follicular helper cells (Tfh. These cells have opposing roles, but may both be important in the pathogenic process. Whether Tregs are failing in their role to limit lymphocyte activation is unclear, but there is no doubt now that Tfh are associated with B cell hyperplasia and increased germinal centre activity. Antiretroviral therapy (ART may reduce the lymphocyte activation, but not completely, and therefore there is a need for interventions that selectively enhance normal CD4 function without exacerbating Tfh, B cell or Treg dysfunction.

  9. CD4 T lymphocyte counts in patients undergoing splenectomy during living donor liver transplantation.

    Science.gov (United States)

    Natsuda, Koji; Eguchi, Susumu; Takatsuki, Mistuhisa; Soyama, Akihiko; Hidaka, Masaaki; Hara, Takanobu; Kugiyama, Tota; Baimakhanov, Zhassulan; Ono, Shinichiro; Kitasato, Amane; Fujita, Fumihiko; Kanetaka, Kengo; Kuroki, Tamotsu

    2016-02-01

    The role of splenectomy in increasing the CD4-positive T lymphocyte counts (hereafter: CD4 counts) and the CD4 to CD8 ratio have not yet been fully investigated, especially in the case of HIV-positive patients undergoing liver transplantation (LT). The change in the total lymphocyte counts of 32 patients who underwent one-stage splenectomy with living donor (LD) LT with (n=13) or without rituximab (RTX, n=19) therapy were examined to validate our cohort of ABO-incompatible LDLT with RTX. Subsequently, perioperative changes in CD4 counts and the CD 4 to CD8 ratio were measured in 13 patients who underwent ABO-incompatible LDLT/RTX with splenectomy. (1) The administration of RTX did not significantly affect the total lymphocyte counts of patients after LDLT/splenectomy in any of the observation periods. (2) The CD4 counts were significantly higher at 2years after LDLT in comparison to the perioperative CD4 counts but not within the 3-month period (p=0.039). The CD4/CD8 ratio gradually decreased after LDLT/splenectomy under RTX treatment. An immediate increase in the CD4 counts therefore cannot be expected after LDLT with splenectomy. The total lymphocyte and CD4 counts were rather stable in the peritransplant period even in ABO incompatible LDLT with RTX. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. 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.

  11. Multidimensional Clusters of CD4+T Cell Dysfunction Are Primarily Associated with the CD4/CD8 Ratio in Chronic HIV Infection

    DEFF Research Database (Denmark)

    Frederiksen, Juliet Wairimu; Buggert, Marcus; Noyan, Kajsa

    2015-01-01

    was compared to a multidimensional clustering tool, FLOw Clustering with K (FLOCK) in two cohorts of 47 untreated HIV-infected individuals and 21 age and sex matched healthy controls. In order to reduce the subjectivity of FLOCK, we developed an "artificial reference", using 2% of all CD4+ gated T cells from...... each of the HIV-infected individuals. Principle component analyses demonstrated that using an artificial reference lead to a better separation of the HIV-infected individuals from the healthy controls as compared to using a single HIV-infected subject as a reference or analyzing data manually. Multiple...... correlation analyses between laboratory parameters and pathological CD4+ clusters revealed that the CD4/CD8 ratio was the preeminent surrogate marker of CD4+ T cells dysfunction using all three methods. Increased frequencies of an early-differentiated CD4+ T cell cluster with high CD38, HLA-DR and PD-1...

  12. A viral long terminal repeat expressed in CD4+CD8+ precursors is downregulated in mature peripheral CD4-CD8+ or CD4+CD8- T cells.

    OpenAIRE

    Paquette, Y; Doyon, L; Laperrière, A; Hanna, Z; Ball, J; Sekaly, R P; Jolicoeur, P

    1992-01-01

    The long terminal repeat from a thymotropic mouse mammary tumor virus variant, DMBA-LV, was used to drive the expression of two reporter genes, murine c-myc and human CD4, in transgenic mice. Expression was observed specifically in thymic immature cells. Expression of c-myc in these cells induced oligoclonal CD4+ CD8+ T-cell thymomas. Expression of human CD4 was restricted to thymic progenitor CD4- CD8- and CD4+ CD8+ T cells and was shut off in mature CD4+ CD8- and CD4- CD8+ T cells, known to...

  13. Chromosomal localisation of the CD4cre transgene in B6·Cg-Tg(Cd4-cre)1Cwi mice.

    Science.gov (United States)

    Westendorf, Kerstin; Durek, Pawel; Ayew, Samia; Mashreghi, Mir-Farzin; Radbruch, Andreas

    2016-09-01

    The B6·Cg-Tg(Cd4-cre)1Cwi line expresses CRE recombinase under the control of the promoter and regulatory elements of the Cd4 gene. Here we show that CRE recombinase expression reduces the number and frequencies of CD4 positive subsets in a dose-dependent manner and localize the integration site of the transgenic construct to position 60335693-60341285 (qD) of chromosome 3. The insert contains at least 15 complete sequential copies of the transgenic construct. Based on this information we describe a novel PCR assay for genetic typing of transgenic mice. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Increased Hepatitis E Virus Seroprevalence Correlates with Lower CD4+ Cell Counts in HIV-Infected Persons in Argentina.

    Directory of Open Access Journals (Sweden)

    José D Debes

    Full Text Available Hepatitis E virus (HEV is a single-stranded RNA virus that can cause hepatitis in an epidemic fashion. HEV usually causes asymptomatic or limited acute infections in immunocompetent individuals, whereas in immunosuppressed individuals such as transplant recipients, HEV can cause chronic infections. The risks and outcomes of HEV co-infection in patients infected with human immunodeficiency virus (HIV are poorly characterized. We used a third generation immunoassay to measure serum IgG antibodies specific for HEV in 204 HIV-infected individuals from Argentina and a control group of 433 HIV-negative individuals. We found 15 of 204 (7.3%, 95%CI 3.74-10.96% individuals in the HIV-positive group to have positive HEV IgG levels suggestive of previous infection, compared to 19 of 433 (4.4%, 95% CI 2.5-6.3% individuals in the HIV-negative control group (p = 0.12. Among HIV-positive individuals, those with HEV seropositivity had lower CD4 counts compared to those that were HEV seronegative (average CD4 count of 234 vs 422 mm3, p = 0.01, indicating that patients with lower CD4 counts were more likely to be HEV IgG positive. Moreover, HEV seropositivity in patients with CD4 counts 200 mm3 (p = 0.012. We found a positive PCR result for HEV in one individual. Our study found that increased seroprevalence of HEV IgG correlated with lower CD4 counts in HIV-infected patients in Argentina.

  15. Cytotoxic human CD4(+) T cells

    NARCIS (Netherlands)

    van de Berg, Pablo J.; van Leeuwen, Ester M.; ten Berge, Ineke J.; van Lier, Rene

    2008-01-01

    The induction of adaptive immune responses critically depends on helper signals provided by CD4(+) T cells. These signals not only license antigen presenting cells (APC) to activate naïve CD8(+) T cells leading to the formation of vast numbers of cytotoxic T lymphocytes but also support the

  16. Functional Heterogeneity in the CD4+ T Cell Response to Murine γ-Herpesvirus 68

    Science.gov (United States)

    Hu, Zhuting; Blackman, Marcia A.; Kaye, Kenneth M.; Usherwood, Edward J.

    2015-01-01

    CD4+ T cells are critical for the control of virus infections, T cell memory and immune surveillance. Here we studied the differentiation and function of murine γ-herpesvirus 68 (MHV-68)-specific CD4+ T cells using gp150-specific TCR transgenic mice. This allowed a more detailed study of the characteristics of the CD4+ T cell response than previously available approaches for this virus. Most gp150-specific CD4+ T cells expressed T-bet and produced IFN-γ, indicating MHV-68 infection triggered differentiation of CD4+ T cells largely into the Th1 subset, whereas some became TFH and Foxp3+ regulatory T cells. These CD4+ T cells were protective against MHV-68 infection, in the absence of CD8+ T cells and B cells, and protection depended on IFN-γ secretion. Marked heterogeneity was observed in the CD4+ T cells, based on Ly6C expression. Ly6C expression positively correlated with IFN-γ, TNF-α and granzyme B production, T-bet and KLRG1 expression, proliferation and CD4+ T cell-mediated cytotoxicity. Ly6C expression inversely correlated with survival, CCR7 expression and secondary expansion potential. Ly6C+ and Ly6C− gp150-specific CD4+ T cells were able to interconvert in a bidirectional manner upon secondary antigen exposure in vivo. These results indicate that Ly6C expression is closely associated with antiviral activity in effector CD4+ T cells, but inversely correlated with memory potential. Interconversion between Ly6C+ and Ly6C− cells may maintain a balance between the two antigen-specific CD4+ T cell populations during MHV-68 infection. These findings have significant implications for Ly6C as a surface marker to distinguish functionally distinct CD4+ T cells during persistent virus infection. PMID:25662997

  17. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL

    DEFF Research Database (Denmark)

    O'Connor, Jemma; Vjecha, Michael J; Phillips, Andrew N

    2017-01-01

    BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high...... μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4...... had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p

  18. Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

    Science.gov (United States)

    Datta, Jashodeep; Berk, Erik; Xu, Shuwen; Fitzpatrick, Elizabeth; Rosemblit, Cinthia; Lowenfeld, Lea; Goodman, Noah; Lewis, David A; Zhang, Paul J; Fisher, Carla; Roses, Robert E; DeMichele, Angela; Czerniecki, Brian J

    2015-05-23

    A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C. Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization. Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p vs. 22.4 SFC/10(6), p non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2

  19. eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients.

    Directory of Open Access Journals (Sweden)

    Meredith E Davis-Gardner

    2017-12-01

    Full Text Available Antibody-dependent cell-mediated cytotoxity (ADCC can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8. Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1 can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2 exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells.

  20. Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity.

    Science.gov (United States)

    Wang, Dongrui; Aguilar, Brenda; Starr, Renate; Alizadeh, Darya; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R; Forman, Stephen J; Brown, Christine E

    2018-05-17

    Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.

  1. eCD4-Ig variants that more potently neutralize HIV-1.

    Science.gov (United States)

    Fetzer, Ina; Gardner, Matthew R; Davis-Gardner, Meredith E; Prasad, Neha R; Alfant, Barnett; Weber, Jesse A; Farzan, Michael

    2018-03-28

    The HIV-1 entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralizes all HIV-1, HIV-2 and SIV isolates that it has been tested against, suggesting that it may be useful in clinical settings where antibody escape is a concern. Here we characterize three new eCD4-Ig variants, each with different architectures and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig, and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications. IMPORTANCE HIV-1 bNAbs have properties different from antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral lifecycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the

  2. CD4+ Primary T Cells Expressing HCV-Core Protein Upregulate Foxp3 and IL-10, Suppressing CD4 and CD8 T Cells

    Science.gov (United States)

    Aguado, Enrique; Garcia-Cozar, Francisco

    2014-01-01

    Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein. PMID:24465502

  3. CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells.

    Directory of Open Access Journals (Sweden)

    Cecilia Fernandez-Ponce

    Full Text Available Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127(lowPD-1(highTIM-3(high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.

  4. HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+ Gag-Specific CD4+ T Cells in Chronic Clade C HIV-1 Infection.

    Science.gov (United States)

    Laher, Faatima; Ranasinghe, Srinika; Porichis, Filippos; Mewalal, Nikoshia; Pretorius, Karyn; Ismail, Nasreen; Buus, Søren; Stryhn, Anette; Carrington, Mary; Walker, Bruce D; Ndung'u, Thumbi; Ndhlovu, Zaza M

    2017-04-01

    Immune control of viral infections is heavily dependent on helper CD4 + T cell function. However, the understanding of the contribution of HIV-specific CD4 + T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4 + T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4 + T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4 + T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4 + T cells in HIV controllers than progressors ( P = 0.0001), and these expanded Gag-specific CD4 + T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control ( r = -0.5, P = 0.02). These data identify an association between HIV-specific CD4 + T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4 + T cell responses in natural infections. IMPORTANCE Increasing evidence suggests that virus-specific CD4 + T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4 + T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV

  5. The Influence of the Coexpression of CD4 and CD8 in Cutaneous Lesions on Prognosis of Mycosis Fungoides: A Preliminary Study

    Directory of Open Access Journals (Sweden)

    Sergio Umberto De Marchi

    2014-01-01

    Full Text Available Background. Although techniques of immunophenotyping have been successful in characterizing the cells in the cutaneous infiltrates of mycosis fungoides little evidence suggests that variations in the phenotypic characterization correlate with prognosis. Objectives. In a preliminary prospective, single-centre, study we correlated the T-cell phenotype in cutaneous biopsies with the progression of the disease to determine whether the coexpression of CD4 and CD8 has an impact on prognosis. Methods. Skin biopsy specimens from 30 newly diagnosed patients were stained with immunoperoxidase techniques to determine their phenotypic characteristics. After a median followup of 42 months patients were divided into two groups with stable and progressive disease. Results. Eighteen patients had the conventional CD4+CD8− T-cell phenotype. Ten patients showed the coexpression of CD4 and CD8 and had a slightly lower rate of progressive disease. Conclusions. The coexpression of CD4 and CD8 in cutaneous lesions is not rare and is associated with a slightly lower rate of progressive disease. Since double positive CD4/CD8 phenotype is rarely reported in mycosis fungoides the presence on conventional immunophenotyping of both CD may be due to a “mixture” of neoplastic cells and inflammatory CD8+ tumor infiltrating lymphocytes. Immunohistochemical study combined with confocal microscopy could clarify this issue.

  6. Baseline CD4 lymphocyte count among HIV patients in Kano ...

    African Journals Online (AJOL)

    kemrilib

    macrophages), the devastating effect of HIV on the immune system is not surprising. Given that HIV induced immunodeficiency is largely due to infection and gradual depletion of. CD4+ T-helper cells, CD4 count has become a useful indicator of immune function in infected patients. Hence CD4 count along with viral load ...

  7. Self triggered single pulse beam position monitor

    International Nuclear Information System (INIS)

    Rothman, J.L.; Blum, E.B.

    1993-01-01

    A self triggered beam position monitor (BPM) has been developed for the NSLS injection system to provide single pulse orbit measurements in the booster synchrotron, linac, and transport lines. The BPM integrates the negative going portion of 3 nS wide bipolar pickup electrode signals. The gated, self triggering feature confines critical timing components to the front end, relaxing external timing specifications. The system features a low noise high speed FET sampler, a fiber optic gate for bunch and turn selection, and an inexpensive interface to a standard PC data acquisition system

  8. In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes.

    Science.gov (United States)

    Matta, Poojitha; Sherrod, Stacy D; Marasco, Christina C; Moore, Daniel J; McLean, John A; Weitkamp, Joern-Hendrik

    2017-11-01

    Histological chorioamnionitis (HCA) is an intrauterine inflammatory condition that increases the risk for preterm birth, death, and disability because of persistent systemic and localized inflammation. The immunological mechanisms sustaining this response in the preterm newborn remain unclear. We sought to determine the consequences of HCA exposure on the fetal CD4 + T lymphocyte exometabolome. We cultured naive CD4 + T lymphocytes from HCA-positive and -negative preterm infants matched for gestational age, sex, race, prenatal steroid exposure, and delivery mode. We collected conditioned media samples before and after a 6-h in vitro activation of naive CD4 + T lymphocytes with soluble staphylococcal enterotoxin B and anti-CD28. We analyzed samples by ultraperformance liquid chromatography ion mobility-mass spectrometry. We determined the impact of HCA on the CD4 + T lymphocyte exometabolome and identified potential biomarker metabolites by multivariate statistical analyses. We discovered that: 1) CD4 + T lymphocytes exposed to HCA exhibit divergent exometabolomic profiles in both naive and activated states; 2) ∼30% of detected metabolites differentially expressed in response to activation were unique to HCA-positive CD4 + T lymphocytes; 3) metabolic pathways associated with glutathione detoxification and tryptophan degradation were altered in HCA-positive CD4 + T lymphocytes; and 4) flow cytometry and cytokine analyses suggested a bias toward a T H 1-biased immune response in HCA-positive samples. HCA exposure primes the neonatal adaptive immune processes by inducing changes to the exometabolomic profile of fetal CD4 + T lymphocytes. These exometabolomic changes may link HCA exposure to T H 1 polarization of the neonatal adaptive immune response. Copyright © 2017 by The American Association of Immunologists, Inc.

  9. LAG-3 Represents a Marker of CD4+ T Cells with Regulatory Activity in Patients with Bone Fracture.

    Science.gov (United States)

    Wang, Jun; Ti, Yunfan; Wang, Yicun; Guo, Guodong; Jiang, Hui; Chang, Menghan; Qian, Hongbo; Zhao, Jianning; Sun, Guojing

    2018-04-19

    The lymphocyte activation gene 3 (LAG-3) is a CD4 homolog with binding affinity to MHC class II molecules. It is thought that LAG-3 exerts a bimodal function, such that co-ligation of LAG-3 and CD3 could deliver an inhibitory signal in conventional T cells, whereas, on regulatory T cells, LAG-3 expression could promote their inhibitory function. In this study, we investigated the role of LAG-3 expression on CD4 + T cells in patients with long bone fracture. We found that LAG-3 + cells represented approximately 13% of peripheral blood CD4 + T cells on average. Compared to LAG-3 - CD4 + T cells, LAG-3 + CD4 + T cells presented significantly higher Foxp3 and CTLA-4 expression. Directly ex vivo or with TCR stimulation, LAG-3 + CD4 + T cells expressed significantly higher levels of IL-10 and TGF-β than LAG-3 - CD4 + T cells. Interestingly, blocking the LAG-3-MHC class II interaction actually increased the IL-10 expression by LAG-3 + CD4 + T cells. The frequency of LAG-3 + CD4 + T cell was positively correlated with restoration of healthy bone function in long bone fracture patients. These results together suggested that LAG-3 is a marker of CD4 + T cells with regulatory function; at the same time, LAG-3 might have limited the full suppressive potential of Treg cells.

  10. Varicella Zoster Virus Necrotizing Retinitis in Two Patients with Idiopathic CD4 Lymphocytopenia.

    Science.gov (United States)

    Gupta, Meenakashi; Jardeleza, Maria Stephanie R; Kim, Ivana; Durand, Marlene L; Kim, Leo; Lobo, Ann-Marie

    2016-10-01

    Progressive outer retinal necrosis (PORN) associated with varicella zoster virus (VZV) is usually diagnosed in HIV positive or immunosuppressed patients. We report two cases of immunocompetent patients with necrotizing viral retinitis found to have idiopathic CD4 lymphocytopenia. Clinical presentation, examination, imaging, and laboratory testing of two patients with VZV retinitis are presented. An HIV negative patient with history of herpes zoster presented with rapid loss of vision and examination consistent with PORN. PCR testing confirmed VZV. Lymphocytopenia was noted with a CD4 count of 25/mm(3). A second HIV negative patient presented with blurred vision and lid swelling and was found to have peripheral VZV retinitis confirmed by PCR. Laboratory workup revealed lymphocytopenia with a CD4 count of 133/mm(3). VZV necrotizing retinitis classic for PORN can occur in HIV negative patients. Idiopathic CD4 lymphocytopenia should be considered healthy patients who develop ocular infections seen in the immunocompromised.

  11. CD4+, CD8+, CD3+ cell counts and CD4+/CD8+ ratio among patients with mycobacterial diseases (leprosy, tuberculosis), HIV infections, and normal healthy adults: a comparative analysis of studies in different regions of India.

    Science.gov (United States)

    Hussain, Tahziba; Kulshreshtha, K K; Yadav, V S; Katoch, Kiran

    2015-01-01

    In this study, we estimated the CD4+, CD8+, CD3+ cell counts and the CD4/CD8 ratio among normal healthy controls (adults and children), leprosy patients (without any complications and during reactional states), TB patients (with and without HIV), and HIV-positive patients (early infection and full-blown AIDS) and correlated the changes with disease progression. In our study, it was observed that among adults, CD4+ cell counts ranged from 518-1098, CD8+ from 312-952, whereas CD4/CD8 ratio from 0.75-2.30. Among children, both CD4+ and CD8+ cells were more and the CD4/CD8 ratio varied from 0.91-3.17. With regard to leprosy patients, we observed that CD4+ and CD8+ cell counts were lower among PB (pauci-bacillary) and MB (multi-bacillary) patients. CD4/CD8 ratio was 0.99 ± 0.28 among PB patients while the ratio was lower, 0.78 ± 0.20, among MB patients. CD4+ cell counts were raised during RR (reversal reactions) and ENL (erythema nodosum leprosum) among the PB and MB patients whereas the CD8+ cell counts were lower among PB and MB patients. CD4/CD8 ratio doubled during reactional episodes of RR and ENL. Among the HIV-negative tuberculosis (TB) patients, both the CD4+ and CD8+ cell counts were found to be less and the CD4/CD8 ratio varied between 0.53-1.75. Among the HIV-positive TB patients and HIV-positive patients, both the CD4+ and CD8+ cells were very less and ratio drops significantly. In the initial stages of infection, as CD4+ counts drop, an increase in the CD8+ cell counts was observed and the ratio declines. In full-blown cases, CD4+ cell counts were very low, 3-4 to 54 cells, CD8+ cells from 12-211 and the ratio drops too low. This study is the first of its kind in this region of the country and assumes importance since no other study has reported the values of CD4+ and CD8+ T-lymphocyte counts among patients with mycobacterial diseases (leprosy and TB), HIV infections along with normal healthy individuals of the region, and correlation with clinical

  12. CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity

    International Nuclear Information System (INIS)

    Sterjovski, Jasminka; Churchill, Melissa J.; Roche, Michael; Ellett, Anne; Farrugia, William; Wesselingh, Steven L.; Cunningham, Anthony L.; Ramsland, Paul A.; Gorry, Paul R.

    2011-01-01

    CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n = 16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.

  13. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Kara G Lassen

    2006-07-01

    Full Text Available HIV-1 latency in resting CD4+ T cells represents a major barrier to virus eradication in patients on highly active antiretroviral therapy (HAART. We describe here a novel post-transcriptional block in HIV-1 gene expression in resting CD4+ T cells from patients on HAART. This block involves the aberrant localization of multiply spliced (MS HIV-1 RNAs encoding the critical positive regulators Tat and Rev. Although these RNAs had no previously described export defect, we show that they exhibit strict nuclear localization in resting CD4+ T cells from patients on HAART. Overexpression of the transcriptional activator Tat from non-HIV vectors allowed virus production in these cells. Thus, the nuclear retention of MS HIV-1 RNA interrupts a positive feedback loop and contributes to the non-productive nature of infection of resting CD4+ T cells. To define the mechanism of nuclear retention, proteomic analysis was used to identify proteins that bind MS HIV-1 RNA. Polypyrimidine tract binding protein (PTB was identified as an HIV-1 RNA-binding protein differentially expressed in resting and activated CD4+ T cells. Overexpression of PTB in resting CD4+ T cells from patients on HAART allowed cytoplasmic accumulation of HIV-1 RNAs. PTB overexpression also induced virus production by resting CD4+ T cells. Virus culture experiments showed that overexpression of PTB in resting CD4+ T cells from patients on HAART allowed release of replication-competent virus, while preserving a resting cellular phenotype. Whether through effects on RNA export or another mechanism, the ability of PTB to reverse latency without inducing cellular activation is a result with therapeutic implications.

  14. Different thresholds of T cell activation regulate FIV infection of CD4+CD25+ and CD4+CD25- cells

    International Nuclear Information System (INIS)

    Joshi, Anjali; Garg, Himanshu; Tompkins, Mary B.; Tompkins, Wayne A.

    2005-01-01

    Cellular activation plays an important role in retroviral replication. Previously, we have shown that CD4 + CD25 + T cells by the virtue of their partially activated phenotype represent ideal candidates for a productive feline immunodeficiency virus (FIV) infection. In the present study, we extended our previous observations with regard to FIV replication in CD4 + CD25 + and CD4 + CD25 - cells under different stimulation conditions. Both CD4 + CD25 + and CD4 + CD25 - cells remain latently infected in the absence of IL-2 or concanvalinA (ConA), respectively; harboring a replication competent provirus capable of reactivation several days post-infection. While CD4 + CD25 + cells require low levels of exogenous IL-2 and virus inputs for an efficient FIV replication, CD4 + CD25 - T cells can only be productively infected in the presence of either high concentrations of IL-2 or high virus titers, even in the absence of mitogenic stimulation. Interestingly, while high virus input activates CD4 + CD25 - cells to replicate FIV, it induces apoptosis in a high percentage of CD4 + CD25 + T cells. High IL-2 concentrations but not high virus inputs lead to surface upregulation of CD25 and significant cellular proliferation in CD4 + CD25 - cells. These results suggest that CD4 + CD25 + and CD4 + CD25 - T cells have different activation requirements which can be modulated by both viral and cytokine stimuli to reach threshold activation levels in order to harbor a productive FIV infection. This holds implications in vivo for CD4 + CD25 + and CD4 + CD25 - cells to serve as potential reservoirs of a productive and latent FIV infection

  15. Multiple dendritic cell populations activate CD4+ T cells after viral stimulation.

    Directory of Open Access Journals (Sweden)

    Adele M Mount

    2008-02-01

    Full Text Available Dendritic cells (DC are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8alpha DC play a prominent, and sometimes exclusive, role in driving amplification of CD8(+ T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4(+ T cell activation is unknown. We used a direct ex vivo antigen presentation assay to probe the capacity of flow cytometrically purified DC populations to drive amplification of CD4(+ and CD8(+ T cells following infection with influenza virus by different routes. This study examined the contributions of non-CD8alpha DC populations in the amplification of CD8(+ and CD4(+ T cells in cutaneous and systemic influenza viral infections. We confirmed that in vivo, effective immune responses for CD8(+ T cells are dominated by presentation of antigen by CD8alpha DC but can involve non-CD8alpha DC. In contrast, CD4(+ T cell responses relied more heavily on the contributions of dermal DC migrating from peripheral lymphoid tissues following cutaneous infection, and CD4 DC in the spleen after systemic infection. CD4(+ T cell priming by DC subsets that is dependent upon the route of administration raises the possibility that vaccination approaches could be tailored to prime helper T cell immunity.

  16. Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells.

    Science.gov (United States)

    Lee, Guinevere Q; Orlova-Fink, Nina; Einkauf, Kevin; Chowdhury, Fatema Z; Sun, Xiaoming; Harrington, Sean; Kuo, Hsiao-Hsuan; Hua, Stephane; Chen, Hsiao-Rong; Ouyang, Zhengyu; Reddy, Kavidha; Dong, Krista; Ndung'u, Thumbi; Walker, Bruce D; Rosenberg, Eric S; Yu, Xu G; Lichterfeld, Mathias

    2017-06-30

    HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells.

  17. Nanostructure and force spectroscopy analysis of human peripheral blood CD4+ T cells using atomic force microscopy

    International Nuclear Information System (INIS)

    Hu Mingqian; Wang Jiongkun; Cai Jiye; Wu Yangzhe; Wang Xiaoping

    2008-01-01

    To date, nanoscale imaging of the morphological changes and adhesion force of CD4 + T cells during in vitro activation remains largely unreported. In this study, we used atomic force microscopy (AFM) to study the morphological changes and specific binding forces in resting and activated human peripheral blood CD4 + T cells. The AFM images revealed that the volume of activated CD4 + T cells increased and the ultrastructure of these cells also became complex. Using a functionalized AFM tip, the strength of the specific binding force of the CD4 antigen-antibody interaction was found to be approximately three times that of the unspecific force. The adhesion forces were not randomly distributed over the surface of a single activated CD4 + T cell, indicated that the CD4 molecules concentrated into nanodomains. The magnitude of the adhesion force of the CD4 antigen-antibody interaction did not change markedly with the activation time. Multiple bonds involved in the CD4 antigen-antibody interaction were measured at different activation times. These results suggest that the adhesion force involved in the CD4 antigen-antibody interaction is highly selective and of high affinity

  18. Nanostructure and force spectroscopy analysis of human peripheral blood CD4+ T cells using atomic force microscopy.

    Science.gov (United States)

    Hu, Mingqian; Wang, Jiongkun; Cai, Jiye; Wu, Yangzhe; Wang, Xiaoping

    2008-09-12

    To date, nanoscale imaging of the morphological changes and adhesion force of CD4(+) T cells during in vitro activation remains largely unreported. In this study, we used atomic force microscopy (AFM) to study the morphological changes and specific binding forces in resting and activated human peripheral blood CD4(+) T cells. The AFM images revealed that the volume of activated CD4(+) T cells increased and the ultrastructure of these cells also became complex. Using a functionalized AFM tip, the strength of the specific binding force of the CD4 antigen-antibody interaction was found to be approximately three times that of the unspecific force. The adhesion forces were not randomly distributed over the surface of a single activated CD4(+) T cell, indicated that the CD4 molecules concentrated into nanodomains. The magnitude of the adhesion force of the CD4 antigen-antibody interaction did not change markedly with the activation time. Multiple bonds involved in the CD4 antigen-antibody interaction were measured at different activation times. These results suggest that the adhesion force involved in the CD4 antigen-antibody interaction is highly selective and of high affinity.

  19. CD4~+Foxp3~+ regulatory T cells converted by rapamycin from peripheral CD4~+ CD25~-naive T cells display more potent regulatory ability in vitro

    Institute of Scientific and Technical Information of China (English)

    CHEN Jian-fei; GAO Jie; ZHANG Dong; WANG Zi-han; ZHU Ji-ye

    2010-01-01

    Background Rapamycin (RAPA) is a relatively new immunosuppressant drug that functions as a serine/threonine kinase inhibitor to prevent rejection in organ transplantation. RAPA blocks activation of T-effector (Teff) cells by inhibiting the response to interleukin-2. Recently, RAPA was also shown to selectively expand the T-regulator (Treg) cell population. To date, no studies have examined the mechanism by which RAPA converts Teff cells to Treg cells. Methods Peripheral CD4~+CD25~- naive T cells were cultivated with RAPA and B cells as antigen-presenting cells (APCs) in vitro. CD4~+CD25~- T cells were harvested after 6 days and analyzed for expression of forkhead box protein 3 (Foxp3) using flow cytometry. CD4~+CD25~+CD127~- subsets as the converted Tregs were isolated from the mixed lymphocyte reactions (MLR) with CD127 negative selection, followed by CD4 and CD25 positive selection using microbeads and magnetic separation column (MSC). Moreover, mRNA was extracted from converted Tregs and C57BL/6 naive CD4~+CD25~+ T cells and Foxp3 levels were examined by quantitative real-time polymerase chain reaction (rt-PCR). A total of 1×10~5 carboxyfluorescein succinimidyl ester (CFSE)-labeled naive CD4~+CD25~- T cells/well from C57BL/6 mice were cocultured with DBA/2 or C3H maturation of dendritic cells (mDCs) (0.25×10~5/well) in 96-well round-bottom plates for 6 days. Then 1×10~5 or 0.25×10~5 converted Treg cells were added to every well as regulatory cells. Cells were harvested after 6 days of culture and analyzed for proliferation of CFSE-labeled naive CD4~+CD25~- T cells using flow cytometry. Data were analyzed using CellQuest software.Results We found that RAPA can convert peripheral CD4~+CD25~- naive T Cells to CD4~+Foxp3~+ Treg cells using B cells as APCs, and this subtype of Treg can potently suppress Teff proliferation and maintain antigenic specificity. Conclusion Our findings provide evidence that RAPA induces Treg cell conversion from Teff cells and

  20. Food insecurity, CD4 counts, and incomplete viral suppression among HIV+ patients from Texas Children's Hospital: A pilot study

    Science.gov (United States)

    Our goal was to determine the relationship between food insecurity and CD4 counts and viral suppression among pediatric HIV-positive patients. Food insecurity was assessed by validated survey. CD4 counts and viral load were abstracted from patients’ charts. We used linear regression for the dependen...

  1. Effects of estrogen on CD4+CD25+ regulatory T cell in peripheral blood during pregnancy

    Institute of Scientific and Technical Information of China (English)

    Yuan-Huan Xiong; Zhen Yuan; Li He

    2013-01-01

    Objective:To investigate the effects of estrogen (E2) level on regulatory T cells (Treg) in peripheral blood during pregnancy. Methods:A total of 30 healthy non-pregnant women were selected as control group, 90 pregnant women of early, middle and late pregnancy and 30 postpartum women at 1 month after parturition were selected as experimental groups including early pregnancy group, middle pregnancy group and late pregnancy group;the proportions of CD4+CD25+Treg and CD4+CD25+CD127-Treg among CD4+T cells were detected by flow cytometry;the serum estrogen content in peripheral blood was detected by electrochemical immune luminescence method. Results: E2 level was coincident with the change of Tregs number during pregnancy. The estrogen content in peripheral blood increased gradually from early pregnancy to late pregnancy, then decreased significantly after parturition, and the level at 1 month after parturition down to the level in non-pregnancy group (P>0.05);the level of E2 in pregnancy groups were significantly higher than those in non-pregnancy group (P0.05);the proportions in middle and late pregnancy groups were significantly higher than those in early pregnancy group (P0.05). There was correlation between Tregs number with estrogen level during pregnancy. The proportion of CD4+CD25+ Treg and CD4+CD25+CD127- Treg were positively correlated with estrogen level. Conclusions:High proportion of CD4+CD25+Treg and CD4+CD25+CD127-Treg is closely related to the high level of E2 during pregnancy. It suggested that high level of estrogen may induce an increase of CD4+CD25+Treg in peripheral blood, and then influence the immune function of pregnant women. The results of this experiment might play an important role of estrogen in immune-modulation during pregnancy.

  2. Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.

    Directory of Open Access Journals (Sweden)

    Michaela Lucas

    2007-07-01

    Full Text Available CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays.Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C.During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.

  3. Haematological changes in HIV infection with correlation to CD4 cell count

    Directory of Open Access Journals (Sweden)

    SS Parinitha

    2012-03-01

    Full Text Available BackgroundHIV infection is associated with a wide range of haematological abnormalities.Methods and ObjectivesThe objectives in this study were to study haematological changes in HIV patients and to correlate them with CD4 cell counts. Two hundred and fifty HIV positive patients referred to the haematology laboratory section for complete haemogram in whom CD4 count was done were included in the study. Haematologic parameters and CD4 counts were studied in each of these patients.Descriptive statistics were applied. Association between two attributes was calculated by chi-square test and p value less than 0.05 was considered statistically significant.ResultsAmong 250 patients, anaemia was seen in 210 (84% cases. The most common type was normocytic normochromic (40.4%. Lymphopenia was seen in 163 (65.2% cases and thrombocytopenia in 45 (18% cases. The majority of cases (70% had CD4 cell counts below 200 cells/mm3. Fifty-four cases (21.6% had CD4 counts between 200 to 499 cells/mm3 and 21 (8.4% cases had CD4 counts more than 500 cells/ mm3.In patients with CD4 counts less than 200 cells/mm3, anaemia was seen in 91.4% cases, leucopenia in 26.8%cases, lymphopenia in 80% cases and thrombocytopenia in 21.7% cases.ConclusionHaematologic manifestations of HIV infection are common and more frequent with progression of disease. The present study revealed a significant increase in the number of cases of anaemia, and lymphopenia, with decreasing CD4 cell counts. Thrombocytopenia is also seen but does not show significant increase with disease progression. The study also highlights the importance of simultaneously treating HIV patients for haematologic manifestations to reduce morbidity.

  4. Interleukin 4-producing CD4+ T cells in the skin of cats with allergic dermatitis.

    Science.gov (United States)

    Roosje, P J; Dean, G A; Willemse, T; Rutten, V P M G; Thepen, T

    2002-03-01

    Lesional skin of cats with allergic dermatitis has a cellular infiltrate and a CD4/CD8 ratio comparable to that in humans with atopic dermatitis. CD4+ helper T cells and in particular cells belonging to the Th2 subset play an important role in disease pathogenesis in humans. We investigated the cytokine pattern of CD4+ T cells in situ, with special emphasis on the putative presence of cells producing interleukin 4 (IL4), in cats with allergic dermatitis. Immunohistochemical procedures were used to determine that CD4+ T cells in lesional and nonlesional skin of cats with allergic dermatitis can produce IL4, as occurs in humans. Lesional and nonlesional skin of cats with allergic dermatitis had significantly more IL4+ T cells (P = 0.001) than did skin of healthy control cats. Double staining indicated that all IL4+ cells were positive for pan-T or CD4 markers. Double labeling for mast cell chymase and IL4 stained primarily different cells. Western blotting demonstrated cross-reactivity between the antibody against human IL4 and a feline recombinant IL4. These results indicate that IL4 is primarily produced by CD4+ T cells and is also present in clinically uninvolved skin, indicating a role in the pathogenesis of allergic dermatitis in cats.

  5. Correlation between total lymphocyte count, hemoglobin, hematocrit and CD4 count in HIV patients in Nigeria.

    Science.gov (United States)

    Emuchay, Charles Iheanyichi; Okeniyi, Shemaiah Olufemi; Okeniyi, Joshua Olusegun

    2014-04-01

    The expensive and technology limited setting of CD4 count testing is a major setback to the initiation of HAART in a resource limited country like Nigeria. Simple and inexpensive tools such as Hemoglobin (Hb) measurement and Total Lymphocyte Count (TLC) are recommended as substitute marker. In order to assess the correlations of these parameters with CD4 count, 100 "apparently healthy" male volunteers tested HIV positive aged ≥ 20 years but ≤ 40 years were recruited and from whom Hb, Hct, TLC and CD4 count were obtained. The correlation coefficients, R, the Nash-Sutcliffe Coefficient of Efficiency (CoE) and the p-values of the ANOVA model of Hb, Hct and TLC with CD4 count were assessed. The assessments show that there is no significant relationship of any of these parameters with CD4 count and the correlation coefficients are very weak. This study shows that Hb, Hct and TLC cannot be substitute for CD4 count as this might lead to certain individuals' deprivation of required treatment.

  6. Korelasi Kadar Feritin dengan Jumlah CD4, CD8, dan Rasio CD4/CD8 pada Penyandang Talasemia Mayor Anak

    Directory of Open Access Journals (Sweden)

    Bonnie Arseno

    2017-11-01

    Hasil. Didapatkan jumlah CD4 absolut, CD4%, CD8 absolut dan rasio CD4/CD8 menurun. Selain itu, terdapat jumlah CD4 absolut, CD8 absolut dan CD8% meningkat. Pada kelompok usia ≤5 tahun, korelasi kadar feritin dengan CD8 absolut, CD8%, dan rasio CD4/CD8 berturut-turut menghasilkan koefisien korelasi 0,691, 0,557, -0,680, dan p<0,05. Sementara pada kelompok lama terapi ≤5 tahun korelasi kadar feritin dengan CD8 absolut, CD8%, dan rasio CD4/CD8 menghasilkan koefisien korelasi 0,709, 0,571, -0,726 dengan p<0,05. Kesimpulan. Tidak terdapat korelasi antara kadar feritin dengan jumlah CD4, CD8, rasio CD4/CD8. Peningkatan kadar feritin akan diikuti dengan peningkatan jumlah CD8 absolut dan CD8%, serta penurunan rasio CD4/CD8 pada penyandang talasemia mayor anak berdasar atas usia dan lama terapi ≤5 tahun.

  7. Establishment of reference CD4+ T cell values for adult Indian population

    Directory of Open Access Journals (Sweden)

    Ray Krishnangshu

    2011-10-01

    Full Text Available Abstract Background CD4+ T lymphocyte counts are the most important indicator of disease progression and success of antiretroviral treatment in HIV infection in resource limited settings. The nationwide reference range of CD4+ T lymphocytes was not available in India. This study was conducted to determine reference values of absolute CD4+ T cell counts and percentages for adult Indian population. Methods A multicentric study was conducted involving eight sites across the country. A total of 1206 (approximately 150 per/centre healthy participants were enrolled in the study. The ratio of male (N = 645 to female (N = 561 of 1.14:1. The healthy status of the participants was assessed by a pre-decided questionnaire. At all centers the CD4+ T cell count, percentages and absolute CD3+ T cell count and percentages were estimated using a single platform strategy and lyse no wash technique. The data was analyzed using the Statistical Package for the Social Scientist (SPSS, version 15 and Prism software version 5. Results The absolute CD4+ T cell counts and percentages in female participants were significantly higher than the values obtained in male participants indicating the true difference in the CD4+ T cell subsets. The reference range for absolute CD4 count for Indian male population was 381-1565 cells/μL and for female population was 447-1846 cells/μL. The reference range for CD4% was 25-49% for male and 27-54% for female population. The reference values for CD3 counts were 776-2785 cells/μL for Indian male population and 826-2997 cells/μL for female population. Conclusion The study used stringent procedures for controlling the technical variation in the CD4 counts across the sites and thus could establish the robust national reference ranges for CD4 counts and percentages. These ranges will be helpful in staging the disease progression and monitoring antiretroviral therapy in HIV infection in India.

  8. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs ...

    African Journals Online (AJOL)

    enhances immunity by sustained HIV- viral suppression, increase in CD4+ cell count and immune restoration. ... Seventy three (70.9%) of patients still had immune depletion with low CD4+ cell counts at one year of receiving HAART. ..... homeostasis and function in advanced HIV disease. Science 1997; 277: 112- 116. 7.

  9. Immunophenotypic enumeration of CD4 T-lymphocyte values in ...

    African Journals Online (AJOL)

    McRoy

    lymphocytes play a central role in regulation of immune response.[2] These ..... influence of sex hormones on lymphocyte subpopulations. ... Friedland GH. Early treatment for HIV-The Time. Has Come. N Engl J Med 1990;322:1000-1002. 7. Gebo KA, Gallant JE, Keruly JC, Moore RD. Absolute CD4 vs. CD4 percentage for ...

  10. Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations.

    Directory of Open Access Journals (Sweden)

    Maria Duenas-Decamp

    2016-11-01

    Full Text Available The conformation of HIV-1 envelope (Env glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines.

  11. Validation of Microcapillary Flow Cytometry for Community-Based CD4+ T Lymphocyte Enumeration in Remote Burkina Faso

    Science.gov (United States)

    Renault, Cybèle A; Traore, Arouna; Machekano, Rhoderick N; Israelski, Dennis M

    2010-01-01

    Background: CD4+ T lymphocyte enumeration plays a critical role in the initiation and monitoring of HIV-infected patients on antiretroviral therapy. There is an urgent need for low-cost CD4+ enumeration technologies, particularly for use in dry, dusty climates characteristic of many small cities in Sub-Saharan Africa. Design: Cross-sectional study. Methods: Blood samples from 98 HIV-infected patients followed in a community HIV clinic in Ouahigouya, Burkina Faso were obtained for routine CD4+ T lymphocyte count monitoring. The blood samples were divided into two aliquots, on which parallel CD4+ measurements were performed using microcapillary (Guava EasyCD4) and dedicated (Becton Dickinson FACSCount) CD4+ enumeration systems. Spearman rank correlation coefficient was calculated, and the sensitivity, specificity and positive predictive value (PPV) for EasyCD4 <200 cells/µL were determined compared to the reference standard FACSCount CD4 <200 cells/µL. Results: Mean CD4 counts for the EasyCD4 and FACSCount were 313.75 cells/µL and 303.47 cells/µL, respectively. The Spearman rank correlation coefficient was 0.92 (p<0.001). Median values using EasyCD4 were higher than those with the FACSCount (p=0.004). For a CD4<350 cells/uL, sensitivity of the EasyCD4 was 93.9% (95%CI 85.2-98.3%), specificity was 90.6% (95% CI 75.0-98.0%), and PPV was 95.4% (95%CI 87.1-99.0%). Conclusion: Use of the EasyCD4 system was feasible and highly accurate in the harsh conditions of this remote city in Sub-Saharan Africa, demonstrating acceptable sensitivity and specificity compared to a standard operating system. Microcapillary flow cytometry offers a cost-effective alternative for community-based, point-of-care CD4+ testing and could play a substantial role in scaling up HIV care in remote, resource-limited settings. PMID:21253463

  12. Single-position Hall effect measurements

    DEFF Research Database (Denmark)

    2014-01-01

    A method for determining a distance (Y) between a first position on and an electrical boundary (34) of a test sample by a multi-point probe comprising four contact elements, comprising: contacting the test sample with the four contact elements (20,22,24,26) at the first position, applying a magne...

  13. [Increased expressions of peripheral PD-1+ lymphocytes and CD4+CD25+FOXP3+ T cells in gastric adenocarcinoma patients].

    Science.gov (United States)

    Li, Hao; Li, Songyan; Hu, Shidong; Zou, Guijun; Hu, Zilong; Wei, Huahua; Wang, Yufeng; Du, Xiaohui

    2017-01-01

    Objective To detect the frequencies of peripheral programmed death-1 + (PD-1 + ) lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in patients with gastric adenocarcinoma. Methods The study enrolled 29 patients with gastric adenocarcinoma and 29 age- and sex-matched healthy controls. Frequencies of PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells were detected using flow cytometry. Results The number of PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in peripheral blood was higher in patients with gastric adenocarcinoma than that in the control group. Moreover, linear correlation analysis indicated a positive correlation between PD-1 expression and frequency of CD4 + CD25 + FOXP3 + regulatory T cells in peripheral blood of the patients. Conclusion Gastric adenocarcinoma patients present with increased PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in the peripheral blood.

  14. Correlation of CD4 counts with microalbuminuria in HIV patients

    Science.gov (United States)

    Bakri, S.; Haerani, R.; Hasyim, K.; Sudirman, K.; Tarukallo, N.

    2018-03-01

    One of the manifestations of kidney disease is Microalbuminuria (MA). CD4 T cells are cells that play a central role in immune protection, wherein HIV infections, they are the primary target of the virus. CD4 cells counts is an indirect reflection of the activity and viral load of HIV. This study aimed to determine the correlation of CD4 counts with MA in HIV patients. A cross-sectional with thedescriptive analytical study was in HIV patients >18 years old without a history of Diabetes Mellitus. The result of thestatistical test is significant if the value of p HIV patients.

  15. Access to CD4 Testing for Rural HIV Patients: Findings from a Cohort Study in Zimbabwe.

    Directory of Open Access Journals (Sweden)

    Florian Vogt

    Full Text Available CD4 cell count measurement remains an important diagnostic tool for HIV care in developing countries. Insufficient laboratory capacity in rural Sub-Saharan Africa is frequently mentioned but data on the impact at an individual patient level are lacking. Urban-rural discrepancies in CD4 testing have not been quantified to date. Such evidence is crucial for public health planning and to justify new yet more expensive diagnostic procedures that could circumvent access constraints in rural areas.To compare CD4 testing among rural and urban HIV patients during the first year of treatment.Records from 2,145 HIV positive adult patients from a Médecins sans Frontières (Doctors without Borders HIV project in Beitbridge, Zimbabwe, during 2011 and 2012 were used for a retrospective cohort analysis. Covariate-adjusted risk ratios were calculated to estimate the effects of area of residence on CD4 testing at treatment initiation, six and 12 months among rural and urban patients.While the proportion of HIV patients returning for medical consultations at six and 12 months decreased at a similar rate in both patient groups, CD4 testing during consultations dropped to 21% and 8% for urban, and 2% and 1% for rural patients at six and 12 months, respectively. Risk ratios for missing CD4 testing were 0.8 (95% CI 0.7-0.9, 9.2 (95% CI 5.5-15.3, and 7.6 (95% 3.7-17.1 comparing rural versus urban patients at treatment initiation, six and 12 months, respectively.CD4 testing was low overall, and particularly poor in rural patients. Difficulties with specimen transportation were probably a major factor underlying this difference and requires new diagnostic approaches. Our findings point to severe health system constraints in providing CD4 testing overall that need to be addressed if effective monitoring of HIV patients is to be achieved, whether by alternative CD4 diagnostics or newly-recommended routine viral load testing.

  16. CD147-mediated chemotaxis of CD4+CD161+ T cells may contribute to local inflammation in rheumatoid arthritis.

    Science.gov (United States)

    Lv, Minghua; Miao, Jinlin; Zhao, Peng; Luo, Xing; Han, Qing; Wu, Zhenbiao; Zhang, Kui; Zhu, Ping

    2018-01-01

    CD161 is used as a surrogate marker for Th17 cells, which are implicated in the pathogenesis of rheumatoid arthritis (RA). In this study, we evaluated the percentage, clinical significance, and CD98 and CD147 expression of CD4 + CD161 + T cells. The potential role of CD147 and CD98 in cyclophilin A-induced chemotaxis of CD4 + CD161 + T cells was analyzed. Thirty-seven RA patients, 15 paired synovial fluid (SF) of RA, and 22 healthy controls were recruited. The cell populations and surface expression of CD98 and CD147 were analyzed by flow cytometry. Spearman's rank correlation coefficient and multiple linear regression were applied to calculate the correlations. Chemotaxis assay was used to investigate CD4 + CD161 + T cell migration. We found that the percentage of CD4 + CD161 + T cells and their expression of CD147 and CD98 in SF were higher than in the peripheral blood of RA patients. Percentage of SF CD4 + CD161 + T cells was positively correlated with 28-Joint Disease Activity Score (DAS28). CD147 monoclonal antibody (HAb18) attenuated the chemotactic ability of CD4 + CD161 + T cells. An increased CD4 + CD161 + T cell percentage and expression of CD147 and CD98 were shown in RA SF. Percentage of SF CD4 + CD161 + T cells can be used as a predictive marker of disease activity in RA. CD147 block significantly decreased the chemotactic index of CD4 + CD161 + cells induced by cyclophilin A (CypA). These results imply that the accumulation of CD4 + CD161 + T cells in SF and their high expression of CD147 may be associated with CypA-mediated chemotaxis and contribute to local inflammation in RA.

  17. Interleukin 1-induced down-regulation of antibody binding to CD4 molecules on human lymphocytes

    DEFF Research Database (Denmark)

    Tvede, N; Christensen, L D; Ødum, Niels

    1988-01-01

    Interleukin 1 (IL-1) is involved in the early activation of T lymphocytes. The CD4 antigen, described as a phenotypic marker of helper T cells, is also important in early T-cell activation by its ability to bind to MHC class II molecules on antigen-presenting cells, and to transmit positive (and...

  18. Dietary Fructo-Oligosaccharides Attenuate Early Activation of CD4+ T Cells Which Produce both Th1 and Th2 Cytokines in the Intestinal Lymphoid Tissues of a Murine Food Allergy Model.

    Science.gov (United States)

    Tsuda, Masato; Arakawa, Haruka; Ishii, Narumi; Ubukata, Chihiro; Michimori, Mana; Noda, Masanari; Takahashi, Kyoko; Kaminogawa, Shuichi; Hosono, Akira

    2017-01-01

    Fructo-oligosaccharides (FOS) are prebiotic agents with immunomodulatory effects involving improvement of the intestinal microbiota and metabolome. In this study, we investigated the cellular mechanisms through which FOS modulate intestinal antigen-specific CD4+ T cell responses in food allergy, using OVA23-3 mice. OVA23-3 mice were fed an experimental diet containing either ovalbumin (OVA) or OVA and FOS for 1 week. Body weight and mucosal mast cell protease 1 in the serum were measured as the indicator of intestinal inflammation. Single-cell suspensions were prepared from intestinal and systemic lymphoid tissues for cellular analysis. Cytokine production was measured by ELISA. Activation markers and intracellular cytokines in CD4+ T cells were analyzed by flow cytometry. Activated CD4+ T cells were purified to examine cytokine production. Dietary intake of FOS provided moderate protection from the intestinal inflammation induced by the OVA-containing diet. FOS significantly reduced food allergy-induced Th2 cytokine responses in intestinal tissues but not in systemic tissues. FOS decreased OVA diet-induced IFN-γ+IL-4+ double-positive CD4+ T cells and early-activated CD45RBhighCD69+CD4+ T cells in the mesenteric lymph nodes. Furthermore, we confirmed that these CD45RBhighCD69+CD4+ T cells are able to produce high levels of IFN-γ and moderate level of IL-4, IL-10, and IL-13. Dietary intake of FOS during the development of food allergy attenuates the induction of intestinal Th2 cytokine responses by regulating early activation of naïve CD4+ T cells, which produce both Th1 and Th2 cytokines. Our results suggest FOS might be a potential food agent for the prevention of food allergy by modulating oral sensitization to food antigens. © 2017 S. Karger AG, Basel.

  19. Reference values of CD4 T-lymphocytes in human ...

    African Journals Online (AJOL)

    exposed uninfected infants in Kano.Nigeria. ... Journal of Medicine in the Tropics ... Studies to evaluate CD4 count in vertically exposed, but human immunodeficiency virus (HIV) negative infants from this region have not been done previously.

  20. CD4 T cell autophagy is integral to memory maintenance.

    Science.gov (United States)

    Murera, Diane; Arbogast, Florent; Arnold, Johan; Bouis, Delphine; Muller, Sylviane; Gros, Frédéric

    2018-04-13

    Studies of mice deficient for autophagy in T cells since thymic development, concluded that autophagy is integral to mature T cell homeostasis. Basal survival and functional impairments in vivo, limited the use of these models to delineate the role of autophagy during the immune response. We generated Atg5 f/f distal Lck (dLck)-cre mice, with deletion of autophagy only at a mature stage. In this model, autophagy deficiency impacts CD8 + T cell survival but has no influence on CD4 + T cell number and short-term activation. Moreover, autophagy in T cells is dispensable during early humoral response but critical for long-term antibody production. Autophagy in CD4 + T cells is required to transfer humoral memory as shown by injection of antigen-experienced cells in naive mice. We also observed a selection of autophagy-competent cells in the CD4 + T cell memory compartment. We performed in vitro differentiation of memory CD4 + T cells, to better characterize autophagy-deficient memory cells. We identified mitochondrial and lipid load defects in differentiated memory CD4 + T cells, together with a compromised survival, without any collapse of energy production. We then propose that memory CD4 + T cells rely on autophagy for their survival to regulate toxic effects of mitochondrial activity and lipid overload.

  1. Percentages of CD4+CD161+ and CD4−CD8−CD161+ T Cells in the Synovial Fluid Are Correlated with Disease Activity in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Jinlin Miao

    2015-01-01

    Full Text Available Objective. CD161 has been identified as a marker of human IL-17-producing T cells that are implicated in the pathogenesis of rheumatoid arthritis (RA. This study aimed to investigate the potential link between the percentage of CD161+ T cells and disease activity in RA patients. Methods. Peripheral blood (PB from 54 RA patients and 21 healthy controls was evaluated. Paired synovial fluid (SF (n = 17 was analyzed. CD161 expression levels on CD4+, CD8+, and CD4−CD8− T cells were assessed by flow cytometry. Results. The percentage of CD4+CD161+ T cells in RA SF was higher than RA PB, and it was positively correlated with DAS28, erythrocyte sedimentation rate (ESR, and C-reactive protein (CRP. CD4−CD8−CD161+ T cell percentage was decreased in RA PB and was further reduced in RA SF, and its level in SF was inversely correlated with DAS28, ESR, and CRP. However, CD8+CD161+ T cell percentage was neither changed in RA PB and SF nor correlated with disease activity indices. Conclusion. An increased CD4+CD161+ T cell percentage and a decreased CD4−CD8−CD161+ T cell percentage are present in RA SF and are associated with disease activity, and the accumulation of CD4+CD161+ T cells in SF may contribute to the local inflammation of RA.

  2. Rapid assay of intrinsic radiosensitivity based on apoptosis in human CD4 and CD8 T-lymphocytes

    International Nuclear Information System (INIS)

    Ozsahin, Mahmut; Ozsahin, Huelya; Yuquan, Shi; Larsson, Boerje; Wuergler, Friedrich E.; Crompton, Nigel E. A.

    1997-01-01

    Purpose: An assay for radiosensitivity has numerous applications in the clinic. Avoidance of acute responses, prediction of normal tissue toxicity, and individualization of patient radiotherapy are included among these. We have developed a rapid assay (about 24 h) able to predict intrinsic radiosensitivity of CD4 and CD8 T-lymphocytes based on radiation-induced apoptosis. Methods and Materials: Fresh blood samples (1-2 ml in heparinized tubes) were irradiated with 0-, 2-, and 8-Gy X rays at a dose rate of approximately 3 Gy/min. Following irradiation, the cells were collected and prepared for flow-cytometric analysis and cell sorting. In conjunction with the CellQuest software available with the FACSVantage cell sorter (Becton-Dickinson), two T-lymphocyte types were analyzed on the basis of their cell-specific antigens (CD4 and CD8), and DNA was stained with DAPI. Following the separation of these cell types, radiation-induced cell death was assessed. Cytotoxicity was characterized by gradual degradation of internucleosomal DNA which results in a sub-G1 peak on the DNA histogram, and by the associated loss of surface antigens causing an intermediate positive peak in the antibody histogram. Using the assay, we investigated the interdonor variation in a cohort of 45 healthy adult blood donors and 5 children [one had immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF), and one had ataxia telangiectasia (AT)]. Intradonor variation was assessed with 10 different experiments from a single donor. Results: CD4 and CD8 T-lymphocyte radiosensitivities were correlated (r 0.63 and 0.65 for 2 and 8 Gy, respectively) in 45 adult donors. Both for CD4 and CD8 cells, 2 and 8 Gy irradiation responses showed a good correlation (r 0.77 for both). Interdonor variation was significantly higher than intradonor variation (p < 0.0005) for all CD4 and CD8 data. We observed a decrease in the antigen fluorescence of dying cells, a phenomenon referred to as antigen

  3. Toll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function.

    Science.gov (United States)

    Karim, Ahmad Faisal; Reba, Scott M; Li, Qing; Boom, W Henry; Rojas, Roxana E

    2017-09-01

    We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on CD4 + T cells and up-regulate T-cell receptor (TCR) triggered Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4 + T-cell differentiation and function, we conducted a gene expression analysis of murine naïve CD4 + T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naïve CD4 + T-cells co-stimulated via TLR2 showed a significant up-regulation of Il9 mRNA compared to cells co-stimulated via CD28. Under TH9 differentiation, we observed up-regulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants in the presence of TLR2 agonist both in polyclonal and Ag85B cognate peptide specific stimulations. Under non-polarizing conditions, TLR2 engagement on CD4 + T-cells had minimal effect on IL-9 secretion and TH9 differentiation, likely due to a prominent effect of TLR2 signaling on IFN-γ secretion and TH1 differentiation. We also report that, TLR2 signaling in CD4 + T cells increased expression of transcription factors BATF and PU.1, known to positively regulate TH9 differentiation. These results reveal a novel role of T-cell expressed TLR2 in enhancing the differentiation and function of TH9 T cells. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer.

    Science.gov (United States)

    Ma, Qin-Yun; Huang, Da-Yu; Zhang, Hui-Jun; Wang, Shaohua; Chen, Xiao-Feng

    2017-11-15

    LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4 + CD25 - T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4 + T cells directly ex vivo and primarily in the CD4 + CD25 - fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4 + CD25 - cells Compared to LAG3-nonexpressing CD4 + CD25 - cells, LAG3-expressing CD4 + CD25 - cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8 + T effector cells. LAG3-expressing CD4 + CD25 - cells also presented impaired proliferation compared with LAG3-nonexpressing CD4 + CD25 - cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8 + T cells co-incubated with LAG3-expressing CD4 + CD25 - cells at equal cell numbers demonstrated significantly lower proliferation than CD8 + T cells incubated alone. Co-culture with CD8 + T cell and LAG3-expressing CD4 + CD25 - T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4 + CD25 - T cells. In addition, we found that LAG3-expressing CD4 + CD25 - T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4 + CD25 - T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4+ Lymphocytes.

    Directory of Open Access Journals (Sweden)

    Markus Fehrholz

    Full Text Available Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP- B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown.The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4+ lymphocytes.Purified human CD4+ T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®. Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry.Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4+ lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were

  6. Magnetic cell sorting purification of differentiated embryonic stem cells stably expressing truncated human CD4 as surface marker.

    Science.gov (United States)

    David, Robert; Groebner, Michael; Franz, Wolfgang-Michael

    2005-04-01

    Embryonic stem (ES) cells offer great potential in regenerative medicine and tissue engineering. Clinical applications are still hampered by the lack of protocols for gentle, high-yield isolation of specific cell types for transplantation expressing no immunogenic markers. We describe labeling of stably transfected ES cells expressing a human CD4 molecule lacking its intracellular domain (DeltaCD4) under control of the phosphoglycerate kinase promoter for magnetic cell sorting (MACS). To track the labeled ES cells, we fused DeltaCD4 to an intracellular enhanced green fluorescent protein domain (DeltaCD4EGFP). We showed functionality of the membrane-bound fluorescent fusion protein and its suitability for MACS leading to purities greater than 97%. Likewise, expression of DeltaCD4 yielded up to 98.5% positive cells independently of their differentiation state. Purities were not limited by the initial percentage of DeltaCD4(+) cells, ranging from 0.6%-16%. The viability of MACS-selected cells was demonstrated by reaggregation and de novo formation of embryoid bodies developing all three germ layers. Thus, expression of DeltaCD4 in differentiated ES cells may enable rapid, high-yield purification of a desired cell type for tissue engineering and transplantation studies.

  7. Visualization of the human CD4+ T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/γcnull (NOG) mice by retrogenic expression of the human TCR gene

    International Nuclear Information System (INIS)

    Takahashi, Takeshi; Katano, Ikumi; Ito, Ryoji; Ito, Mamoru

    2015-01-01

    Highlights: • β-Lactoglobulin (BLG) specific TCR genes were introduced to human HSC by retrovirus. • Human HSC with BLG-specific TCR were transplanted into NOG-HLA-DR4 I-A −/− mice. • BLG-specific TCR induced positive selection of thymocytes. • BLG-specific TCR positive CD4 + T cells mediated immune responses in humanized mice. - Abstract: The development of severe immunodeficient mouse strains containing various human genes, including cytokines or HLA, has enabled the reconstitution of functional human immune systems after transplantation of human hematopoietic stem cells (HSC). Accumulating evidence has suggested that HLA-restricted antigen-specific human T-cell responses can be generated in these humanized mice. To directly monitor immune responses of human CD4 + T cells, we introduced β-lactoglobulin (BLG)-specific T cell receptor (TCR) genes derived from CD4 + T-cell clones of cow-milk allergy patients into HSCs, and subsequently transplanted them into NOG-HLA-DR4 transgenic/I-Aβ deficient mice (NOG-DR4/I-A o ). In the thymus, thymocytes with BLG-specific TCR preferentially differentiated into CD4 + CD8 − single-positive cells. Adoptive transfer of mature CD4 + T cells expressing the TCR into recipient NOG-DR4/I-A o mice demonstrated that human CD4 + T cells proliferated in response to antigenic stimulation and produced IFN-γ in vivo, suggesting that functional T-cell reactions (especially Th1-skewed responses) were induced in humanized mice

  8. Visualization of the human CD4{sup +} T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/γc{sup null} (NOG) mice by retrogenic expression of the human TCR gene

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Takeshi, E-mail: takeshi-takahashi@ciea.or.jp; Katano, Ikumi; Ito, Ryoji; Ito, Mamoru

    2015-01-02

    Highlights: • β-Lactoglobulin (BLG) specific TCR genes were introduced to human HSC by retrovirus. • Human HSC with BLG-specific TCR were transplanted into NOG-HLA-DR4 I-A{sup −/−} mice. • BLG-specific TCR induced positive selection of thymocytes. • BLG-specific TCR positive CD4{sup +} T cells mediated immune responses in humanized mice. - Abstract: The development of severe immunodeficient mouse strains containing various human genes, including cytokines or HLA, has enabled the reconstitution of functional human immune systems after transplantation of human hematopoietic stem cells (HSC). Accumulating evidence has suggested that HLA-restricted antigen-specific human T-cell responses can be generated in these humanized mice. To directly monitor immune responses of human CD4{sup +} T cells, we introduced β-lactoglobulin (BLG)-specific T cell receptor (TCR) genes derived from CD4{sup +} T-cell clones of cow-milk allergy patients into HSCs, and subsequently transplanted them into NOG-HLA-DR4 transgenic/I-Aβ deficient mice (NOG-DR4/I-A{sup o}). In the thymus, thymocytes with BLG-specific TCR preferentially differentiated into CD4{sup +}CD8{sup −} single-positive cells. Adoptive transfer of mature CD4{sup +} T cells expressing the TCR into recipient NOG-DR4/I-A{sup o} mice demonstrated that human CD4{sup +} T cells proliferated in response to antigenic stimulation and produced IFN-γ in vivo, suggesting that functional T-cell reactions (especially Th1-skewed responses) were induced in humanized mice.

  9. Alternative pathway for the development of Vα14+ NKT cells directly from CD4-CD8- thymocytes that bypasses the CD4+CD8+ stage.

    Science.gov (United States)

    Dashtsoodol, Nyambayar; Shigeura, Tomokuni; Aihara, Minako; Ozawa, Ritsuko; Kojo, Satoshi; Harada, Michishige; Endo, Takaho A; Watanabe, Takashi; Ohara, Osamu; Taniguchi, Masaru

    2017-03-01

    Although invariant V α 14 + natural killer T cells (NKT cells) are thought to be generated from CD4 + CD8 + double-positive (DP) thymocytes, the developmental origin of CD4 - CD8 - double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (T H 1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage. These findings provide new insight into understanding of the development of NKT cells and propose a role for timing of expression of the invariant T cell antigen receptor in determining the functional properties of NKT cells.

  10. CD4+ T Cells Mediate Aspergillosis Vaccine Protection.

    Science.gov (United States)

    Diaz-Arevalo, Diana; Kalkum, Markus

    2017-01-01

    Adaptive effector CD4 + T cells play essential roles in the defense against fungal infections, especially against invasive aspergillosis (IA). Such protective CD4 + T cells can be generated through immunization with specialized antifungal vaccines, as has been demonstrated for pulmonary Aspergillus fumigatus infections in mouse experiments. Adaptive transfer of fungal antigen-specific CD4 + T cells conferred protection onto non-immunized naive mice, an experimental approach that could potentially become a future treatment option for immunosuppressed IA patients, focusing on the ultimate goal to improve their otherwise dim chances for survival. Here, we describe the different techniques to analyze CD4 + T cell immune responses after immunization with a recombinant fungal protein. We present three major methods that are used to analyze the role of CD4 + T cells in protection against A. fumigatus challenge. They include (1) transplantation of CD4 + T cells from vaccinated mice into immunosuppressed naive mice, observing increasing protection of the cell recipients, (2) depletion of CD4 + T cells from vaccinated mice, which abolishes vaccine protection, and (3) T cell proliferation studies following stimulation with overlapping synthetic peptides or an intact protein vaccine. The latter can be used to validate immunization status and to identify protective T cell epitopes in vaccine antigens. In the methods detailed here, we used versions of the well-studied Asp f3 protein expressed in a bacterial host, either as the intact full length protein or its N-terminally truncated version, comprised of residues 15-168. However, these methods are generally applicable and can well be adapted to study other protein-based subunit vaccines.

  11. Predominant CD4 T-lymphocyte tropism of human herpesvirus 6-related virus.

    OpenAIRE

    Takahashi, K; Sonoda, S; Higashi, K; Kondo, T; Takahashi, H; Takahashi, M; Yamanishi, K

    1989-01-01

    Human herpesvirus 6 (HHV-6)-related virus was isolated from CD4+ CD8- and CD3+ CD4+ mature T lymphocytes but could not be isolated from CD4- CD8+, CD4- CD8-, and CD3- T cells in the peripheral blood of exanthem subitum patients. HHV-6-related virus predominantly infected CD4+ CD8+, CD4+ CD8-, and CD3+ CD4+ cells with mature phenotypes and rarely infected CD4- CD8+ cells from cord blood mononuclear cells, which suggested predominant CD4 mature T-lymphocyte tropism of HHV-6-related virus.

  12. How Do CD4+ T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules?

    Science.gov (United States)

    Haabeth, Ole Audun Werner; Tveita, Anders Aune; Fauskanger, Marte; Schjesvold, Fredrik; Lorvik, Kristina Berg; Hofgaard, Peter O.; Omholt, Hilde; Munthe, Ludvig A.; Dembic, Zlatko; Corthay, Alexandre; Bogen, Bjarne

    2014-01-01

    CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed. PMID:24782871

  13. How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules?

    Directory of Open Access Journals (Sweden)

    Ole Audun Werner Haabeth

    2014-04-01

    Full Text Available CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor specific antigen by host antigen presenting cells (APCs appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315, where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

  14. Human Immunodeficiency Virus Type-1 Elite Controllers Maintain Low Co-Expression of Inhibitory Receptors on CD4+ T Cells.

    Science.gov (United States)

    Noyan, Kajsa; Nguyen, Son; Betts, Michael R; Sönnerborg, Anders; Buggert, Marcus

    2018-01-01

    Human immunodeficiency virus type-1 (HIV-1) elite controllers (ELCs) represent a unique population that control viral replication in the absence of antiretroviral therapy (cART). It is well established that expression of multiple inhibitory receptors on CD8+ T cells is associated with HIV-1 disease progression. However, whether reduced co-expression of inhibitory receptors on CD4+ T cells is linked to natural viral control and slow HIV-1 disease progression remains undefined. Here, we report on the expression pattern of numerous measurable inhibitory receptors, associated with T cell exhaustion (programmed cell death-1, CTLA-4, and TIGIT), on different CD4+ T cell memory populations in ELCs and HIV-infected subjects with or without long-term cART. We found that the co-expression pattern of inhibitory receptors was significantly reduced in ELCs compared with HIV-1 cART-treated and viremic subjects, and similar to healthy controls. Markers associated with T cell exhaustion varied among different memory CD4+ T cell subsets and highest levels were found mainly on transitional memory T cells. CD4+ T cells co-expressing all inhibitory markers were positively correlated to T cell activation (CD38+ HLA-DR+) as well as the transcription factors Helios and FoxP3. Finally, clinical parameters such as CD4 count, HIV-1 viral load, and the CD4/CD8 ratio all showed significant associations with CD4+ T cell exhaustion. We demonstrate that ELCs are able to maintain lower levels of CD4+ T cell exhaustion despite years of ongoing viral replication compared with successfully cART-treated subjects. Our findings suggest that ELCs harbor a "healthy" state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status.

  15. Total lymphocyte count as a substitute to cd4 count in management of hiv infected individuals in resource limited society

    International Nuclear Information System (INIS)

    Daud, M.Y.; Qazi, R.A.

    2015-01-01

    Pakistan is a resource limited society and gold standard parameters to monitor HIV disease activity are very costly. The objective of the study was to evaluate total lymphocyte count (TLC) as a surrogate to CD4 count to monitor disease activity in HIV/AIDS in resource limited society. Methods: This cross sectional study was carried out at HIV/AIDS treatment centre, Pakistan Institute of Medical Sciences (PIMS), Islamabad. A total of seven hundred and seventy four (774) HIV positive patients were enrolled in this study, and their CD4 count and total lymphocyte count were checked to find any correlation between the two by using Spearman ranked correlation coefficient. Results: The mean CD4 count was (434.30 ± 269.23), with minimum CD4 count of (9.00), and maximum of (1974.00). The mean total lymphocyte count (TLC) was (6764.0052 ± 2364.02) with minimum TLC (1200.00) and maximum TLC was (20200.00). Using the Pearson's correlation (r) there was a significant and positive correlation between TLC and CD4 count. (r2=0.127 and p=0.000) at 0.01 level. Conclusion: Our study showed a significant positive correlation between CD4 count and total lymphocyte count (TLC), so TLC can be used as a marker of disease activity in HIV infected patients. (author)

  16. Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Lawn Stephen D

    2008-07-01

    Full Text Available Abstract Background Viral load monitoring is not available for the vast majority of patients receiving antiretroviral therapy in resource-limited settings. However, the practical utility of CD4 cell count measurements as an alternative monitoring strategy has not been rigorously assessed. Methods In this study, we used a novel modelling approach that accounted for all CD4 cell count and VL values measured during follow-up from the first date that VL suppression was achieved. We determined the associations between CD4 counts (absolute values and changes during ART, VL measurements and risk of virological failure (VL > 1,000 copies/ml following initial VL suppression in 330 patients in South Africa. CD4 count changes were modelled both as the difference from baseline (ΔCD4 count and the difference between consecutive values (CD4 count slope using all 3-monthly CD4 count measurements during follow-up. Results During 7093.2 patient-months of observation 3756 paired CD4 count and VL measurements were made. In patients who developed virological failure (n = 179, VL correlated significantly with absolute CD4 counts (r = - 0.08, P = 0.003, ΔCD4 counts (r = - 0.11, P P P = 0.99, P = 0.92 and P = 0.75, respectively. Moreover, in a receiver operating characteristic (ROC curve, the association between a negative CD4 count slope and virological failure was poor (area under the curve = 0.59; sensitivity = 53.0%; specificity = 63.6%; positive predictive value = 10.9%. Conclusion CD4 count changes correlated significantly with VL at group level but had very limited utility in identifying virological failure in individual patients. CD4 count is an inadequate alternative to VL measurement for early detection of virological failure.

  17. Pengaruh Suplementasi Seng terhadap CD 4+ Pengidap Human Immunodeficiency Virus

    Directory of Open Access Journals (Sweden)

    Mohammad Zen Rahfiludin

    2015-01-01

    Full Text Available ABSTRACT Optimal immune response is needed to viral elimination, but in HIV infection the immune cell is the main target. Zinc has proved to increase immune response to various infection. However, its role in HIV infection has not understood. This study aimed to analyze the effect of zinc supplementation to increase CD4+ in HIV-infected patients. This was an experimental study with pre test post test with control group design. Twenty HIV-infected persons were devided into 2 groups: control group which received Anti Retroviral Therapy (AZT and the Zn+ART group received 5 mg zinc/d orally for one month and AZT. Field workers visited patients for checking compliance. Venous blood was taken from all of the subjects, the CD4+ cell count was measured and daily nutrient intake was analyzed. CD4+ cell count was determined by flowcytometri method. Daily food intake was determined by two 24 hour recall periods during 2 non consecutive days. Differential test between the two groups was performed using independent t-test or Mann Whitney test, when the distribution was not normal. Analysis of CD4+ differences before and after treatment in each group by paired t-test. The mean of CD4+ before zinc supplementation was 371.3 ± 126.8 cell/μL and increase to 415.2 ± 194.1 cell/μL after supplementation. However the increase 43.9 ± 83.5 cell/μL was not significantly different (p= 0.131. There was not a significant change CD4+ (p= 0.112 between both groups, possibly because the dose and duration of zinc supplementation. Moreover, only one type of micronutrient given (zinc, also led to an increase CD4+ in our study did not significantly. Zinc supplementation in complement with AZT therapy was not significantly increase CD4+ in HIV patients. Keywords: zinc supplementation, CD4+, HIV, AZT.   ABSTRAK Respon imun yang optimal diperlukan untuk pemusnahan virus, namun dalam infeksi HIV justru sel sistem imun yang diserang. Seng telah terbukti dapat meningkatkan

  18. Prevalence of Oral Manifestations and Their Association with CD4/CD8 Ratio and HIV Viral Load in South India

    Directory of Open Access Journals (Sweden)

    Sharma Gaurav

    2011-01-01

    Full Text Available The objective of the present research was to determine the prevalence of oral manifestations in an HIV infected population from south India and evaluate their association with HIV viral load and CD4/CD8 ratio. Intraoral examination of 103 patients, whose CD4/CD8 ratio was available, were conducted. HIV viral loads were available for thirty patients only. The prevalence of oral manifestations was 80.6% (83/103. The most common oromucosal lesion was erythematous candidiasis (EC (38.8% followed by melanotic hyperpigmentation (35.9%. Patients having any oral manifestation had a mean CD4/CD8 ratio of 0.24. EC had positive predictive value of 85.0% for CD4/CD8 ratio 20,000 copies/mL (20,000 copies/mL.

  19. HIV-1 induces DCIR expression in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Alexandra A Lambert

    2010-11-01

    Full Text Available The C-type lectin receptor DCIR, which has been shown very recently to act as an attachment factor for HIV-1 in dendritic cells, is expressed predominantly on antigen-presenting cells. However, this concept was recently challenged by the discovery that DCIR can also be detected in CD4(+ T cells found in the synovial tissue from rheumatoid arthritis (RA patients. Given that RA and HIV-1 infections share common features such as a chronic inflammatory condition and polyclonal immune hyperactivation status, we hypothesized that HIV-1 could promote DCIR expression in CD4(+ T cells. We report here that HIV-1 drives DCIR expression in human primary CD4(+ T cells isolated from patients (from both aviremic/treated and viremic/treatment naive persons and cells acutely infected in vitro (seen in both virus-infected and uninfected cells. Soluble factors produced by virus-infected cells are responsible for the noticed DCIR up-regulation on uninfected cells. Infection studies with Vpr- or Nef-deleted viruses revealed that these two viral genes are not contributing to the mechanism of DCIR induction that is seen following acute infection of CD4(+ T cells with HIV-1. Moreover, we report that DCIR is linked to caspase-dependent (induced by a mitochondria-mediated generation of free radicals and -independent intrinsic apoptotic pathways (involving the death effector AIF. Finally, we demonstrate that the higher surface expression of DCIR in CD4(+ T cells is accompanied by an enhancement of virus attachment/entry, replication and transfer. This study shows for the first time that HIV-1 induces DCIR membrane expression in CD4(+ T cells, a process that might promote virus dissemination throughout the infected organism.

  20. Antigen-specific and non-specific CD4+ T cell recruitment and proliferation during influenza infection

    International Nuclear Information System (INIS)

    Chapman, Timothy J.; Castrucci, Maria R.; Padrick, Ryan C.; Bradley, Linda M.; Topham, David J.

    2005-01-01

    To track epitope-specific CD4 + T cells at a single-cell level during influenza infection, the MHC class II-restricted OVA 323-339 epitope was engineered into the neuraminidase stalk of influenza/A/WSN, creating a surrogate viral antigen. The recombinant virus, influenza A/WSN/OVA II , replicated well, was cleared normally, and stimulated both wild-type and DO11.10 or OT-II TCR transgenic OVA-specific CD4 + T cells. OVA-specific CD4 T cells proliferated during infection only when the OVA epitope was present. However, previously primed (but not naive) transgenic CD4 + T cells were recruited to the infected lung both in the presence and absence of the OVA 323-339 epitope. These data show that, when primed, CD4 + T cells may traffic to the lung in the absence of antigen, but do not proliferate. These results also document a useful tool for the study of CD4 T cells in influenza infection

  1. GM-CSF production allows the identification of immunoprevalent antigens recognized by human CD4+ T cells following smallpox vaccination.

    Directory of Open Access Journals (Sweden)

    Valeria Judkowski

    Full Text Available The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a "T cell-driven" methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens.

  2. Immunophenotypic enumeration of CD4 + T-lymphocyte values in ...

    African Journals Online (AJOL)

    Background: The enumeration of CD4+ T-lymphocytes in Human Immunodeficiency Virus (HIV)-infected individuals is an essential tool for staging HIV disease, to make decisions for initiation of anti-retroviral therapy (ART), for monitoring response to ART and to initiate chemoprophylaxis against opportunistic infections.

  3. Circulating CXCR5+CD4+ T cells participate in the IgE accumulation in allergic asthma.

    Science.gov (United States)

    Gong, Fang; Zhu, Hua-Yan; Zhu, Jie; Dong, Qiao-Jing; Huang, Xuan; Jiang, Dong-Jin

    2018-05-01

    The pathogenesis of allergic asthma is primarily characterized by abnormality in immunoglobin(Ig)E pathway, suggesting a possible role for follicular helper T cells (Tfh) in the genesis of excessive IgE accumulation. The blood chemokine (C-X-C motif) receptor 5 (CXCR)5 + CD4 + T cells, known as "circulating" Tfh, share common functional characteristics with Tfh cells from germinal centers. The aim of this study was to determine the phenotypes and functions of circulating CXCR5 + CD4 + T cells in allergic asthmatics. Here we found the frequency of the circulating CXCR5 + CD4 + T cells was raised in allergic asthma compared with healthy control (HC). Phenotypic assays showed that activated circulating CXCR5 + CD4 + T cells display the key features of Tfh cells, including invariably coexpressed programmed cell death (PD)-1 and inducible costimulator (ICOS). The frequency of interleukin IL-4 + -, IL-21 + -producing CXCR5 + CD4 + T cells was increased in allergic asthma patients compared with HC. Furthermore, sorted circulating CXCR5 + CD4 + T cells from allergic asthma patients boosted IgE production in coculture assay which could be inhibited by IL-4 or IL-21 blockage. Interestingly, IL-4 + -, IL-21 + -CXCR5 + CD4 + T cells positively correlated with total IgE in the blood. Our data indicated that circulating CXCR5 + CD4 + T cells may have a significant role in facilitating IgE production in allergic asthma patients. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  4. Enumeration of CD4 and CD8 T-cells in HIV infection in Zimbabwe using a manual immunocytochemical method

    DEFF Research Database (Denmark)

    Gomo, E; Ndhlovu, P; Vennervald, B J

    2001-01-01

    OBJECTIVES: To enumerate CD4 and CD8 T-cells using the simple and cheap immuno-alkaline phosphatase (IA) method and to compare it with flow cytometry (FC); and to study the effects of duration of sample storage on the IA method results. DESIGN: Method comparison study. SETTING: Blair Research...... Laboratory, Harare, Zimbabwe. SUBJECTS: 41 HIV positive and 11 HIV negative men and women from Harare participating in HIV studies at Blair Research Laboratory, Zimbabwe. MAIN OUTCOME MEASURES: CD4 and CD8 T-cell counts by FC and the IA method. RESULTS: The IA method and FC were highly correlated for CD4...... counts (Spearman rs = 0.91), CD4 percentage (rs = 0.84), CD8 count (rs = 0.83), CD8 percentage (rs = 0.96) and CD4/CD8 ratio (rs = 0.89). However, CD4 cell counts and percentage measured by the IA method were (mean difference +/- SE) 133 +/- 24 cells/microL [corrected] and 6.7 +/- 1.1% higher than those...

  5. Maternal CD4+ cell count decline after interruption of antiretroviral prophylaxis for the prevention of mother-to-child transmission of HIV.

    Science.gov (United States)

    Ekouevi, Didier; Abrams, Elaine J; Schlesinger, Malka; Myer, Landon; Phanuphak, Nittaya; Carter, Rosalind J

    2012-01-01

    We evaluated maternal CD4+ cell count (CD4+) decline after PMTCT prophylaxis in a multi-country HIV care program. Analysis was restricted to antiretroviral therapy (ART)-naive, HIV-infected pregnant women with CD4+ ≥250 cells/mm(3) at enrollment. Single-dose nevirapine (sd-NVP) or short-course antiretroviral prophylaxis (sc-ARVp) with zidovudine (AZT) or AZT + lamivudine (3TC) was initiated in 11 programs while 2 programs offered triple-drug antiretroviral prophylaxis (tARVp) (AZT+3TC+ NVP or nelfinavir). All regimens were stopped at delivery. CD4+ decline was defined as proportion of women who declined to CD4+ cells/mm(3) or cells/mm(3) at 24 months. Weibull regression was used for multivariable analysis. A total of 1,393 women with enrollment CD4+ ≥250 cells/mm(3) initiated tARVp (172; 12%) or sc-ARVp (532; 38%) during pregnancy or received intrapartum sd-NVP (689; 50%). At enrollment, maternal median age was 27 years (interquartile range (IQR) 23-30), median CD4+ was 469 cells/mm(3) (IQR: 363-613). At 24 months post-delivery, the cumulative probability of CD4+ decline to cells/mm(3) was 12% (95% CI: 10-14). Among a subgroup of 903 women with CD4+ ≥400 cells at enrollment, the 24 month cumulative probability of decline to CD4+ cells/mm(3) was 28%; (95% CI: 25-32). Lower antepartum CD4+ was associated with higher probability of CD4+ decline to cells/mm(3): 46% (CD4+400-499 cells/mm(3)) vs. 19% (CD4+ ≥500 cells/mm(3)). After adjusting for age, enrollment CD4+ and WHO stage, women who received tARVp or sd-NVP were twice as likely to experience CD4+ decline to cells/mm(3) within 24 months than women receiving sc-ARVp (adjusted hazard ratio: 2.2; 95% CI: 1.5-3.2, pcell count to ART eligibility thresholds by 24 months postpartum was common among women receiving PMTCT prophylaxis during pregnancy and/or delivery.

  6. Mass Cytometric Analysis of HIV Entry, Replication, and Remodeling in Tissue CD4+ T Cells

    Directory of Open Access Journals (Sweden)

    Marielle Cavrois

    2017-07-01

    Full Text Available To characterize susceptibility to HIV infection, we phenotyped infected tonsillar T cells by single-cell mass cytometry and created comprehensive maps to identify which subsets of CD4+ T cells support HIV fusion and productive infection. By comparing HIV-fused and HIV-infected cells through dimensionality reduction, clustering, and statistical approaches to account for viral perturbations, we identified a subset of memory CD4+ T cells that support HIV entry but not viral gene expression. These cells express high levels of CD127, the IL-7 receptor, and are believed to be long-lived lymphocytes. In HIV-infected patients, CD127-expressing cells preferentially localize to extrafollicular lymphoid regions with limited viral replication. Thus, CyTOF-based phenotyping, combined with analytical approaches to distinguish between selective infection and receptor modulation by viruses, can be used as a discovery tool.

  7. Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.

    Directory of Open Access Journals (Sweden)

    David Beauparlant

    2017-03-01

    Full Text Available A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.

  8. Detection and Significance of CD4+CD25+CD127dim Regulatory T Cells in Individuals with Severe Aplastic Anemia

    Directory of Open Access Journals (Sweden)

    Weiwei Qi

    2015-09-01

    Full Text Available Objective: To investigate the relationship between CD4+CD25+CD127dim regulatory T cells (Tregs and immune imbalance in acquired severe aplastic anemia (SAA. Materials and Methods: The quantity of CD4+CD25+CD127dim Tregs in 44 SAA patients and 23 normal controls was measured by flow cytometry. Correlations between Tregs and T cell subsets, dendritic cell (DC subsets, granulocyte counts, and percentage of reticulocytes (RET% were analyzed. Results: The percentage of CD4+CD25+CD127dim Tregs in peripheral blood lymphocytes (PBLs of untreated patients was lower than in recovery patients and normal controls (0.83±0.44% vs. 2.91±1.24% and 2.18±0.55%, respectively, p<0.05. The percentage of CD4+CD25+CD127dim Tregs in CD4+ T lymphocytes of recovery patients was higher than that of untreated patients and normal controls (9.39±3.51% vs. 7.61±5.3% and 6.83±1.4%, respectively, p<0.05. The percentage of CD4+ T lymphocytes in PBLs of untreated patients was lower than in recovery patients and normal controls (13.55±7.37% vs. 31.82±8.43% and 32.12±5.88%, respectively, p<0.05. T cell subset (CD4+/CD8+ ratio was 0.41±0.24 in untreated patients, which was lower than in recovery patients (1.2±0.4 and normal controls (1.11±0.23 (p<0.05. DC subset (myeloid DC/plasmacytoid DC ratio, DC1/DC2 ratio was 3.08±0.72 in untreated patients, which was higher than in recovery patients (1.61±0.49 and normal controls (1.39±0.36 (p<0.05. The percentage of CD4+CD25+CD127dim Tregs in PBLs was positively associated with T cell subset (r=0.955, p<0.01 and negatively associated with DC subset (r=-0.765, p<0.01. There were significant positive correlations between CD4+CD25+CD127dim Tregs/PBL and granulocyte counts and RET% (r=0.739 and r=0.749, respectively, p<0.01. Conclusion: The decrease of CD4+CD25+CD127dim Tregs in SAA patients may cause excessive functioning of T lymphocytes and thus lead to hematopoiesis failure in SAA.

  9. Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa.

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    Alastair Heffernan

    Full Text Available Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3% of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness.

  10. Multifunctional Analysis of CD4+ T-Cell Response as Immune-Based Model for Tuberculosis Detection

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    Miriam Lichtner

    2015-01-01

    Full Text Available Mono- and multifunctional specific CD4+ and CD8+ T-cell responses were evaluated to improve the immune-based detection of active tuberculosis (TB and latent infection (LTBI. We applied flow cytometry to investigate cytokines profile (IFN-γ, TNF-α, and IL-2 of T cells after stimulation with TB antigens in 28 TB-infected subjects (18 active TB and 10 LTBI and 10 uninfected controls. Cytokines production by CD4+ T cells at single-cell levels was higher in TB-infected subjects than uninfected controls P0.45%, it was possible to differentiate TB-infected (>0.45% by uninfected subjects (0.182%. The magnitude of CD8+ T-cell responses showed no differences between active TB and LTBI. Multifunctional CD4+ T-cell responses could have the potential to identify at single time point subjects without TB infection and patients having active or latent TB.

  11. cd4 t-lymphocyte subsets in women with invasive cervical cancer

    African Journals Online (AJOL)

    2013-10-01

    Oct 1, 2013 ... Only nine (20%) of the 45 HIV+ women had CD4 cell count of 0-200. HIV+ women had lower CD4 ... that may have biological influence on the dependent variable. A P value ... Married. 206. 60. Widowed. 86. 25. Divorced/separated. 24. 7. Polygamous (344) ..... Guidelines for the performance of CD4+CD4.

  12. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    NARCIS (Netherlands)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-01-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is

  13. An integrated tiered service delivery model (ITSDM based on local CD4 testing demands can improve turn-around times and save costs whilst ensuring accessible and scalable CD4 services across a national programme.

    Directory of Open Access Journals (Sweden)

    Deborah K Glencross

    Full Text Available The South African National Health Laboratory Service (NHLS responded to HIV treatment initiatives with two-tiered CD4 laboratory services in 2004. Increasing programmatic burden, as more patients access anti-retroviral therapy (ART, has demanded extending CD4 services to meet increasing clinical needs. The aim of this study was to review existing services and develop a service-model that integrated laboratory-based and point-of-care testing (POCT, to extend national coverage, improve local turn-around/(TAT and contain programmatic costs.NHLS Corporate Data Warehouse CD4 data, from 60-70 laboratories and 4756 referring health facilities was reviewed for referral laboratory workload, respective referring facility volumes and related TAT, from 2009-2012.An integrated tiered service delivery model (ITSDM is proposed. Tier-1/POCT delivers CD4 testing at single health-clinics providing ART in hard-to-reach areas (350-1500 tests/day, serving ≥ 200 health-clinics. Tier-6 provides national support for standardisation, harmonization and quality across the organization.The ITSDM offers improved local TAT by extending CD4 services into rural/remote areas with new Tier-3 or Tier-2/POC-Hub services installed in existing community laboratories, most with developed infrastructure. The advantage of lower laboratory CD4 costs and use of existing infrastructure enables subsidization of delivery of more expensive POC services, into hard-to-reach districts without reasonable access to a local CD4 laboratory. Full ITSDM implementation across 5 service tiers (as opposed to widespread implementation of POC testing to extend service can facilitate sustainable 'full service coverage' across South Africa, and save>than R125 million in HIV/AIDS programmatic costs. ITSDM hierarchical parental-support also assures laboratory/POC management, equipment maintenance, quality control and on-going training between tiers.

  14. CD4 T-Cell Memory Generation and Maintenance

    Science.gov (United States)

    Gasper, David J.; Tejera, Melba Marie; Suresh, M.

    2014-01-01

    Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance. PMID:24940912

  15. Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory

    Science.gov (United States)

    Shedlock, Devon J.; Shen, Hao

    2003-04-01

    Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.

  16. CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma.

    Science.gov (United States)

    Zhou, Yong; Zha, Jie; Lin, Zhijuan; Fang, Zhihong; Zeng, Hanyan; Zhao, Jintao; Luo, Yiming; Li, Zhifeng; Xu, Bing

    2018-01-15

    Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4 + T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19 + cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19 + cells than patients who did not show recurrence. Examining cytotoxic CD4 + T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4 + T cells. Also, frequency of cytotoxic CD4 + T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4 + T cells against autologous CD19 + cells was investigated. We found that the cytotoxic potential of CD4 + T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19 + cells presented a significant reduction after longer incubation with cytotoxic CD4 + T cells, suggesting that cytotoxic CD4 + T cells preferentially eliminated MHC II-expressing CD19 + cells. Blocking MHC II on CD19 + cells significantly reduced the cytolytic capacity of CD4 + T cells. Despite these discoveries, the frequency of cytotoxic CD4 + T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4 + T cells presented an MHC II-dependent cytotoxic potential against autologous CD19 + cells and could potentially represent a future treatment option for DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. CD4 and viral load dynamics in antiretroviral-naïve HIV-infected adults from Soweto, South Africa: a prospective cohort.

    Science.gov (United States)

    Martinson, Neil A; Gupte, Nikhil; Msandiwa, Reginah; Moulton, Lawrence H; Barnes, Grace L; Ram, Malathi; Gray, Glenda; Hoffmann, Chris; Chaisson, Richard E

    2014-01-01

    CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates. HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003-2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of 100,000 (N = 122) copies/ml. Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.

  18. CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

    Science.gov (United States)

    Ramberger, Melanie; Högl, Birgit; Stefani, Ambra; Mitterling, Thomas; Reindl, Markus; Lutterotti, Andreas

    2017-03-01

    Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. © Sleep Research Society 2016. Published by Oxford University Press [on behalf of the Sleep Research Society].

  19. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells.

    Science.gov (United States)

    Boudousquie, Caroline; Bossi, Giovanna; Hurst, Jacob M; Rygiel, Karolina A; Jakobsen, Bent K; Hassan, Namir J

    2017-11-01

    The success of immune system-based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC™ molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti-CD3 scFv antibody) were previously shown to redirect CD8 + and CD4 + T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma-specific protein, gp100, presented by HLA-A*0201) efficiently redirects and activates effector and memory cells from both CD8 + and CD4 + repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8 + T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4 + effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8 + and CD4 + repertoires secrete key pro-inflammatory cytokines (tumour necrosis factor-α, interferon-γ, interleukin-6) and chemokines (macrophage inflammatory protein-1α-β, interferon-γ-inducible protein-10, monocyte chemoattractant protein-1). At an individual cell level, IMCgp100-redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti-cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8 + T cell-mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  20. CD4+ T-cell epitope prediction using antigen processing constraints.

    Science.gov (United States)

    Mettu, Ramgopal R; Charles, Tysheena; Landry, Samuel J

    2016-05-01

    T-cell CD4+ epitopes are important targets of immunity against infectious diseases and cancer. State-of-the-art methods for MHC class II epitope prediction rely on supervised learning methods in which an implicit or explicit model of sequence specificity is constructed using a training set of peptides with experimentally tested MHC class II binding affinity. In this paper we present a novel method for CD4+ T-cell eptitope prediction based on modeling antigen-processing constraints. Previous work indicates that dominant CD4+ T-cell epitopes tend to occur adjacent to sites of initial proteolytic cleavage. Given an antigen with known three-dimensional structure, our algorithm first aggregates four types of conformational stability data in order to construct a profile of stability that allows us to identify regions of the protein that are most accessible to proteolysis. Using this profile, we then construct a profile of epitope likelihood based on the pattern of transitions from unstable to stable regions. We validate our method using 35 datasets of experimentally measured CD4+ T cell responses of mice bearing I-Ab or HLA-DR4 alleles as well as of human subjects. Overall, our results show that antigen processing constraints provide a significant source of predictive power. For epitope prediction in single-allele systems, our approach can be combined with sequence-based methods, or used in instances where little or no training data is available. In multiple-allele systems, sequence-based methods can only be used if the allele distribution of a population is known. In contrast, our approach does not make use of MHC binding prediction, and is thus agnostic to MHC class II genotypes. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells.

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    Leslie R Cockerham

    Full Text Available The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1 in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4+ and CD8+ T cells expressing HLA-DR and the frequency of resting CD4+ T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies.

  2. Regulation of allergic airway inflammation by adoptive transfer of CD4+ T cells preferentially producing IL-10.

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    Matsuda, Masaya; Doi, Kana; Tsutsumi, Tatsuya; Fujii, Shinya; Kishima, Maki; Nishimura, Kazuma; Kuroda, Ikue; Tanahashi, Yu; Yuasa, Rino; Kinjo, Toshihiko; Kuramoto, Nobuyuki; Mizutani, Nobuaki; Nabe, Takeshi

    2017-10-05

    Anti-inflammatory pharmacotherapy for asthma has mainly depended on the inhalation of glucocorticoids, which non-specifically suppress immune responses. If the anti-inflammatory cytokine interleukin (IL)-10 can be induced by a specific antigen, asthmatic airway inflammation could be suppressed when individuals are exposed to the antigen. The purpose of this study was to develop cellular immunotherapeutics for atopic diseases using IL-10-producing CD4 + T cells. Spleen cells isolated from ovalbumin (OVA)-sensitized mice were cultured with the antigen, OVA and growth factors, IL-21, IL-27 and TGF-β for 7 days. After the 7-day culture, the CD4 + T cells were purified using a murine CD4 magnetic beads system. When the induced CD4 + T cells were stimulated by OVA in the presence of antigen-presenting cells, IL-10 was preferentially produced in vitro. When CD4 + T cells were adoptively transferred to OVA-sensitized mice followed by intratracheal OVA challenges, IL-10 was preferentially produced in the serum and bronchoalveolar lavage fluid in vivo. IL-10 production coincided with the inhibition of eosinophilic airway inflammation and epithelial mucus plugging. Most of the IL-10-producing CD4 + T cells were negative for Foxp3 and GATA-3, transcription factors of naturally occurring regulatory T cells and Th2 cells, respectively, but double positive for LAG-3 and CD49b, surface markers of inducible regulatory T cells, Tr1 cells. Collectively, most of the induced IL-10-producing CD4 + T cells could be Tr1 cells, which respond to the antigen to produce IL-10, and effectively suppressed allergic airway inflammation. The induced Tr1 cells may be useful for antigen-specific cellular immunotherapy for atopic diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154.

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    Kunnath-Velayudhan, Shajo; Goldberg, Michael F; Saini, Neeraj K; Johndrow, Christopher T; Ng, Tony W; Johnson, Alison J; Xu, Jiayong; Chan, John; Jacobs, William R; Porcelli, Steven A

    2017-10-01

    Analysis of Ag-specific CD4 + T cells in mycobacterial infections at the transcriptome level is informative but technically challenging. Although several methods exist for identifying Ag-specific T cells, including intracellular cytokine staining, cell surface cytokine-capture assays, and staining with peptide:MHC class II multimers, all of these have significant technical constraints that limit their usefulness. Measurement of activation-induced expression of CD154 has been reported to detect live Ag-specific CD4 + T cells, but this approach remains underexplored and, to our knowledge, has not previously been applied in mycobacteria-infected animals. In this article, we show that CD154 expression identifies adoptively transferred or endogenous Ag-specific CD4 + T cells induced by Mycobacterium bovis bacillus Calmette-Guérin vaccination. We confirmed that Ag-specific cytokine production was positively correlated with CD154 expression by CD4 + T cells from bacillus Calmette-Guérin-vaccinated mice and show that high-quality microarrays can be performed from RNA isolated from CD154 + cells purified by cell sorting. Analysis of microarray data demonstrated that the transcriptome of CD4 + CD154 + cells was distinct from that of CD154 - cells and showed major enrichment of transcripts encoding multiple cytokines and pathways of cellular activation. One notable finding was the identification of a previously unrecognized subset of mycobacteria-specific CD4 + T cells that is characterized by the production of IL-3. Our results support the use of CD154 expression as a practical and reliable method to isolate live Ag-specific CD4 + T cells for transcriptomic analysis and potentially for a range of other studies in infected or previously immunized hosts. Copyright © 2017 by The American Association of Immunologists, Inc.

  4. Association of CD4+ T cell subpopulations and psychological stress measures in women living with HIV.

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    Rehm, Kristina E; Konkle-Parker, Deborah

    2017-09-01

    Psychological stress is a known immunomodulator. In individuals with HIV, depression, the most common manifestation of increased psychological stress, can affect immune function with lower CD4+ T cell counts correlating with higher levels of depression. It is unknown how other forms of psychological stress can impact immune markers in people living with HIV. We conducted a cross-sectional study to determine how CD4+ T cell subpopulations correlated with different forms of psychological stress. We recruited 50 HIV-positive women as part of the Women's Interagency HIV Study. We assessed perceived stress, worry, acute anxiety, trait anxiety, and depression through self-report questionnaires and CD4+ T cell subpopulations using flow cytometry. Our sample was 96% African-American with a mean ± SD age and body mass index of 42 ± 8.8 years and 36.6 ± 11.5 kg/m 2 , respectively. The mean ± SD scores on the psychological measures were as follows: Perceived Stress Scale (PSS), 16.5 ± 6.4; Penn State Worry Questionnaire (PSWQ), 47.7 ± 13.8; State-Trait Anxiety Inventory - State (STAIS), 39.1 ± 12.3; State-Trait Anxiety Inventory - Trait (STAIT), 40.2 ± 11.4; Center for Epidemiological Studies Depression Scale (CES-D), 15.6 ± 11.4. The mean + SD values for the immune parameters were as follows: regulatory T cells (Treg), 1.25% ± 0.7; T helper 1 (Th1), 14.9% ± 6.1; T helper 2 (Th2), 3.8% ± 2; Th1/Th2 ratio, 4.6 ± 3; and CD4+ T cell count (cells/mm 3 ), 493 ± 251. Treg levels positively correlated with PSS, STAIS, and STAIT. CD4+ T cell count negatively correlated with PSS, PSWQ, STAIS, STAIT, and CES-D. These data suggest that immune function may be impacted by various forms of psychological stress in HIV-positive women. Interventions that target stress reduction may be useful in improving immune parameters and quality of life.

  5. CD4 and viral load dynamics in antiretroviral-naive HIV-infected adults from Soweto, South Africa: a prospective cohort.

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    Neil A Martinson

    Full Text Available BACKGROUND: CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates. METHODS: HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV treatment were randomized to a trial of preventive treatment from 2003-2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to 100,000 (N = 122 copies/ml. CONCLUSIONS: Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.

  6. [Effect of total glucosides of peony on expression and DNA methylation status of ITGAL gene in CD4(+) T cells of systemic lupus erythematosus].

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    Zhao, Ming; Liang, Gongping; Luo, Shuangyan; Lu, Qianjin

    2012-05-01

    To investigate the effect of total glucosides of peony (TGP) on expression and DNA methylation status of ITGAL gene (CD11a) in CD4(+) T cells from patients with systemic lupus erythematosus (SLE). CD4(+) T cells were isolated by positive selection using CD4 beads. CD4(+) T cells were treated by TGP at 0, 62.5, 312.5 and 1562.5 mg/L for 48 h. The MTT method was used to assess cell viability; mRNA expression level was measured by realtime-PCR; protein level of CD11a was measured by flow cytometric analysis; DNA methylation status was assayed by bisulfite sequencing. No significant change in cell viability was found in CD4(+) T cells among the different concentration groups (P>0.05). Compared with control, the mRNA and protein levels of ITGAL were down-regulated significantly in SLE CD4(+) T cells treated with TGP (1562.5 mg/L) (PTGP (1562.5 mg/L) treated CD4(+) T cells compared with control group (PTGP can repress CD11a gene expression through enhancing DNA methylation of ITGAL promoter in CD4(+) T cells from patients with SLE. This observation represents a preliminary step in understanding the mechanism of TGP in SLE therapy.

  7. Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected adults: A small randomized controlled trial

    Science.gov (United States)

    Creswell, J. David; Myers, Hector F.; Cole, Steven W.; Irwin, Michael R.

    2009-01-01

    Mindfulness meditation training has stress reduction benefits in various patient populations, but its effects on biological markers of HIV-1 progression are unknown. The present study tested the efficacy of an 8-week Mindfulness-based stress reduction (MBSR) meditation program compared to a 1-day control seminar on CD4+ T lymphocyte counts in stressed HIV infected adults. A single-blind randomized controlled trial was conducted with enrollment and follow-up occurring between November 2005 and December 2007. A diverse community sample of 48 HIV-1 infected adults was randomized and entered treatment in either an 8-week MBSR or a 1-day control stress reduction education seminar. The primary outcome was circulating counts of CD4+ T lymphocytes. Participants in the 1-day control seminar showed declines in CD4+ T lymphocyte counts whereas counts among participants in the 8-week MBSR program were unchanged from baseline to post-intervention (time × treatment condition interaction, p = .02). This effect was independent of antiretroviral (ARV) medication use. Additional analyses indicated that treatment adherence to the mindfulness meditation program, as measured by class attendance, mediated the effects of mindfulness meditation training on buffering CD4+ T lymphocyte declines. These findings provide an initial indication that mindfulness meditation training can buffer CD4+ T lymphocyte declines in HIV-1 infected adults. PMID:18678242

  8. Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T Cells: Implications for HIV Microbicides.

    Science.gov (United States)

    Mukhopadhya, Indrani; Murray, Graeme I; Duncan, Linda; Yuecel, Raif; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

    2016-09-06

    CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.

  9. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity.

    Science.gov (United States)

    Heit, Antje; Gebhardt, Friedemann; Lahl, Katharina; Neuenhahn, Michael; Schmitz, Frank; Anderl, Florian; Wagner, Hermann; Sparwasser, Tim; Busch, Dirk H; Kastenmüller, Kathrin

    2008-06-01

    Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.

  10. Estimated average annual rate of change of CD4(+) T-cell counts in patients on combination antiretroviral therapy

    DEFF Research Database (Denmark)

    Mocroft, Amanda; Phillips, Andrew N; Ledergerber, Bruno

    2010-01-01

    BACKGROUND: Patients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4(+) T-cell count according to levels of viraemia in patients on cART. METHODS: A total of 111,371 CD4(+) T-cell counts...... and viral load measurements in 8,227 patients were analysed. Annual change in CD4(+) T-cell numbers was estimated using mixed models. RESULTS: After adjustment, the estimated average annual change in CD4(+) T-cell count significantly increased when viral load was cells/mm(3), 95......% confidence interval [CI] 26.6-34.3), was stable when viral load was 500-9,999 copies/ml (3.1 cells/mm(3), 95% CI -5.3-11.5) and decreased when viral load was >/=10,000 copies/ml (-14.8 cells/mm(3), 95% CI -4.5--25.1). Patients taking a boosted protease inhibitor (PI) regimen had more positive annual CD4(+) T-cell...

  11. CD4+CD25hiFOXP3+ cells in cord blood of neonates born from filaria infected mother are negatively associated with CD4+Tbet+ and CD4+RORγt+ T cells.

    Science.gov (United States)

    Ateba-Ngoa, Ulysse; Mombo-Ngoma, Ghyslain; Zettlmeissl, Eva; van der Vlugt, Luciën E P M; de Jong, Sanne E; de Jong, Sanne; Matsiegui, Pierre-Blaise; Ramharter, Michael; Kremsner, Peter G; Yazdanbakhsh, Maria; Adegnika, Ayola Akim

    2014-01-01

    Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses. Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3. No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = -0.242, P = 0.002; B = -0.178, P = 0.013 respectively). Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check.

  12. Memory T follicular helper CD4 T cells

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    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.

  13. CD4-dependent characteristics of coreceptor use and HIV type 1 V3 sequence in a large population of therapy-naive individuals.

    Science.gov (United States)

    Low, Andrew J; Marchant, David; Brumme, Chanson J; Brumme, Zabrina L; Dong, Winnie; Sing, Tobias; Hogg, Robert S; Montaner, Julio S G; Gill, Vikram; Cheung, Peter K; Harrigan, P Richard

    2008-02-01

    We investigated the associations between coreceptor use, V3 loop sequence, and CD4 count in a cross-sectional analysis of a large cohort of chronically HIV-infected, treatment-naive patients. HIV coreceptor usage was determined in the last pretherapy plasma sample for 977 individuals initiating HAART in British Columbia, Canada using the Monogram Trofile Tropism assay. Relative light unit (RLU) readouts from the Trofile assay, as well as HIV V3 loop sequence data, were examined as a function of baseline CD4 cell count for 953 (97%) samples with both phenotype and genotype data available. Median CCR5 RLUs were high for both R5 and X4-capable samples, while CXCR4 RLUs were orders of magnitude lower for X4 samples (p < 0.001). CCR5 RLUs in R5 samples (N = 799) increased with decreasing CD4 count (p < 0.001), but did not vary with plasma viral load (pVL) (p = 0.74). In X4 samples (N = 178), CCR5 RLUs decreased with decreasing CD4 count (p = 0.046) and decreasing pVL (p = 0.097), while CXCR4 RLUs increased with decreasing pVL (p = 0.0008) but did not vary with CD4 (p = 0.96). RLUs varied with the presence of substitutions at V3 loop positions 11, 25, and 6-8. The prevalence and impact of substitutions at codons 25 and 6-8 were CD4 dependent as was the presence of amino acid mixtures in the V3; substitutions at position 11 were CD4 independent. Assay RLU measures predictably vary with both immunological and virological parameters. The ability to predict X4 virus using genotypic determinants at positions 25 and 6-8 of the V3 loop is CD4 dependent, while position 11 appears to be CD4 independent.

  14. No Neurocognitive Advantage for Immediate Antiretroviral Treatment in adults with greater than 500 CD4+ T Cell Counts

    DEFF Research Database (Denmark)

    Wright, Edwina J; Grund, Birgit; Robertson, Kevin R

    2018-01-01

    OBJECTIVE: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with >500 CD4+ cells/μL. DESIGN: Randomized trial. METHODS: The START parent study randomized participants to commence immediate...... versus deferred ART until CD4+ cells/μL. The START Neurology substudy used 8 neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight...... test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. RESULTS: 592 participants had a median age of 34 years; median baseline CD4+ count of 629 cells...

  15. Utility of the point of care CD4 analyzer, PIMA, to enumerate CD4 counts in the field settings in India

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    Thakar Madhuri

    2012-09-01

    Full Text Available Abstract Background In resource limited settings non-availability of CD4 count facility at the site could adversely affect the ART roll out programme. Point of care CD4 enumerating equipments can make the CD4 count available at the site of care and improve the patients’ management considerably. This study is aimed at determining the utility of a Point of Care PIMA CD4 analyzer (Alere, Germany in the field settings in India. Method The blood samples were collected from 1790 participants at 21 ART centers from different parts of the country and tested using PIMA and the reference methods (FACSCalibur, FACSCount and CyFlow SL3. The paired finger prick and venous blood samples from 175 participants were tested by the PIMA CD4 Analyzer and then by FACSCalibur. Result The CD4 counts obtained by PIMA CD4 analyzer showed excellent correlation with the counts obtained by the reference methods; for venous blood the Pearson’s r was 0.921, p 500 cells/mm3, the differences in the median CD4 counts obtained by the reference method and the PIMA analyzer were not significant (P > 0.05 and the relative bias were low (−7 to 5.1%. The Intermachine comparison showed variation within the acceptable limit of%CV of 10%. Conclusion In the field settings, the POC PIMA CD4 analyzer gave CD4 counts comparable to the reference methods for all CD4 ranges. The POC equipment could identify the patients eligible for ART in 91% cases. Adequate training is necessary for finger prick sample collection for optimum results. Decentralization of CD4 testing by making the CD4 counts available at primary health centers, especially in remote areas with minimum or no infrastructure would reduce the missed visits and improve adherence of the patients.

  16. Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations.

    Science.gov (United States)

    Sweiss, Nadera J; Salloum, Rafah; Gandhi, Seema; Ghandi, Seema; Alegre, Maria-Luisa; Sawaqed, Ray; Badaracco, Maria; Pursell, Kenneth; Pitrak, David; Baughman, Robert P; Moller, David R; Garcia, Joe G N; Niewold, Timothy B

    2010-02-05

    Sarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets. Lymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4x10(-10)). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy. Significant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment.

  17. Stability and Hopf bifurcation on a model for HIV infection of CD4{sup +} T cells with delay

    Energy Technology Data Exchange (ETDEWEB)

    Wang Xia [College of Mathematics and Information Science, Xinyang Normal University, Xinyang, Henan 464000 (China)], E-mail: xywangxia@163.com; Tao Youde [College of Mathematics and Information Science, Xinyang Normal University, Xinyang, Henan 464000 (China); Beijing Institute of Information Control, Beijing 100037 (China); Song Xinyu [College of Mathematics and Information Science, Xinyang Normal University, Xinyang, Henan 464000 (China) and Research Institute of Forest Resource Information Techniques, Chinese Academy of Forestry, Beijing 100091 (China)], E-mail: xysong88@163.com

    2009-11-15

    In this paper, a delayed differential equation model that describes HIV infection of CD4{sup +} T cells is considered. The stability of the positive equilibrium and the existence of Hopf bifurcation are investigated. In succession, using the normal form theory and center manifold argument, we derive the explicit formulas which determine the stability, direction and other properties of bifurcating periodic solutions.

  18. Idiopathic CD4+ lymphocytopenia in Hispanic male: case report and literature review

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    Said S

    2014-07-01

    Full Text Available Sarmad Said,1 Haider Alkhateeb,1 Chad J Cooper,1 Emmanuel Rodriguez,1 Remi Trien,1 German T Hernandez,1,2 Hasan S Salameh1,2 1Department of Internal Medicine, 2Department of Internal Medicine, Division of Nephrology and Hypertension, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, USA Introduction: Idiopathic cluster of differentiation 4 (CD4+ T-cell lymphocytopenia (ICL is a rare non human immunodeficiency virus (HIV-related syndrome with unclear natural history and prognosis that was first reported and defined in 1992. ICL has been observed in patients after the onset of an opportunistic infection without known immunosuppression. Case presentation: A 20-year-old Hispanic male patient without significant past medical history presented with progressive shortness of breath and cough for 3 weeks. Chest computed tomography showed bilateral cavitary lesions in the upper lung lobes. The HIV rapid screening test as well as the sputum acid-fast bacilli test were both positive. The patient was started on antituberculosis therapy. The CD4 count was noticed to be low. However, the HIV Western blot test was negative, and the HIV viral load was within normal limit. Further radiologic studies, hemato-oncologic, and autoimmune workups were normal. The patient was discharged on the treatment for tuberculosis. Follow-up after 8 weeks revealed a persistent low CD4+ count, and the repeated HIV tests were negative. Conclusion: The clinical features of ICL range from an asymptomatic condition to life-threatening complications that imitate the clinical course of HIV-infected patients. The differential diagnosis in adults comprises primarily HIV infection and other diseases or drug side effects. ICL is very rare and should be considered in the absence of any defined immunodeficiency or therapy associated with depressed levels of CD4+ T-cells. Early detection and recognition of the disease allow purposeful and

  19. Is an increase in CD4/CD8 T-cell ratio in lymph node fine needle aspiration helpful for diagnosing Hodgkin lymphoma? A study of 85 lymph node FNAs with increased CD4/CD8 ratio

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    Hernandez Osvaldo

    2005-01-01

    Full Text Available Abstract Background An elevated CD4/CD8 T-cell ratio on flow cytometry (FCM analysis has been reported in the literature to be associated with Hodgkin lymphoma (HL. The purpose of our study was to determine the diagnostic significance of an elevated CD4/CD8 ratio in lymph node fine needle aspiration (FNA specimens. Design Between 1996 and 2002, out of 837 lymph node FNAs submitted for flow cytometry analysis, 85 cases showed an elevated CD4/CD8 ratio, defined as greater than or equal to 4, without definitive evidence of a lymphoproliferative disorder. The cytologic diagnoses of these 85 cases were grouped into four categories: reactive, atypical, Hodgkin lymphoma (HL, and non-Hodgkin lymphoma (NHL. Histologic follow-up was available in 17/85 (20% of the cases. Results 5 of the 64 cases in which FCM and cytology did not reveal evidence of a lymphoproliferative disease had tissue follow-up because of persistent lymphadenopathy and high clinical suspicion. 3/5 (60% confirmed the diagnosis of reactive lymphadenopathy. The two remaining cases (40% were positive for lymphoma (1HL, 1NHL. 8/15 cases called atypical on cytology had histologic follow-up. 7/8 (87.5% cases were positive for lymphoma (3HL, 4NHL. 3/4 cases called HL on cytology had tissue follow-up and all 3 (100% confirmed the diagnosis of HL. One case diagnosed as NHL on cytology was found to be a diffuse large B-cell lymphoma. In summary, out of 17 cases with histologic follow-up 4/17 (24% were reactive with CD4/CD8 T-cell ratio of 4.1–29, 7/17 (41% were HLs with CD4/CD8 T-cell ratio of 5.3 – 11, and 6/17 (35% were NHLs with CD4/CD8 T-cell ratio of 4.2 – 14. Conclusion An elevated CD4/CD8 ratio on FCM is a nonspecific finding which may be seen in both reactive and lymphoproliferative disorders. The cytomorphologic features of the smear are more relevant than the sole flow cytometric finding of an elevated CD4/CD8 ratio.

  20. Are Mucosa CD4+/CD8+ T-Cells Expressions Correlated with the Endoscopic Appearance of Chronic Gastritis Related with Helicobacter pylori Infection?

    Science.gov (United States)

    Ratnasari, Neneng; Bayupurnama, Putut; Maduseno, Sutanto; Indrarti, Fahmi; Triwikatmani, Catharina; Harijadi, Achmad; Nurdjanah, Siti

    2016-06-01

    Local inflammatory processes in the gastric mucosa are followed by extensive immune cell infiltration, resulting in chronic active gastritis characterized by a marked infiltration of T(h)1 cytokine-producing CD4+ and CD8+T-cells Objective. To investigate the correlation between CD4+/CD8+ T-cells in gastric mucosa with endoscopic appearance in chronic gastritis with or without H.pylori infection. Prospective, cross sectional study is performed in a chronic dyspepsia population in July-November 2009 at Dr. Sardjito General Hospital Yogyakarta, Indonesia. The update Sydney system was used to analyze the gastroscopy appearance. Biopsy specimens were stained with HE-stain and IHC-stain. Data were analyzed by t-test, Mann-Whitney and Spearman correlation test. Number of 88 consecutive subjects are enrolled the study (50% male; 50% female), age 46±15 years; 25% H.pylori positive. The expression of CD4+ and CD8+ were higher in H.pylori negative subjects, but only the CD4+ was significant (P=0.011). A significant correlation was found between CD4+ and CD8+ in both subjects (r(Hp+)=0.62 and r(Hp-)=0.68; P<0.05). The expression of CD4+ and CD8+ in H.pylori positive showed a significant correlation with gastric lesions (r(CD4+)=-0.60; r(CD8+)=-0.42 ; P<0.05), only erosion showed a significant difference in both subjects. A positive correlation was found between CD4+ and CD8+ infiltration in both subjects with or without H.pylori infection, and a negative correlation was only found between gastric lesion with CD4+ and CD8+ infiltration in H.pylori subject.

  1. Percentage and function of CD4+CD25+ regulatory T cells in patients with hyperthyroidism

    Science.gov (United States)

    Jiang, Ting-Jun; Cao, Xue-Liang; Luan, Sha; Cui, Wan-Hui; Qiu, Si-Huang; Wang, Yi-Chao; Zhao, Chang-Jiu; Fu, Peng

    2018-01-01

    The current study observed the percentage of peripheral blood (PB) CD4+CD25+ regulatory T cells (Tregs) and the influence of CD4+CD25+ Tregs on the proliferation of naïve CD4 T cells in patients with hyperthyroidism. Furthermore, preliminary discussions are presented on the action mechanism of CD4+CD25+ Tregs on hyperthyroidism attacks. The present study identified that compared with the percentage of PB CD4+CD25+ Tregs in healthy control subjects, no significant changes were observed in the percentage of PB CD4+CD25+ Tregs in patients with hyperthyroidism (P>0.05). For patients with hyperthyroidism, CD4+CD25+ Tregs exhibited significantly reduced inhibition of the proliferation of naïve CD4 T cells and decreased secretion capacity on the cytokines of CD4 T cells, compared with those of healthy control subjects (Phyperthyroidism was significantly improved (Phyperthyroidism before treatment, no significant changes were observed in the percentage of PB CD4+CD25+ Tregs in hyperthyroidism patients following treatment (P>0.05). In the patients with hyperthyroidism, following treatment, CD4+CD25+ Tregs exhibited significantly increased inhibition of the proliferation of naïve CD4 T cells and increased secretion capacity of CD4 T cell cytokines, compared with those of the patients with hyperthyroidism prior to treatment (Phyperthyroidism, and its non-proportional decrease may be closely associated with the occurrence and progression of hyperthyroidism. PMID:29207121

  2. [Changes of CD(4)(+) Foxp3+ regulatory T cells and CD(4)(+)IL-17+T cells in acrolein exposure rats].

    Science.gov (United States)

    Wei, Ming; Tu, Ling; Liang, Yinghong; Li, Jia; Gong, Yanjie; Zhang, Yihua; Yang, Lu

    2015-09-01

    To evaluate the changes of CD(4)(+) IL-17+T (Th17) and CD(4)(+)Foxp3+regulatory T (Treg) cells in peripheral blood and bronchoalveolar lavage fluid (BALF) , and therefore to explore the role of Th17 and Treg in acrolein exposure airway inflammation in rats. Forty male Wistar rats were randomly divided into 4 groups: a 2 wk acrolein exposure group, a 4 wk acrolein exposure group, a 2 wk control group and a 4 wk control group (n=10 each). Cells in BALF were collected and analyzed by absolute and differential cell counts.IL-17 and IL-6 levels in serum and BALF were tested by enzyme linked immunosorbent assay (ELISA). The proportion of CD(4)(+)IL-17+T and CD(4)(+) Foxp3+Treg in peripheral blood and BALF were determined by flow cytometry.The mRNA expressions of IL-17 and Foxp3 were measured by real-time PCR. Comparisons of the data between different groups were performed using one-way ANOVA, and SNK and Games-Howell test were used for comparison between 2 groups. Levels of IL-17 were remarkable increased in the 2 wk acrolein exposure group and the 4 wk acrolein exposure group in serum [(52.64 ± 1.89) ng/L, (76.73 ± 5.57) ng/L], and BALF [(79.07 ± 5.67) ng/L, (96.61 ± 6.44) ng/L] compared with the 2 wk control group [(40.05 ± 3.12) ng/L, (56.75 ± 4.37) ng/L] and the 4 wk control group [(38.75 ± 3.23) ng/L, (53.27 ± 4.48) ng/L], all Pcells and macrophages (r=0.5126, 0.5437, all Pcells and an vary of inflammatory cytokines were evident in airway inflammation of acrolein exposed rats, suggesting that Treg was involved in the immunological regulation and Th17 was associated with the persistent inflammation in acrolein induced airway inflammation in rats.

  3. A photon position sensor consisting of single-electron circuits

    International Nuclear Information System (INIS)

    Kikombo, Andrew Kilinga; Amemiya, Yoshihito; Tabe, Michiharu

    2009-01-01

    This paper proposes a solid-state sensor that can detect the position of incident photons with a high spatial resolution. The sensor consists of a two-dimensional array of single-electron oscillators, each coupled to its neighbors through coupling capacitors. An incident photon triggers an excitatory circular wave of electron tunneling in the oscillator array. The wave propagates in all directions to reach the periphery of the array. By measuring the arrival time of the wave at the periphery, we can know the position of the incident photon. The tunneling wave's generation, propagation, arrival at the array periphery, and the determination of incident photon positions are demonstrated with the results of Monte Carlo based computer simulations.

  4. Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells.

    Science.gov (United States)

    Baldauf, Hanna-Mari; Stegmann, Lena; Schwarz, Sarah-Marie; Ambiel, Ina; Trotard, Maud; Martin, Margarethe; Burggraf, Manja; Lenzi, Gina M; Lejk, Helena; Pan, Xiaoyu; Fregoso, Oliver I; Lim, Efrem S; Abraham, Libin; Nguyen, Laura A; Rutsch, Frank; König, Renate; Kim, Baek; Emerman, Michael; Fackler, Oliver T; Keppler, Oliver T

    2017-03-07

    Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2-like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.

  5. Changes in Reactivity In Vitro of CD4+CD25+ and CD4+CD25− T Cell Subsets in Transplant Tolerance

    Science.gov (United States)

    Hall, Bruce M.; Robinson, Catherine M.; Plain, Karren M.; Verma, Nirupama D.; Tran, Giang T.; Nomura, Masaru; Carter, Nicole; Boyd, Rochelle; Hodgkinson, Suzanne J.

    2017-01-01

    Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4+CD25+ T cells, yet in many models, proliferation of CD4+ T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4+, CD4+CD25+, and CD4+CD25− T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4+ T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naïve CD4+CD25− T cells was greater than naïve CD4+ T cells. In contrast, proliferation of CD4+CD25− T cells from tolerant hosts to specific-donor PVG was not greater than CD4+ T cells, whereas their response to Lewis and self-DA was greater than CD4+ T cells. Paradoxically, CD4+CD25+ T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4+CD25+ T cells proliferate to both PVG and Lewis but not to self-DA. CD4+CD25+ T cells from tolerant, but not naïve hosts, expressed receptors for interferon (IFN)-γ and IL-5 and these cytokines promoted their proliferation to specific-alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naïve hosts. Most relevant is that CD4+CD25+ T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-γ or IL-5. The proliferation to third-party and self of each cell population from tolerant and naïve hosts was similar and not affected by IFN-γ or IL-5. Our findings suggest CD4+CD25+ T cells that mediate transplant tolerance depend on IFN−γ or IL-5 from alloactivated Th1 and Th2 cells. PMID:28878770

  6. Direct ex vivo detection of HLA-DR3-restricted cytomegalovirus- and Mycobacterium tuberculosis-specific CD4+ T cells.

    Science.gov (United States)

    Bronke, Corine; Palmer, Nanette M; Westerlaken, Geertje H A; Toebes, Mireille; van Schijndel, Gijs M W; Purwaha, Veenu; van Meijgaarden, Krista E; Schumacher, Ton N M; van Baarle, Debbie; Tesselaar, Kiki; Geluk, Annemieke

    2005-09-01

    In order to detect epitope-specific CD4+ T cells in mycobacterial or viral infections in the context of human class II major histocompatibility complex protein human leukocyte antigen (HLA)-DR3, two HLA-DR3 tetrameric molecules were successfully produced. One contained an immunodominant HLA-DR3-restricted T-cell epitope derived from the 65-kDa heat-shock protein of Mycobacterium tuberculosis, peptide 1-13. For the other tetramer, we used an HLA-DR3-restricted T-cell epitope derived from cytomegalovirus (CMV) pp65 lower matrix protein, peptide 510-522, which induced high levels of interferon (IFN)-gamma-producing CD4+ T cells in three of four HLA-DR3-positive CMV-seropositive individuals up to 0.84% of CD4+ T cells by intracellular cytokine staining. In peripheral blood mononuclear cells from M. tuberculosis-exposed, Mycobacterium bovis bacille Calmette-Guérin (BCG)-vaccinated, or CMV-seropositive individuals, we were able to directly detect with both tetramers epitope-specific T cells up to 0.62% and 0.45% of the CD4+ T-cell population reactive to M. tuberculosis and CMV, respectively. After a 6-day culture with peptide p510-522, the frequency of CMV-specific tetramer-binding T cells was expanded up to 9.90% tetramer+ CFSElow (5,6-carboxyfluorescein diacetate succinimidyl ester) cells within the CD4+ T-cell population, further confirming the specificity of the tetrameric molecules. Thus, HLA-DR3/peptide tetrameric molecules can be used to investigate HLA-DR3-restricted antigen-specific CD4+ T cells in clinical disease or after vaccination.

  7. Evaluation of CD4+/CD8+ status and urinary tract infections ...

    African Journals Online (AJOL)

    Evaluation of CD4+/CD8+ status and urinary tract infections associated with urinary schistosomiasis ... African Health Sciences ... by <50 ova /10ml of urine had a mean CD4+:CD8+ ratio of 1.57 while those with heavy infections as ... Key words: CD4+, CD8+, urinary tract infections, urinary schistosomiasis, rural Nigerians

  8. Nutritional status, quality of life and CD4 cell count of adults living ...

    African Journals Online (AJOL)

    Keywords: CD4 cell count; Quality of Life; adults; nutritional status; nutritional intake. Nutritional status .... used to calculate the Body Mass Index (BMI). BMI was ... fat consumption as a percentage of the total food energy intake, and component ..... except when the CD4 counts fall very low.5,27 The CD4 cell count may offer a ...

  9. Inter- and intra-laboratory variability of CD4 cell counts in Swaziland

    African Journals Online (AJOL)

    2012-06-01

    Jun 1, 2012 ... The gold standard technique for CD4 enumeration is flow cytometry.3,4 Biological and analytical (laboratory) variations are known to affect CD4 enumeration; biological factors can that influence CD4 results include haemodilution in pregnancy, seasonal and diurnal variations (lowest at approximately 12: ...

  10. Induction of CD4 suppressor T cells with anti-Leu-8 antibody

    International Nuclear Information System (INIS)

    Kanof, M.E.; Strober, W.; James, S.P.

    1987-01-01

    To characterize the conditions under which CD4 T cells suppress polyclonal immunoglobulin synthesis, we investigated the capacity of CD4 T cells that coexpress the surface antigen recognized by the monoclonal antibody anti-Leu-8 to mediate suppression. In an in vitro system devoid of CD8 T cells, CD4, Leu-8+ T cells suppressed pokeweed mitogen-induced immunoglobulin synthesis. Similarly, suppressor function was induced in unfractionated CD4 T cell populations after incubation with anti-Leu-8 antibody under cross-linking conditions. This induction of suppressor function by anti-Leu-8 antibody was not due to expansion of the CD4, Leu-8+ T cell population because CD4 T cells did not proliferate in response to anti-Leu-8 antibody. However, CD4, Leu-8+ T cell-mediated suppression was radiosensitive. Finally, CD4, Leu-8+ T cells do not inhibit immunoglobulin synthesis when T cell lymphokines were used in place of helper CD4 T cells (CD4, Leu-8- T cells), suggesting that CD4 T cell-mediated suppression occurs at the T cell level. We conclude that CD4 T cells can be induced to suppress immunoglobulin synthesis by modulation of the membrane antigen recognized by anti-Leu-8 antibody

  11. Circulating CD4+CD28null T Cells May Increase the Risk of an Atherosclerotic Vascular Event Shortly after Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Michiel G. H. Betjes

    2013-01-01

    Full Text Available Proinflammatory CD4+ T cells without the costimulatory molecule CD28 (CD4+CD28null T cells are expanded in patients with end-stage renal disease (ESRD and associated with atherosclerotic vascular events (AVE. In a prospective study, the number of circulating CD4+CD28null T cells was established in 295 ESRD patients prior to receiving a kidney allograft. Within the first year after transplantation, an AVE occurred in 20 patients. Univariate analysis showed that besides a history of cardiovascular disease (CVDpos, HR 8.1, , age (HR 1.04, , dyslipidaemia (HR 8.8, , and the % of CD4+CD28null T cells (HR 1.04 per % increase, 95% CI 1.00–1.09, were significantly associated with the occurrence of a posttransplantation AVE. In a multivariate analysis, only CVDpos remained a significant risk factor with a significant and positive interaction between the terms CVDpos and the % of CD4+CD28null T cells (HR 1.05, 95% CI 1.03–1.11, . Within the CVDpos group, the incidence of an AVE was 13% in the lowest tertile compared to 25% in the highest tertile of % of CD4+CD28null T cells. In conclusion, the presence of circulating CD4+CD28null T cells is associated with an increased risk for a cardiovascular event shortly after kidney transplantation.

  12. CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

    Science.gov (United States)

    Barinov, Aleksandr; Galgano, Alessia; Krenn, Gerald; Tanchot, Corinne; Vasseur, Florence

    2017-01-01

    CD4+ T cell help to CD8+ T cell responses requires that CD4+ and CD8+ T cells interact with the same antigen presenting dendritic cell (Ag+DC), but it remains controversial whether helper signals are delivered indirectly through a licensed DC and/or involve direct CD4+/CD8+ T cell contacts and/or the formation of ternary complexes. We here describe the first in vivo imaging of the intact spleen, aiming to evaluate the first interactions between antigen-specific CD4+, CD8+ T cells and Ag+DCs. We show that in contrast to CD4+ T cells which form transient contacts with Ag+DC, CD8+ T cells form immediate stable contacts and activate the Ag+DC, acquire fragments of the DC membranes by trogocytosis, leading to their acquisition of some of the DC properties. They express MHC class II, and become able to present the specific Marilyn peptide to naïve Marilyn CD4+ T cells, inducing their extensive division. In vivo, these CD8+ T cells form direct stable contacts with motile naïve CD4+ T cells, recruiting them to Ag+DC binding and to the formation of ternary complexes, where CD4+ and CD8+ T cells interact with the DC and with one another. The presence of CD8+ T cells during in vivo immune responses leads to the early activation and up-regulation of multiple functions by CD4+ T lymphocytes. Thus, while CD4+ T cell help is important to CD8+ T cell responses, CD8+ T cells can interact directly with naïve CD4+ T cells impacting their recruitment and differentiation. PMID:28686740

  13. HIV-1 Infection Is Associated with Depletion and Functional Impairment of Mycobacterium tuberculosis-Specific CD4 T Cells in Individuals with Latent Tuberculosis Infection.

    Science.gov (United States)

    Day, Cheryl L; Abrahams, Deborah A; Harris, Levelle D; van Rooyen, Michele; Stone, Lynnett; de Kock, Marwou; Hanekom, Willem A

    2017-09-15

    Coinfection with HIV is the single greatest risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to active tuberculosis disease. HIV-associated dysregulation of adaptive immunity by depletion of CD4 Th cells most likely contributes to loss of immune control of LTBI in HIV-infected individuals, although the precise mechanisms whereby HIV infection impedes successful T cell-mediated control of M. tuberculosis have not been well defined. To further delineate mechanisms whereby HIV impairs protective immunity to M. tuberculosis , we evaluated the frequency, phenotype, and functional capacity of M. tuberculosis -specific CD4 T cells in HIV-infected and HIV-uninfected adults with LTBI. HIV infection was associated with a lower total frequency of cytokine-producing M. tuberculosis -specific CD4 T cells, and preferential depletion of a discrete subset of M. tuberculosis -specific IFN-γ + IL-2 - TNF-α + CD4 T cells. M. tuberculosis -specific CD4 T cells in HIV-infected individuals expressed significantly higher levels of Ki67, compared with HIV-uninfected individuals, thus indicating recent activation and turnover of these cells in vivo. The ex vivo proliferative capacity of M. tuberculosis -specific CD4 T cells was markedly impaired in HIV-infected individuals, compared with HIV-uninfected individuals. Moreover, HIV infection was associated with increased M. tuberculosis Ag-induced CD4 T cell death ex vivo, indicating a possible mechanism contributing to impaired proliferative capacity of M. tuberculosis -specific CD4 T cells in HIV-infected individuals. These data provide new insights into the parameters of M. tuberculosis -specific CD4 T cell immunity that are impaired in HIV-infected individuals with LTBI, which may contribute to their increased risk of developing active tuberculosis disease. Copyright © 2017 by The American Association of Immunologists, Inc.

  14. Structure of Simian Immunodeficiency Virus Envelope Spikes Bound with CD4 and Monoclonal Antibody 36D5.

    Science.gov (United States)

    Hu, Guiqing; Liu, Jun; Roux, Kenneth H; Taylor, Kenneth A

    2017-08-15

    The human immunodeficiency virus type 1 (HIV-1)/simian immunodeficiency virus (SIV) envelope spike (Env) mediates viral entry into host cells. The V3 loop of the gp120 component of the Env trimer contributes to the coreceptor binding site and is a target for neutralizing antibodies. We used cryo-electron tomography to visualize the binding of CD4 and the V3 loop monoclonal antibody (MAb) 36D5 to gp120 of the SIV Env trimer. Our results show that 36D5 binds gp120 at the base of the V3 loop and suggest that the antibody exerts its neutralization effect by blocking the coreceptor binding site. The antibody does this without altering the dynamics of the spike motion between closed and open states when CD4 is bound. The interaction between 36D5 and SIV gp120 is similar to the interaction between some broadly neutralizing anti-V3 loop antibodies and HIV-1 gp120. Two conformations of gp120 bound with CD4 are revealed, suggesting an intrinsic dynamic nature of the liganded Env trimer. CD4 binding substantially increases the binding of 36D5 to gp120 in the intact Env trimer, consistent with CD4-induced changes in the conformation of gp120 and the antibody binding site. Binding by MAb 36D5 does not substantially alter the proportions of the two CD4-bound conformations. The position of MAb 36D5 at the V3 base changes little between conformations, indicating that the V3 base serves as a pivot point during the transition between these two states. IMPORTANCE Glycoprotein spikes on the surfaces of SIV and HIV are the sole targets available to the immune system for antibody neutralization. Spikes evade the immune system by a combination of a thick layer of polysaccharide on the surface (the glycan shield) and movement between spike domains that masks the epitope conformation. Using SIV virions whose spikes were "decorated" with the primary cellular receptor (CD4) and an antibody (36D5) at part of the coreceptor binding site, we visualized multiple conformations trapped by the

  15. High level of surface CD4 prevents stable human immunodeficiency virus infection of T-cell transfectants.

    OpenAIRE

    Marshall, W L; Diamond, D C; Kowalski, M M; Finberg, R W

    1992-01-01

    CD4 is the principal receptor for the human immunodeficiency virus (HIV). We have isolated and studied CD4-expressing tumor cell clones made by expressing CD4 in the T-cell tumor line HSB. Two clones, one designated HSBCD4, a clone expressing low levels of CD4, and the other, HSB10xCD4, a high-expresser CD4+ clone, were studied for their ability to bind and replicate HIV. In contrast to many other CD4+ cells that down-modulate CD4 following HIV infection, the HSB10xCD4 clones continued to exp...

  16. Single-baseline RTK GNSS Positioning for Hydrographic Surveying

    Science.gov (United States)

    Metin Alkan, Reha; Murat Ozulu, I.; Ilçi, Veli; Kahveci, Muzaffer

    2015-04-01

    Positioning with GNSS technique can be carried out in two ways, absolute and relative. It has been possible to reach a few meters absolute point positioning accuracies in real time after disabling SA permanently in May 2000. Today, accuracies obtainable from absolute point positioning using code observations are not sufficient for most surveying applications. Thus to meet higher accuracy requirements, differential methods using single or dual frequency geodetic-grade GNSS receivers that measure carrier phase have to be used. However, this method requires time-cost field and office works and if the measurement is not carried out with conventional RTK method, user needs a GNSS data processing software to estimate the coordinates. If RTK is used, at least two or more GNSS receivers are required, one as a reference and the other as a rover. Moreover, the distance between the receivers must not exceed 15-20 km in order to be able to rapidly and reliably resolve the carrier phase ambiguities. On the other hand, based on the innovations and improvements in satellite geodesy and GNSS modernization studies occurred within the last decade, many new positioning methods and new approaches have been developed. One of them is Network-RTK (or commonly known as CORS) and the other is Single-baseline RTK. These methods are widely used for many surveying applications in many countries. The user of the system can obtain his/her position within a few cm level of accuracy in real-time with only a single GNSS receiver that has Network RTK (CORS) capability. When compared with the conventional differential and RTK methods, this technique has several significant advantages as it is easy to use and it produces accurate, cost-effective and rapid solutions. In Turkey, establishment of a multi-base RTK network was completed and opened for civilian use in 2009. This network is called CORS-TR and consists of 146 reference stations having about 80-100 km interstation distances. It is possible

  17. Engaging HIV-infected patients in antiretroviral therapy services: CD4 cell count testing after HIV diagnosis from 2005 to 2009 in Yunnan and Guangxi, China

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yao; Ray Y. Chen; ZHANG Fu-jie; LU Lin; LI Hui-qin; LIU Wei; TANG Zhi-rong; FANG Hua; Jennifer Y. Chen; MA Ye; ZHAO Yan

    2011-01-01

    Background The initiation and expansion of China's national free antiretroviral therapy program has led to significant improvement of survival among its participants. Success of further scaling up treatment coverage rests upon intensifying HIV screening and efficient linkage of care. Timely CD4 cell count testing after HIV diagnosis is necessary to determine whether a patient meets criteria for antiretroviral treatment, and represents a crucial link to engage HIV-infected patients in appropriate care, which has not been evaluated in China.Methods We evaluated all patients ≥16 years who tested HIV positive from 2005 to 2009 in Yunnan and Guangxi.Multivariate Logistic regression models were applied to identify factors associated with lack of CD4 cell count testing within 6 months after HIV diagnosis.Results A total of 83 556 patients were included. Over the study period, 30 635 (37%) of subjects received a CD4 cell count within 6 months of receiving the HIV diagnosis. The rate of CD4 cell count testing within 6 months of HIV diagnosis increased significantly from 7% in 2005 to 62% in 2009. Besides the earlier years of HIV diagnosis, negative predictors for CD4 cell count testing in multivariate analyses included older age, not married or unclear marriage status,incarceration, diagnosis at sexual transmitted disease clinics, mode of HIV transmission classified as men who have sex with men, intravenous drug users or transmission route unclear, while minority ethnicity, receipt of high school or higher education, diagnosis at voluntary counseling and testing clinics, and having HIV positive parents were protective.Conclusions Significant progress has been made in increasing CD4 testing among newly diagnosed HIV positive patients in Yunnan and Guangxi from 2005-2009. However, a sizable proportion of HIV positive patients still lack CD4testing within 6 months of diagnosis. Improving CD4 testing, particularly among patients with identified risk factors, is essential to

  18. Binding of the mannose-specific lectin, griffithsin, to HIV-1 gp120 exposes the CD4-binding site

    CSIR Research Space (South Africa)

    Alexandre, Kabamba B

    2011-09-01

    Full Text Available of the lectin griffithsin (GRFT) with HIV-1 gp120 and its effects on exposure of the CD4-binding site (CD4bs). We found that GRFT enhanced the binding of HIV-1 onto plates coated with anti-CD4bs antibodies b12, b6 or the CD4 receptor mimetic, CD4-IgG2...

  19. Genome-wide expression profiling analysis to identify key genes in the anti-HIV mechanism of CD4+ and CD8+ T cells.

    Science.gov (United States)

    Gao, Lijie; Wang, Yunqi; Li, Yi; Dong, Ya; Yang, Aimin; Zhang, Jie; Li, Fengying; Zhang, Rongqiang

    2018-07-01

    Comprehensive bioinformatics analyses were performed to explore the key biomarkers in response to HIV infection of CD4 + and CD8 + T cells. The numbers of CD4 + and CD8 + T cells of HIV infected individuals were analyzed and the GEO database (GSE6740) was screened for differentially expressed genes (DEGs) in HIV infected CD4 + and CD8 + T cells. Gene Ontology enrichment, KEGG pathway analyses, and protein-protein interaction (PPI) network were performed to identify the key pathway and core proteins in anti-HIV virus process of CD4 + and CD8 + T cells. Finally, we analyzed the expressions of key proteins in HIV-infected T cells (GSE6740 dataset) and peripheral blood mononuclear cells(PBMCs) (GSE511 dataset). 1) CD4 + T cells counts and ratio of CD4 + /CD8 + T cells decreased while CD8 + T cells counts increased in HIV positive individuals; 2) 517 DEGs were found in HIV infected CD4 + and CD8 + T cells at acute and chronic stage with the criterial of P-value T cells. The main biological processes of the DEGs were response to virus and defense response to virus. At chronic stage, ISG15 protein, in conjunction with IFN-1 pathway might play key roles in anti-HIV responses of CD4 + T cells; and 4) The expression of ISG15 increased in both T cells and PBMCs after HIV infection. Gene expression profile of CD4 + and CD8 + T cells changed significantly in HIV infection, in which ISG15 gene may play a central role in activating the natural antiviral process of immune cells. © 2018 Wiley Periodicals, Inc.

  20. IL-15 augments TCR-induced CD4+ T cell expansion in vitro by inhibiting the suppressive function of CD25 High CD4+ T cells.

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    Tom L Van Belle

    Full Text Available Due to its critical role in NK cell differentiation and CD8(+ T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+ T cells. The increased levels of IL-15 found in several CD4(+ T cell-driven (auto- immune diseases prompted us to examine how IL-15 influences murine CD4(+ T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+ and CD8(+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+ T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+ T cell suppression by a gradually expanding CD25(HighCD4(+ T cell subset that expresses Foxp3 and originates from CD4(+CD25(+ Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.

  1. Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides

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    Kristin Kassler

    2011-01-01

    Full Text Available The first step of HIV-1 infection involves interaction between the viral glycoprotein gp120 and the human cellular receptor CD4. Inhibition of the gp120-CD4 interaction represents an attractive strategy to block HIV-1 infection. In an attempt to explore the known lack of affinity of murine CD4 to gp120, we have investigated peptides presenting the putative gp120-binding site of murine CD4 (mCD4. Molecular modeling indicates that mCD4 protein cannot bind gp120 due to steric clashes, while the larger conformational flexibility of mCD4 peptides allows an interaction. This finding is confirmed by experimental binding assays, which also evidenced specificity of the peptide-gp120 interaction. Molecular dynamics simulations indicate that the mCD4-peptide stably interacts with gp120 via an intermolecular β-sheet, while an important salt-bridge formed by a C-terminal lysine is lost. Fixation of the C-terminus by introducing a disulfide bridge between the N- and C-termini of the peptide significantly enhanced the affinity to gp120.

  2. Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins.

    Science.gov (United States)

    Zhang, Mingce; Robinson, Tanya O; Duverger, Alexandra; Kutsch, Olaf; Heath, Sonya L; Cron, Randy Q

    2018-03-01

    During chronic HIV-1 infection, regulatory CD4 T cells (Tregs) frequently represent the largest subpopulation of CD4 T cell subsets, implying relative resistant to HIV-1. When HIV-1 infection of CD4 T cells was explored in vitro and ex vivo from patient samples, Tregs possessed lower levels of HIV-1 DNA and RNA in comparison with conventional effector and memory CD4 T cells. Moreover, Tregs suppressed HIV-1 expression in other CD4 T cells in an in vitro co-culture system. This suppression was mediated in part via multiple inhibitory surface proteins expressed on Tregs. Antibody blockade of CTLA-4, PD-1, and GARP on Tregs resulted in increased HIV-1 DNA integration and mRNA expression in neighboring CD4 T cells. Moreover, antibody blockade of Tregs inhibitory proteins resulted in increased HIV-1 LTR transcription in co-cultured CD4 T cells. Thus, Tregs inhibit HIV-1 infection of other CD4 T cell subsets via interactions with inhibitory cell surface proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Comparison of oral manifestations with CD4 count in HIV-infected patients

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    Subodh Arun Sontakke

    2011-01-01

    Full Text Available Aim and Objective: This study was carried out with the primary aim of correlating oral changes and general changes of HIV-infected patients with their CD4 count. Materials and Methods: 124 patients were selected, and after taking their informed consent, they were subjected to detailed history taking and thorough clinical examination. Specific oral lesions and general physical changes were recorded. Every patient was subjected to laboratory investigation for CD4 count. All these findings were tabulated. The clinical observation and laboratory findings were subjected to critical analysis and correlated. Statistical test, i.e. Student′s " t" test, was applied and objective conclusions were drawn. Result: Out of 124 patients, 40 had oral candidiasis, 6 had oral hairy leukoplakia, 12 had periodontal disease, 20 had xerostomia, 30 had melanin pigmentation, while 4 had HSV2, and atypical ulceration. Out of 40 patients with oral candidiasis, 28 patients had CD4 count 500 cell/mm 3 . Oral hairy leukoplakia occurred in equal proportions in group A and B. These periodontal diseases were more commonly in group B; xerostomia and melanin pigmentation was equally seen in group A and B. Conclusion: Oral candidiasis, oral hairy leukoplakia, linear gingival erythema, necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis are specific oral indicators which will definitely suggest to the dental surgeon that the disease is running a rapid downhill course and due to this the oral physician is in a position to raise a suspicion and alert the general physician regarding the declining immune status of patient.

  4. Manifestations of tuberculosis in HIV/AIDS patients and its relationship with CD4 count

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    Ajay Jaryal

    2011-01-01

    Full Text Available Background: HIV/AIDS pandemic is responsible for the resurgence of TB worldwide, resulting in increased morbidity and mortality. HIV and Mycobacterium tuberculosis have a synergistic interaction; each propagates progression of the other. Coinfection with HIV infection leads to difficulties in both the diagnosis and treatment of tuberculosis, increase risk of death, treatment failure and relapse. Objective: The aim of the present study is to study the clinical, radiological profile of pulmonary and extrapulmonary tuberculosis (EPTB in HIV-seropositive patients and their relationship to CD4 counts. Materials and Methods: It was a prospective study conducted over a period of 1 year in the department of medicine, Indira Gandhi Medical College, Shimla. We examined 87 HIV-infected patients with associated tuberculosis recruited from the department of medicine and antiretroviral center and were subjected to thorough clinical examination, X-ray chest, tuberculin testing and sputum examination for AFB and necessary relevant investigations for EPTB. Results: Most common affected age group was 31-40 years. EPTB is the commonest form of TB in our study detected in 65 patients. Commonest EPTB was CNS tuberculosis. Disseminated tuberculosis was only found in patient with CD4 count less than 200/cmm. Majority of lymph node TB was diagnosed by fine needle aspiration cytology (FNAC examination. All patients with AFB-positive lymph node had CD4 count below 200/cum. Conclusions: The results of this study provide information regarding the various forms of TB and their presentation in HIV-infected persons. Early diagnosis of tuberculosis and prompt institution of antitubercular treatment (ATT reduces mortality and morbidity significantly. In resource-poor areas, the diagnosis can be established with cytological/biochemical analysis of fluid, histopathological examination and ZN staining of tissue coupled with radiological features and response to ATT. Therefore

  5. Mycobacterium tuberculosis complex enhances susceptibility of CD4 T cells to HIV through a TLR2-mediated pathway.

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    Seema M Thayil

    Full Text Available Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC(2155, and stimulated CD4+ cells were infected with R5-and X4-tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01. Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4-tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition.

  6. Tapered fiber coupling of single photons emitted by a deterministically positioned single nitrogen vacancy center

    Energy Technology Data Exchange (ETDEWEB)

    Liebermeister, Lars, E-mail: lars.liebermeister@physik.uni-muenchen.de; Petersen, Fabian; Münchow, Asmus v.; Burchardt, Daniel; Hermelbracht, Juliane; Tashima, Toshiyuki [Fakultät für Physik, Ludwig-Maximilians-Universität München, 80799 München (Germany); Schell, Andreas W.; Benson, Oliver [Institut für Physik, Humboldt-Universität zu Berlin, 12489 Berlin (Germany); Meinhardt, Thomas; Krueger, Anke [Institut für Organische Chemie, Universität Würzburg, 97074 Würzburg (Germany); Wilhelm Conrad Roentgen Research Center for Complex Materials Systems, Universität Würzburg, 97074 Würzburg (Germany); Stiebeiner, Ariane; Rauschenbeutel, Arno [Atominstitut, Technische Universität Wien, 1020 Wien (Austria); Weinfurter, Harald; Weber, Markus, E-mail: markusweber@lmu.de [Fakultät für Physik, Ludwig-Maximilians-Universität München, 80799 München (Germany); Max-Planck-Institut für Quantenoptik, 85748 Garching (Germany)

    2014-01-20

    A diamond nano-crystal hosting a single nitrogen vacancy (NV) center is optically selected with a confocal scanning microscope and positioned deterministically onto the subwavelength-diameter waist of a tapered optical fiber (TOF) with the help of an atomic force microscope. Based on this nano-manipulation technique, we experimentally demonstrate the evanescent coupling of single fluorescence photons emitted by a single NV-center to the guided mode of the TOF. By comparing photon count rates of the fiber-guided and the free-space modes and with the help of numerical finite-difference time domain simulations, we determine a lower and upper bound for the coupling efficiency of (9.5 ± 0.6)% and (10.4 ± 0.7)%, respectively. Our results are a promising starting point for future integration of single photon sources into photonic quantum networks and applications in quantum information science.

  7. Studies on positive conveying in helically channeled single screw extruders

    Directory of Open Access Journals (Sweden)

    L. Pan

    2012-07-01

    Full Text Available A solids conveying theory called double-flight driving theory was proposed for helically channeled single screw extruders. In the extruder, screw channel rotates against static barrel channel, which behaves as cooperative embedded twin-screws for the positive conveying. They turn as two parallel arc plates, between which an arc-plate solid-plug was assumed. By analyzing the forces on the solid-plug in the barrel channel and screw channel, the boundary conditions when the solid-plug is waived of being cut off on barrel wall, were found to have the capacity of the positive conveying. Experimental data were obtained using a specially designed extruder with a helically channeled barrel in the feeding zone and a pressure-adjustable die. The effects of the barrel channel geometry and friction coefficients on the conveying mechanism were presented and compared with the experimental results. The simulations showed that the positive conveying could be achieved after optimizing extruder designs. Compared with the traditional design with the friction-drag conveying, the throughput is higher while screw torque and energy consumption are decreased. Besides, the design criteria of the barrel channel were also discussed.

  8. Single Pass Stripline Beam Position Monitor Design, Fabrication and Commissioning

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    McKinlay J.

    2012-10-01

    Full Text Available To monitor the position of the electron beam during transport from the Booster Synchrotron to the Storage Ring at the Australian Synchrotron, a stripline Beam Position Monitor (BPM has been designed, fabricated and installed in-house. The design was based on an existing stripline in the Booster and modified for the transfer line with a particular emphasis on ensuring the line impedance is properly matched to the detector system. The initial bench tests of a prototype stripline showed that the fabrication of the four individual striplines in the BPM was made precisely, each with a measured standing wave ratio (SWR of 1.8 at 500 MHz. Further optimization for impedance matching will be done for new stripline BPMs. The linearity and gain factor was measured with the detector system. The detector system that digitizes the signals is an Instrumentation Technologies Brilliance Single Pass [1]. The results show an error of 1 mm at an offset (from the electrical centre of 10 mm when a linear gain factor is assumed and an RMS noise of ~150 um that decreases to < 10 um with increasing signal intensity. The results were under our requirements for the transport line. The commissioning results of the stripline will also be presented showing a strong signal for an electron beam with an estimated integrated charge of ~50 nC with a position stability of 28 um (horizontal and 75 um (vertical.

  9. Single Pass Stripline Beam Position Monitor Design, Fabrication and Commissioning

    Science.gov (United States)

    Tan, Y.-R. E.; Wang, D.; Van Garderen, E.; McKinlay, J.

    2012-10-01

    To monitor the position of the electron beam during transport from the Booster Synchrotron to the Storage Ring at the Australian Synchrotron, a stripline Beam Position Monitor (BPM) has been designed, fabricated and installed in-house. The design was based on an existing stripline in the Booster and modified for the transfer line with a particular emphasis on ensuring the line impedance is properly matched to the detector system. The initial bench tests of a prototype stripline showed that the fabrication of the four individual striplines in the BPM was made precisely, each with a measured standing wave ratio (SWR) of 1.8 at 500 MHz. Further optimization for impedance matching will be done for new stripline BPMs. The linearity and gain factor was measured with the detector system. The detector system that digitizes the signals is an Instrumentation Technologies Brilliance Single Pass [1]. The results show an error of 1 mm at an offset (from the electrical centre) of 10 mm when a linear gain factor is assumed and an RMS noise of ~150 um that decreases to < 10 um with increasing signal intensity. The results were under our requirements for the transport line. The commissioning results of the stripline will also be presented showing a strong signal for an electron beam with an estimated integrated charge of ~50 nC with a position stability of 28 um (horizontal) and 75 um (vertical).

  10. Impact of nurse-delivered community-based CD4 services on facilitating pre-ART care in rural South Africa.

    Science.gov (United States)

    Kompala, T; Moll, A P; Mtungwa, N; Brooks, R P; Friedland, G H; Shenoi, S V

    2016-08-11

    HIV testing, diagnosis and treatment programs have expanded globally, particularly in resource-limited settings. Diagnosis must be followed by determination of treatment eligibility and referral to care prior to initiation of antiretroviral treatment (ART). However, barriers and delays along these early steps in the treatment cascade may impede successful ART initiation. New strategies are needed to facilitate the treatment cascade. We evaluated the role of on site CD4+ T cell count phlebotomy services by nurses in facilitating pre-ART care in a community-based voluntary counseling and testing program (CBVCT) in rural South Africa. We retrospectively evaluated CBVCT services during five continuous time periods over three years: three periods when a nurse was present on site, and two periods when the nurse was absent. When a nurse was present, CD4 count phlebotomy was performed immediately after HIV testing to determine ART eligibility. When a nurse was absent, patients were referred to their local primary care clinic for CD4 testing. For each period, we determined the proportion of HIV-positive community members who completed CD4 testing, received notification of CD4 count results, as well as the time to test completion and result notification. Between 2010 and 2013, 7213 individuals accessed CBVCT services; of these, 620 (8.6 %) individuals were HIV-positive, 205 (33.1 %) were eligible for ART according to South African national CD4 count criteria, and 78 (38.0 % of those eligible) initiated ART. During the periods when a professional nurse was available to provide CD4 phlebotomy services, HIV-positive clients were significantly more likely to complete CD4 testing than during periods when these services were not available (85.5 % vs. 37.3 %, p ART care cascade and facilitate timely entry into HIV care.

  11. Cytokines affecting CD4+T regulatory cells in transplant tolerance. II. Interferon gamma (IFN-γ) promotes survival of alloantigen-specific CD4+T regulatory cells.

    Science.gov (United States)

    Nomura, Masaru; Hodgkinson, Suzanne J; Tran, Giang T; Verma, Nirupama D; Robinson, Catherine; Plain, Karren M; Boyd, Rochelle; Hall, Bruce M

    2017-06-01

    CD4 + T cells that transfer alloantigen-specific transplant tolerance are short lived in culture unless stimulated with specific-donor alloantigen and lymphocyte derived cytokines. Here, we examined if IFN-γ maintained survival of tolerance transferring CD4 + T cells. Alloantigen-specific transplant tolerance was induced in DA rats with heterotopic adult PVG heart allografts by a short course of immunosuppression and these grafts functioned for >100days with no further immunosuppression. In previous studies, we found the CD4 + T cells from tolerant rats that transfer tolerance to an irradiated DA host grafted with a PVG heart, lose their tolerance transferring ability after 3days of culture, either with or without donor alloantigen, and effect rejection of specific-donor grafts. If cultures with specific-donor alloantigen are supplemented by supernatant from ConA activated lymphocytes the tolerance transferring cells survive, suggesting these cells depend on cytokines for their survival. In this study, we found addition of rIFN-γ to MLC with specific-donor alloantigen maintained the capacity of tolerant CD4 + T cells to transfer alloantigen-specific tolerance and their ability to suppress PVG allograft rejection mediated by co-administered naïve CD4 + T cells. IFN-γ suppressed the in vitro proliferation of tolerant CD4 + T cells. Tolerant CD4 + CD25 + T cells did not proliferate in MLC to PVG stimulator cells with no cytokine added, but did when IFN-γ was present. IFN-γ did not alter proliferation of tolerant CD4 + CD25 + T cells to third-party Lewis. Tolerant CD4 + CD25 + T cells' expression of IFN-γ receptor (IFNGR) was maintained in culture when IFN-γ was present. This study suggested that IFN-γ maintained tolerance mediating alloantigen-specific CD4 + CD25 + T cells. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  12. Central memory CD4 T cells are associated with incomplete restoration of the CD4 T cell pool after treatment-induced long-term undetectable HIV viraemia.

    Science.gov (United States)

    Rallón, Norma; Sempere-Ortells, José M; Soriano, Vincent; Benito, José M

    2013-11-01

    It is unclear to what extent T cell reconstitution may be possible in HIV-1-infected individuals on continuous successful highly active antiretroviral therapy (HAART). Herein, we analysed distinct phenotypic markers of immune recovery in patients with undetectable viraemia for 8 years, taking as reference untreated patients and healthy controls. Seventy-two subjects were examined: 28 HIV-1+ patients on successful long-term HAART, 24 HIV-1+ untreated viraemic patients and 20 age-matched healthy controls. Analysis of naive and memory CD4 and CD8 T cells was combined with measurements of activation status (expression of CD38) and with thymic function (expression of CD31). Statistical significance was determined by non-parametric tests. After long-term HAART, the majority of parameters were normalized compared with age-matched control values, including T cell activation and thymic function. However, absolute counts of naive and central memory CD4 T cells remained below normal levels. The only parameters significantly associated with CD4 counts at the end of follow-up were the pre-HAART CD4 count ( β ± SD = 0.54 ± 0.16, P = 0.003) and the level of CD4 central memory cells at the end of follow-up (β ± SD = 1.18 ± 0.23, P 350 cells/mm(3) reached a complete normalization of CD4 counts. Even after long-term successful HAART, complete CD4 restoration may be attainable only in patients starting therapy with moderately high CD4 counts, prompting early initiation of antiretroviral therapy. Incomplete CD4 restoration may be associated with a defective restoration of central memory CD4 T cells, a cell subset with a pivotal role in T cell homeostasis.

  13. CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression

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    Luyan Mu

    2017-11-01

    Full Text Available BackgroundAngiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL and tumor blood-vasculatures in the context of glioma progression.MethodsPaired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA recurred as DA, DA recurred as glioblastomas (GBM, and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.ResultsUpon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors. Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS (HR = 4.199, 95% CI 1.522–11.584, p = 0.006.ConclusionThe minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3

  14. Burn-injury affects gut-associated lymphoid tissues derived CD4+ T cells.

    Science.gov (United States)

    Fazal, Nadeem; Shelip, Alla; Alzahrani, Alhusain J

    2013-01-01

    After scald burn-injury, the intestinal immune system responds to maintain immune balance. In this regard CD4+T cells in Gut-Associated Lymphoid Tissues (GALT), like mesenteric lymph nodes (MLN) and Peyer's patches (PP) respond to avoid immune suppression following major injury such as burn. Therefore, we hypothesized that the gut CD4+T cells become dysfunctional and turn the immune homeostasis towards depression of CD4+ T cell-mediated adaptive immune responses. In the current study we show down regulation of mucosal CD4+ T cell proliferation, IL-2 production and cell surface marker expression of mucosal CD4+ T cells moving towards suppressive-type. Acute burn-injury lead to up-regulation of regulatory marker (CD25+), down regulation of adhesion (CD62L, CD11a) and homing receptor (CD49d) expression, and up-regulation of negative co-stimulatory (CTLA-4) molecule. Moreover, CD4+CD25+ T cells of intestinal origin showed resistance to spontaneous as well as induced apoptosis that may contribute to suppression of effector CD4+ T cells. Furthermore, gut CD4+CD25+ T cells obtained from burn-injured animals were able to down-regulate naïve CD4+ T cell proliferation following adoptive transfer of burn-injured CD4+CD25+ T cells into sham control animals, without any significant effect on cell surface activation markers. Together, these data demonstrate that the intestinal CD4+ T cells evolve a strategy to promote suppressive CD4+ T cell effector responses, as evidenced by enhanced CD4+CD25+ T cells, up-regulated CTLA-4 expression, reduced IL-2 production, tendency towards diminished apoptosis of suppressive CD4+ T cells, and thus lose their natural ability to regulate immune homeostasis following acute burn-injury and prevent immune paralysis.

  15. Role of LAP+CD4+ T cells in the tumor microenvironment of colorectal cancer.

    Science.gov (United States)

    Zhong, Wu; Jiang, Zhi-Yuan; Zhang, Lei; Huang, Jia-Hao; Wang, Shi-Jun; Liao, Cun; Cai, Bin; Chen, Li-Sheng; Zhang, Sen; Guo, Yun; Cao, Yun-Fei; Gao, Feng

    2017-01-21

    To investigate the abundance and potential functions of LAP + CD4 + T cells in colorectal cancer (CRC). Proportions of LAP + CD4 + T cells were examined in peripheral blood and tumor/paratumor tissues of CRC patients and healthy controls using flow cytometry. Expression of phenotypic markers such as forkhead box (Fox)p3, cytotoxic T-lymphocyte-associated protein (CTLA)-4, chemokine CC receptor (CCR)4 and CCR5 was measured using flow cytometry. LAP - CD4 + and LAP + CD4 + T cells were isolated using a magnetic cell-sorting system and cell purity was analyzed by flow cytometry. Real-time quantitative polymerase chain reaction was used to measure expression of cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. The proportion of LAP + CD4 + T cells was significantly higher in peripheral blood from patients (9.44% ± 3.18%) than healthy controls (1.49% ± 1.00%, P CD4 + T cells was significantly higher in tumor tissues (11.76% ± 3.74%) compared with paratumor tissues (3.87% ± 1.64%, P CD4 + T cells and TNM stage ( P cell sorting gave an overall enrichment of LAP + CD4 + T cells (95.02% ± 2.87%), which was similar for LAP - CD4 + T cells (94.75% ± 2.76%). In contrast to LAP - CD4 + T cells, LAP + CD4 + T cells showed lower Foxp3 expression but significantly higher levels of CTLA-4, CCR4 and CCR5 ( P CD4 + T cells expressed significantly larger amounts of IL-10 and TGF-β but lower levels of IL-2, IL-4, IL-17 and interferon-γ, compared with LAP - CD4 + T cells. LAP + CD4 + T cells accumulated in the tumor microenvironment of CRC patients and were involved in immune evasion mediated by IL-10 and TGF-β.

  16. HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals

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    Satou Yorifumi

    2012-05-01

    Full Text Available Abstract Background HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4+ T cells. Infection of CD4+ T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4+ T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4+ T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression. Results To investigate the effect of HTLV-1 infection on CD4+ T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC, 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP, 10 patients with adult T-cell leukemia (ATL, and 10 healthy donors. The frequency of FoxP3+ cells in CD4+ T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4+ T cells that were FoxP3+. The CD4+FoxP3+ T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3+ T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the Treg associated molecules CTLA-4 and GITR were decreased in CD4+FoxP3+ T cells. Further we characterized FoxP3+CD4+ T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA−FoxP3low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3+ cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression

  17. IFNA-AS1 regulates CD4+ T cell activation in myasthenia gravis though HLA-DRB1.

    Science.gov (United States)

    Luo, Mengchuan; Liu, Xiaofang; Meng, Huanyu; Xu, Liqun; Li, Yi; Li, Zhibin; Liu, Chang; Luo, Yue-Bei; Hu, Bo; Xue, Yuanyuan; Liu, Yu; Luo, Zhaohui; Yang, Huan

    2017-10-01

    Abnormal CD4 + T cell activation is known to play roles in the pathogenesis of myasthenia gravis (MG). However, little is known about the mechanisms underlying the roles of lncRNAs in regulating CD4 + T cell. In this study, we discovered that the lncRNA IFNG-AS1 is abnormally expressed in MG patients associated with quantitative myasthenia gravis (QMG) and the positive anti-AchR Ab levels patients. IFNG-AS1 influenced Th1/Treg cell proliferation and regulated the expression levels of their transcription factors in an experimental autoimmune myasthenia gravis (EAMG)model. IFNG-AS1 could reduce the expression of HLA-DRB and HLA-DOB and they had a negative correlation in MG. Furthermore IFNG-AS1 influenced the expression levels of CD40L and CD4 + T cells activation in MG patient partly depend on effecting the HLA-DRB1 expression. It suggests that IFNG-AS1 may be involved in CD4 + T cell-mediated immune responses in MG. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. CD4+ T-cell lines used to evaluate a Mycobacterium avium subsp. paratuberculosis (MAP) peptide vaccine

    DEFF Research Database (Denmark)

    Lybeck, Kari; Sjurseth, Siri K.; Al-Touama, Zainab

    The aim of the study was to establish a protocol for generation of MAP-specific T-cell lines and to use these lines for evaluation of a peptide vaccine. A protocol for culturing T-cell lines from peripheral blood of goats naturally infected with MAP was established. CD4+ T cells were positively...... selected using an anti CD4 mAb and Dynabeads. Sorted CD4+ cells were cultivated with purified protein derivative from MAP (PPDj) or E. coli sonicate, IL-2, and IL-15. After two cultivation cycles, T cells were tested for recall responses in a proliferative T-cell assay. T-cell line responses were...... in average 92 % for PPDj, and -3 % for E. coli sonicate. CD4+ T-cell lines stimulated with PPDj showed a 6 fold increase in IFN- γ production compared to controls. These results indicated that the T-cell lines were MAP-specific. The protocol was subsequently used to evaluate MAP-specific peptides as vaccine...

  19. 1-D position sensitive single carrier semiconductor detectors

    International Nuclear Information System (INIS)

    Zhong He; Knoll, G.F.; Wehe, D.K.; Rojeski, R.; Mastrangelo, C.H.; Hammig, M.; Barrett, C.; Uritani, A.

    1996-01-01

    A single polarity charge sensing method has been studied using coplanar electrodes on 5 mm cubes of CdZnTe γ-ray detectors. This method can ameliorate the hole trapping problem of room-temperature semiconductor detectors. Our experimental results confirm that the energy resolution is dramatically improved compared with that obtained using the conventional readout method, but is still about an order of magnitude worse than the theoretical limit. A method to obtain the γ-ray interaction depth between the cathode and the anode is presented here. This technique could be used to correct for the electron trapping as a function of distance from the coplanar electrodes. Experimental results showed that a position resolution of about 0.9 mm FWHM at 122 keV can be obtained. These results will be of interest in the design of higher performance room-temperature semiconductor γ-ray detectors. (orig.)

  20. Cytokines affecting CD4+T regulatory cells in transplant tolerance. III. Interleukin-5 (IL-5) promotes survival of alloantigen-specific CD4+ T regulatory cells.

    Science.gov (United States)

    Hall, Bruce M; Plain, Karren M; Tran, Giang T; Verma, Nirupama D; Robinson, Catherine M; Nomura, Masaru; Boyd, Rochelle; Hodgkinson, Suzanne J

    2017-08-01

    CD4 + T cells mediate antigen-specific allograft tolerance, but die in culture without activated lymphocyte derived cytokines. Supplementation of the media with cytokine rich supernatant, from ConA activated spleen cells, preserves the capacity of tolerant cells to transfer tolerance and suppress rejection. rIL-2 or rIL-4 alone are insufficient to maintain these cells, however. We observed that activation of naïve CD4 + CD25 + FOXP3 + Treg with alloantigen and the Th2 cytokine rIL-4 induces them to express interleukin-5 specific receptor alpha (IL-5Rα) suggesting that IL-5, a Th2 cytokine that is produced later in the immune response may promote tolerance mediating Treg. This study examined if recombinant IL-5(rIL-5) promoted survival of tolerant CD4 + , especially CD4 + CD25 + T cells. CD4 + T cells, from DA rats tolerant to fully allogeneic PVG heart allografts surviving over 100days without on-going immunosuppression, were cultured with PVG alloantigen and rIL-5. The ability of these cells to adoptively transfer tolerance to specific-donor allograft and suppress normal CD4 + T cell mediated rejection in adoptive DA hosts was examined. Tolerant CD4 + CD25 + T cells' response to rIL-5 and expression of IL-5Rα was also assessed. rIL-5 was sufficient to promote transplant tolerance mediating CD4 + T cells' survival in culture with specific-donor alloantigen. Tolerant CD4 + T cells cultured with rIL-5 retained the capacity to transfer alloantigen-specific tolerance and inhibited naïve CD4 + T cells' capacity to effect specific-donor graft rejection. rIL-5 promoted tolerant CD4 + CD25 + T cells' proliferation in vitro when stimulated with specific-donor but not third-party stimulator cells. Tolerant CD4 + CD25 + T cells expressed IL-5Rα. This study demonstrated that IL-5 promoted the survival of alloantigen-specific CD4 + CD25 + T cells that mediate transplant tolerance. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. CD4- and dynamin-dependent endocytosis of HIV-1 into plasmacytoid dendritic cells

    Energy Technology Data Exchange (ETDEWEB)

    Pritschet, Kathrin; Donhauser, Norbert; Schuster, Philipp; Ries, Moritz; Haupt, Sabrina; Kittan, Nicolai A.; Korn, Klaus [Institute of Clinical and Molecular Virology, National Reference Centre for Retroviruses, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, 91054 Erlangen (Germany); Poehlmann, Stefan [Institute of Virology, Hannover Medical School, 30625 Hannover (Germany); Holland, Gudrun; Bannert, Norbert [Robert Koch-Institute, Center for Biological Security 4, 13353 Berlin (Germany); Bogner, Elke [Institute of Virology, Charite University Hospital, 10117 Berlin (Germany); Schmidt, Barbara, E-mail: baschmid@viro.med.uni-erlangen.de [Institute of Clinical and Molecular Virology, National Reference Centre for Retroviruses, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, 91054 Erlangen (Germany)

    2012-02-20

    Chronic immune activation, triggered by plasmacytoid dendritic cell (PDC) interferon (IFN)-alpha production, plays an important role in HIV-1 pathogenesis. As the entry of HIV-1 seems to be important for the activation of PDC, we directly characterized the viral entry into these cells using immuno-electron microscopy, cellular fractionation, confocal imaging, and functional experiments. After attachment to PDC, viruses were taken up in an energy-dependent manner. The virions were located in compartments positive for caveolin; early endosomal antigen 1; Rab GTPases 5, 7 and 9; lysosomal-associated membrane protein 1. PDC harbored more virus in endocytic vesicles than CD4+ T cells (p < 0.05). Blocking CD4 inhibited the uptake of virions into cytosolic and endosomal compartments. Dynasore, an inhibitor of dynamin-dependent endocytosis, not the fusion inhibitor T-20, reduced the HIV-1 induced IFN-alpha production. Altogether, our morphological and functional data support the role of endocytosis for the entry and IFN-alpha induction of HIV-1 in PDC.

  2. CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.

    Directory of Open Access Journals (Sweden)

    Andreas Schweizer

    2008-07-01

    Full Text Available Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. These 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C HIV isolates in the low nanomolar range, independent of coreceptor usage. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins-high physical stability, specificity and low production costs-with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development.

  3. The exhausted CD4+CXCR5+ T cells involve the pathogenesis of human tuberculosis disease.

    Science.gov (United States)

    Bosco, Munyemana Jean; Wei, Ming; Hou, Hongyan; Yu, Jing; Lin, Qun; Luo, Ying; Sun, Ziyong; Wang, Feng

    2018-06-21

    The CD4 + CXCR5 + T cells have been previously established. However, their decreased frequency during tuberculosis (TB) disease is partially understood. The aim of this study was to explore the depletion of CD4 + CXCR5 + T cells in human TB. The frequency and function of CD4 + CXCR5 + T cells were evaluated in active TB (ATB) patients and healthy control (HC) individuals. The function of CD4 + CXCR5 + T cells was determined after blockade of inhibitory receptors. The frequency of CD4 + CXCR5 + T cells was decreased in ATB patients. The expression of activation markers (HLA-DR and ICOS) and inhibitory receptors (Tim-3 and PD-1) on CD4 + CXCR5 + T cells was increased in ATB group. TB-specific antigen stimulation induced higher expression of inhibitory receptors than phytohemagglutinin stimulation in ATB group. In contrast, TB antigen stimulation did not induce a significantly increased expression of IL-21 and Ki-67 on CD4 + CXCR5 + T cells. However, blockade of inhibitory receptors Tim-3 and PD-1 not only increased the frequency of CD4 + CXCR5 + T cells, but also restored their proliferation and cytokine secretion potential. An increased expression of inhibitory receptors involves the depletion of CD4 + CXCR5 + T cells, and blockade of inhibitory receptors can restore the function of CD4 + CXCR5 + T cells in ATB patients. Copyright © 2018. Published by Elsevier Ltd.

  4. Preferential replication of FIV in activated CD4+CD25+T cells independent of cellular proliferation

    International Nuclear Information System (INIS)

    Joshi, Anjali; Vahlenkamp, Thomas W.; Garg, Himanshu; Tompkins, Wayne A.F.; Tompkins, Mary B.

    2004-01-01

    Studies attempting to identify reservoirs of HIV-1 latency have documented that the virus persists as both a latent and productive infection in subsets of CD4 + cells. Reports regarding establishment of a stable HIV-1 infection in quiescent T cells in vitro, however, are controversial. In the present study, we investigated the susceptibility of naive and activated CD4 + cell subsets (distinguished by differential expression of CD25) to feline immunodeficiency virus (FIV) infection, their ability to replicate the virus, and potentially act as a reservoir for virus persistence in infected animals. While both CD4 + CD25 + and CD4 + CD25 - cells are susceptible to FIV infection in vitro and in vivo, only CD4 + CD25 + cells produce infectious virions when cultured with interleukin-2 (IL-2). Latently infected CD4 + CD25 - cells produce infectious virions following ConcanvalinA (ConA) stimulation, which correlates with upregulated surface expression of CD25. In contrast to CD4 + CD25 - cells, CD4 + CD25 + cells remain unresponsive to mitogen stimulation and are relatively resistant to apoptosis whether or not infected with FIV. The ability of CD4 + CD25 + cells to replicate FIV efficiently in the presence of IL-2 but remain anergic and unresponsive to apoptotic signaling suggests that these cells may provide a reservoir of productive FIV infection. On the contrary, CD4 + CD25 - cells seem to establish as latent viral reservoirs capable of being reactivated after stimulation

  5. Regulation of CD4 T cells and their effects on immunopathological inflammation following viral infection.

    Science.gov (United States)

    Bhattacharyya, Mitra; Madden, Patrick; Henning, Nathan; Gregory, Shana; Aid, Malika; Martinot, Amanda J; Barouch, Dan H; Penaloza-MacMaster, Pablo

    2017-10-01

    CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naive CD4 T cells undergo substantial expansion following infection, but can induce lethal T helper type 1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary CD4 T cells, but does not seem to play a critical role in regulating the expansion of secondary CD4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary CD4 T cells following viral infection, despite that this treatment increased the numbers of primary CD4 T-cell responses. Altogether, these data demonstrate important aspects of how primary and secondary CD4 T cells are regulated in vivo, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T-cell therapies against persistent antigens. © 2017 John Wiley & Sons Ltd.

  6. Functional, Antigen-Specific Stem Cell Memory (TSCM CD4+ T Cells Are Induced by Human Mycobacterium tuberculosis Infection

    Directory of Open Access Journals (Sweden)

    Cheleka A. M. Mpande

    2018-03-01

    functional, producing IL-2, IFN-γ, and TNF-α upon antigen stimulation, and their frequencies correlated positively with long-term BCG-specific CD4+ T cell proliferative potential after infant vaccination.ConclusionHuman infection with M. tb induced distinct, antigen-specific CD4+ TSCM cells endowed with effector functions, including expression of cytotoxic molecules and Th1 cytokines, and displayed chemokine receptor profiles consistent with memory Th1/17 cells. Induction of CD4+ TSCM should be considered for vaccination approaches that aim to generate long-lived memory T cells against M. tb.

  7. Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells.

    OpenAIRE

    Desbarats, J; Freed, J H; Campbell, P A; Newell, M K

    1996-01-01

    The CD4 receptor contributes to T-cell activation by coligating major histocompatibility complex class II on antigen presenting cells with the T-cell receptor (TCR)/CD3 complex, and triggering a cascade of signaling events including tyrosine phosphorylation of intracellular proteins. Paradoxically, CD3 cross-linking prior to TCR stimulation results in apoptotic cell death, as does injection of anti-CD4 antibodies in vivo of CD4 ligation by HIV glycoprotein (gp) 120. In this report we investig...

  8. Micro-magnet arrays for specific single bacterial cell positioning

    Energy Technology Data Exchange (ETDEWEB)

    Pivetal, Jérémy, E-mail: jeremy.piv@netcmail.com [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France); Royet, David [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France); Ciuta, Georgeta [Univ. Grenoble Alpes, Inst NEEL, F-38042 Grenoble (France); CNRS, Inst NEEL, F-38042 Grenoble (France); Frenea-Robin, Marie [Université de Lyon, Université Lyon 1, CNRS UMR 5005, Laboratoire Ampère, F-69622 Villeurbanne (France); Haddour, Naoufel [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France); Dempsey, Nora M. [Univ. Grenoble Alpes, Inst NEEL, F-38042 Grenoble (France); CNRS, Inst NEEL, F-38042 Grenoble (France); Dumas-Bouchiat, Frédéric [Univ Limoges, CNRS, SPCTS UMR 7513, 12 Rue Atlantis, F-87068 Limoges (France); Simonet, Pascal [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France)

    2015-04-15

    In various contexts such as pathogen detection or analysis of microbial diversity where cellular heterogeneity must be taken into account, there is a growing need for tools and methods that enable microbiologists to analyze bacterial cells individually. One of the main challenges in the development of new platforms for single cell studies is to perform precise cell positioning, but the ability to specifically target cells is also important in many applications. In this work, we report the development of new strategies to selectively trap single bacterial cells upon large arrays, based on the use of micro-magnets. Escherichia coli bacteria were used to demonstrate magnetically driven bacterial cell organization. In order to provide a flexible approach adaptable to several applications in the field of microbiology, cells were magnetically and specifically labeled using two different strategies, namely immunomagnetic labeling and magnetic in situ hybridization. Results show that centimeter-sized arrays of targeted, isolated bacteria can be successfully created upon the surface of a flat magnetically patterned hard magnetic film. Efforts are now being directed towards the integration of a detection tool to provide a complete micro-system device for a variety of microbiological applications. - Highlights: 1.We report a new approach to selectively micropattern bacterial cells individually upon micro-magnet arrays. 2.Permanent micro-magnets of a size approaching that of bacteria could be fabricated using a Thermo-Magnetic Patterning process. 3.Bacterial cells were labeled using two different magnetic labeling strategies providing flexible approach adaptable to several applications in the field of microbiology.

  9. Rapid point-of-care CD4 testing at mobile HIV testing sites to increase linkage to care: an evaluation of a pilot program in South Africa.

    Science.gov (United States)

    Larson, Bruce A; Schnippel, Kathryn; Ndibongo, Buyiswa; Xulu, Thembisile; Brennan, Alana; Long, Lawrence; Fox, Matthew P; Rosen, Sydney

    2012-10-01

    A mobile HIV counseling and testing (HCT) program around Johannesburg piloted the integration of point-of-care (POC) CD4 testing, using the Pima analyzer, to improve linkages to HIV care. We report results from this pilot program for patients testing positive (n = 508) from May to October 2010. We analyzed 3 primary outcomes: assignment to testing group (offered POC CD4 or not), successful follow-up (by telephone), and completed the referral visit for HIV care within 8 weeks after HIV testing if successfully followed up. Proportions for each outcome were calculated, and relative risks were estimated using a modified Poisson approach. Three hundred eleven patients were offered the POC CD4 test, and 197 patients were not offered the test. No differences in patient characteristics were observed between the 2 groups. Approximately 62.7% of patients were successfully followed up 8 weeks after HIV testing, with no differences observed between testing groups. Among those followed up, 54.4% reported completing their referral visit. Patients offered the POC CD4 test were more likely to complete the referral visit for further HIV care (relative risk 1.25, 95% confidence interval: 1.00 to 1.57). In this mobile HCT setting, patients offered POC CD4 testing as part of the HCT services were more likely to visit a referral clinic after testing, suggesting that rapid CD4 testing technology may improve linkage to HIV care. Future research can evaluate options for adjusting HCT services if POC CD4 testing was included permanently and the cost-effectiveness of the POC CD4 testing compared with other approaches for improving linkage of care.

  10. Microsomal Prostaglandin E Synthase-1 Facilitates an Intercellular Interaction between CD4⁺ T Cells through IL-1β Autocrine Function in Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Takemiya, Takako; Takeuchi, Chisen; Kawakami, Marumi

    2017-12-19

    Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme that produces prostaglandin E₂ (PGE₂). In our previous study, we investigated the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, using mPGES - 1 -deficient ( mPGES-1 -/- ) and wild-type (wt) mice. We found that mPGES-1 facilitated inflammation, demyelination, and paralysis and was induced in vascular endothelial cells and macrophages and microglia around inflammatory foci. Here, we investigated the role of interleukin-1β (IL-1β) in the intercellular mechanism stimulated by mPGES-1 in EAE spinal cords in the presence of inflammation. We found that the area invaded by CD4-positive (CD4⁺) T cells was extensive, and that PGE₂ receptors EP1-4 were more induced in activated CD4⁺ T cells of wt mice than in those of mPGES - 1 -/- mice. Moreover, IL-1β and IL-1 receptor 1 (IL-1r1) were produced by 65% and 48% of CD4⁺ T cells in wt mice and by 44% and 27% of CD4⁺ T cells in mPGES-1 -/- mice. Furthermore, interleukin-17 (IL-17) was released from the activated CD4⁺ T cells. Therefore, mPGES-1 stimulates an intercellular interaction between CD4⁺ T cells by upregulating the autocrine function of IL-1β in activated CD4⁺ T cells, which release IL-17 to facilitate axonal and myelin damage in EAE mice.

  11. Production of Autoantibodies in Chronic Hepatitis B Virus Infection Is Associated with the Augmented Function of Blood CXCR5+CD4+ T Cells.

    Directory of Open Access Journals (Sweden)

    Yu Lei

    Full Text Available T follicular helper cells (Tfh provide help to B cells to support their activation, expansion and differentiation. However, the role of Tfh cells in chronic HBV infection is poorly defined. The aim of this research was to examine the function of Tfh cells and whether they are involved in HBV related disease. Blood CXCR5+CD4+T cells and B cells in 85 patients with chronic HBV infection (HBV patients and health controls (HC were examined by flow cytometry. The molecule expression in blood CXCR5+CD4+ T cells was detected by real-time PCR. Blood CXCR5+CD4+ T cells and B cells were co-cultured and the production of Ig and cytokines was detected by ELISA. Autoantibodies were detected by indirect immunofluorescence and immunospot assay. We found that blood CXCR5+CD4+ T cells in patients with chronic HBV infection (HBV patients expressed higher level of activation related molecules and cytokines than that from health controls (HC.In HBV patients, the frequency of blood CXCR5+CD4+ T cells was significantly correlated with serum ALT and AST. We also found that blood CXCR5+CD4+ T cells from HBV patients could induce B cells to secret higher level of immunoglobulin than that from HC. Several autoantibodies, including ANA, ss-A, ss-B, Scl-70, Jo-1, ect, were indeed positive in 65% HBV patients. Among HBV patients, expression of function related molecules was significantly higher in blood CXCR5+CD4+ T cells from patients with autoantibodies than that without autoantibodies. Our research indicated that blood CXCR5+CD4+ T cells from HBV patients were over activated and show augmented capacity to help B cells for antibody secreting, which might correlated with liver inflammation and the production of autoantibodies in extrahepatic manifestations.

  12. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion

    International Nuclear Information System (INIS)

    Thomas, Elaine R.; Dunfee, Rebecca L.; Stanton, Jennifer; Bogdan, Derek; Taylor, Joann; Kunstman, Kevin; Bell, Jeanne E.; Wolinsky, Steven M.; Gabuzda, Dana

    2007-01-01

    HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion

  13. Association between CD8 T-cell subsets and CD4/CD8 ratio with HS-CRP level in HIV-infected patients on antiretroviral therapy

    Science.gov (United States)

    Isabela, S.; Nugroho, A.; Harijanto, P. N.

    2018-03-01

    Due to improved access and adherence to antiretroviral therapy (ART), most HIV-infected persons worldwide are predicted to live longer. Nowadays the cause of death for most HIV-infected persons has changed to serious non-AIDS events (SNAEs) which is due to low-grade viremia. HIV patients with ART who had undergone CD4 cell count above 500/uL and there is an increase in hs-CRP despite an undetectable viral load. Some conditions CD8 cells count do not decrease with CD4 cells repairs. We researched in Prof Kandou General Hospital with a total sample of 35 HIV patients who had received ART with the level of CD4>350/uL. CD8 levels, CD4/CD8 ratio, and hs-CRP were assessed. This research is analytic descriptive with cross-sectional study design and analysis uses Spearman correlation. The mean CD8 during the study was 1291.8 (IQR 319-2610cells/uL), the mean ratio of CD4:CD8 was 0.57 (IQR 0.16-1.24) and median hs-CRP is 2.18 (IQR 0.3-6.6mg/dL). There was a significant positive correlation between CD8 and increased hs-CRP (r=0.369, pCD4/CD8 ratio and hs-CRP (r=-0.370, p<0.05).

  14. Increased Numbers of CD4+CD25+ and CD8+CD25+ T-Cells in Peripheral Blood of Patients with Rheumatoid Arthritis with Parvovirus B19 Infection.

    Science.gov (United States)

    Naciute, Milda; Maciunaite, Gabriele; Mieliauskaite, Diana; Rugiene, Rita; Zinkeviciene, Aukse; Mauricas, Mykolas; Murovska, Modra; Girkontaite, Irute

    2017-01-01

    To investigate T-cell subpopulations in peripheral blood of human parvovirus B19 DNA-positive (B19 + ) and -negative (B19 - ) patients with rheumatoid arthritis (RA) and healthy persons. Blood samples were collected from 115 patients with RA and 47 healthy volunteers; 27 patients with RA and nine controls were B19 + Cluster of differentiation (CD) 4, 8, 25 and 45RA were analyzed on blood cells. CD25 expression on CD4 + CD45RA + , CD4 + CD45RA - , CD8 + CD45RA + , CD8 + CD45RA - subsets were analyzed by flow cytometry. The percentage of CD25 low and CD25 hi cells was increased on CD4 + CD45RA + , CD4 + CD45RA - T-cells and the percentage of CD25 + cells was increased on CD8 + CD45RA + , CD8 + CD45RA - T-cells of B19 + patients with RA in comparison with B19 - patients and controls. Raised levels of CD4 and CD8 regulatory T-cells in B19 + RA patients could cause down-regulation of antiviral clearance mechanisms and lead to activation of persistent human parvovirus B19 infection in patients with RA. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. The T-cell accessory molecule CD4 recognizes a monomorphic determinant on isolated Ia

    DEFF Research Database (Denmark)

    Gay, D; Buus, S; Pasternak, J

    1988-01-01

    The membrane protein CD4 is commonly found on mature T cells specific for antigen in association with class II major histocompatibility complex (MHC; Ia) proteins. This correlation has led to the suggestion that CD4 binds to a monomorphic region of the Ia molecule on the antigen-presenting cell...... proteins into a planar membrane system, we show that different Ia molecules can greatly enhance the ability of a CD4+ but not a CD4- variant of this class I-restricted T hybrid to respond to isolated class I molecules. T-cell responses can be strongly augmented by the concurrent expression of CD4 on the T...... cell and any of four different Ia proteins on planar membranes, thus supporting the idea that CD4 binds to a monomorphic region of the Ia molecule and increases the avidity with which the T cell can interact with its target....

  16. Chronic exposure to water pollutant trichloroethylene increased epigenetic drift in CD4(+) T cells.

    Science.gov (United States)

    Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Reisfeld, Brad; Zurlinden, Todd J; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Cooney, Craig A

    2016-05-01

    Autoimmune disease and CD4(+) T-cell alterations are induced in mice exposed to the water pollutant trichloroethylene (TCE). We examined here whether TCE altered gene-specific DNA methylation in CD4(+) T cells as a possible mechanism of immunotoxicity. Naive and effector/memory CD4(+) T cells from mice exposed to TCE (0.5 mg/ml in drinking water) for 40 weeks were examined by bisulfite next-generation DNA sequencing. A probabilistic model calculated from multiple genes showed that TCE decreased methylation control in CD4(+) T cells. Data from individual genes fitted to a quadratic regression model showed that TCE increased gene-specific methylation variance in both CD4 subsets. TCE increased epigenetic drift of specific CpG sites in CD4(+) T cells.

  17. Chronic exposure to water pollutant trichloroethylene increased epigenetic drift in CD4+ T cells

    Science.gov (United States)

    Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Reisfeld, Brad; Zurlinden, Todd J; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Cooney, Craig A

    2016-01-01

    Aim: Autoimmune disease and CD4+ T-cell alterations are induced in mice exposed to the water pollutant trichloroethylene (TCE). We examined here whether TCE altered gene-specific DNA methylation in CD4+ T cells as a possible mechanism of immunotoxicity. Materials & methods: Naive and effector/memory CD4+ T cells from mice exposed to TCE (0.5 mg/ml in drinking water) for 40 weeks were examined by bisulfite next-generation DNA sequencing. Results: A probabilistic model calculated from multiple genes showed that TCE decreased methylation control in CD4+ T cells. Data from individual genes fitted to a quadratic regression model showed that TCE increased gene-specific methylation variance in both CD4 subsets. Conclusion: TCE increased epigenetic drift of specific CpG sites in CD4+ T cells. PMID:27092578

  18. NAD+ protects against EAE by regulating CD4+ T-cell differentiation

    Science.gov (United States)

    Tullius, Stefan G.; Biefer, Hector Rodriguez Cetina; Li, Suyan; Trachtenberg, Alexander J.; Edtinger, Karoline; Quante, Markus; Krenzien, Felix; Uehara, Hirofumi; Yang, Xiaoyong; Kissick, Haydn T.; Kuo, Winston P.; Ghiran, Ionita; de la Fuente, Miguel A.; Arredouani, Mohamed S.; Camacho, Virginia; Tigges, John C.; Toxavidis, Vasilis; El Fatimy, Rachid; Smith, Brian D.; Vasudevan, Anju; ElKhal, Abdallah

    2014-01-01

    CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases. PMID:25290058

  19. Bystander CD4+ T lymphocytes survive in HIV-infected human lymphoid tissue

    Science.gov (United States)

    Grivel, Jean-Charles; Biancotto, Angelique; Ito, Yoshinori; Lima, Rosangela G.; Margolis, Leonid B.

    2003-01-01

    HIV infection is associated with depletion of CD4(+) T cells. The mechanisms of this phenomenon remain to be understood. In particular, it remains controversial whether and to what extent uninfected ("bystander") CD4(+) T cells die in HIV-infected individuals. We address this question using a system of human lymphoid tissue ex vivo. Tissue blocks were inoculated with HIV-1. After productive infection was established, they were treated with the reverse transcriptase inhibitor nevirapine to protect from infection those CD4(+) T cells that had not yet been infected. These CD4(+) T cells residing in HIV-infected tissue are by definition bystanders. Our results demonstrate that after nevirapine application the number of bystander CD4(+) T cells is conserved. Thus, in the context of HIV-infected human lymphoid tissue, productive HIV infection kills infected cells but is not sufficient to cause the death of a significant number of uninfected CD4(+) T cells.

  20. Depletion of CD4+ T cells precipitates immunopathology in immunodeficient mice infected with a noncytocidal virus

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Bartholdy, C; Wodarz, D

    2001-01-01

    investigated whether CD4(+) Th cells are required to establish and maintain this new equilibrium. The absence of IFN-gamma does not impair the generation of IL-2-producing CD4(+) cells, and depletion of these cells precipitates severe CD8(+) T cell-mediated immunopathology in IFN-gamma(-/-) mice, indicating...... an important role of CD4(+) T cells in preventing this syndrome. Analysis of organ virus levels revealed a further impairment of virus control in IFN-gamma(-/-) mice following CD4(+) cell depletion. Initially the antiviral CTL response did not require CD4(+) cells, but with time an impaired reactivity toward...... especially the glycoprotein 33--41 epitope was noted. Enumeration of epitope-specific (glycoprotein 33--41 and nucleoprotein 396--404) CD8(+) T cells by use of tetramers gave similar results. Finally, limiting dilution analysis of CTL precursors reveal an impaired capacity to sustain this population in CD4...

  1. Preparation of anti-CD4 monoclonal antibody-conjugated magnetic poly(glycidyl methacrylate) particles and their application on CD4+ lymphocyte separation.

    Science.gov (United States)

    Pimpha, Nuttaporn; Chaleawlert-umpon, Saowaluk; Chruewkamlow, Nuttapol; Kasinrerk, Watchara

    2011-03-15

    Novel immunomagnetic particles have been prepared for separation of CD4(+) lymphocytes. The magnetic nanoparticles with a diameter of approximately 5-6 nm were first synthesized by co-precipitation from ferrous and ferric iron solutions and subsequently encapsulated with poly(glycidyl methacrylate) (PGMA) by precipitation polymerization. Monoclonal antibody specific to CD4 molecules expressed on CD4(+) lymphocytes was conjugated to the surface of magnetic PGMA particles through covalent bonding between epoxide functional groups on the particle surface and primary amine groups of the antibodies. The generated immunomagnetic particles have successfully separated CD4(+) lymphocytes from whole blood with over 95% purity. The results indicated that these particles can be employed for cell separation and provide a strong potential to be applied in various biomedical applications including diagnosis, and monitoring of human diseases. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. Genetic subspecies diversity of the chimpanzee CD4 virus-receptor gene

    DEFF Research Database (Denmark)

    Hvilsom, Christina; Carlsen, Frands; Siegismund, Hans R

    2008-01-01

    six among the subspecies of chimpanzees. We found the CD4 receptor to be conserved in individuals belonging to the P. t. verus subspecies and divergent from the other three subspecies, which harbored highly variable CD4 receptors. The CD4 receptor of chimpanzees differed from that of humans. We...... question whether the observed diversity can explain the species-specific differences in susceptibility to and pathogenicity of SIV/HIV....

  3. CLINICAL AND LABORATORY PROFILE OF PATIENTS WITH IDIOPATHIC CD4 LYMPHOCYTOPENIA- A RARE CLINICAL ENTITY

    OpenAIRE

    Vijayashree Thyagaraj; Karthik Ashok

    2017-01-01

    BACKGROUND Since 1989, several investigators have reported unusual cases of severe opportunistic infections associated with CD4 lymphocytopenia in the absence of human immunodeficiency virus infection. The cause of this condition is unknown. The Centres for Disease Control and Prevention (CDC) defines Idiopathic CD4 T Lymphocytopenia (ICL) as a clinical condition in which patients with depressed numbers of circulating CD4+ T-cell lymphocytes (

  4. Enteroantigen-presenting B cells efficiently stimulate CD4(+) T cells in vitro

    DEFF Research Database (Denmark)

    Schmidt, Esben Gjerløff Wedebye; Kristensen, Nanna Ny; Claesson, Mogens Helweg

    2011-01-01

    Presentation of enterobacterial antigens by antigen-presenting cells and activation of enteroantigen-specific CD4(+) T cells are considered crucial steps in inflammatory bowel disease (IBD) pathology. The detrimental effects of such CD4(+) T cells have been thoroughly demonstrated in models...... of colitis. Also, we have previously established an in vitro assay where murine enteroantigen-specific colitogenic CD4(+) CD25(-) T cells are activated by splenocytes pulsed with an enterobacterial extract....

  5. A DNA vaccine encoding multiple HIV CD4 epitopes elicits vigorous polyfunctional, long-lived CD4+ and CD8+ T cell responses.

    Directory of Open Access Journals (Sweden)

    Daniela Santoro Rosa

    Full Text Available T-cell based vaccines against HIV have the goal of limiting both transmission and disease progression by inducing broad and functionally relevant T cell responses. Moreover, polyfunctional and long-lived specific memory T cells have been associated to vaccine-induced protection. CD4(+ T cells are important for the generation and maintenance of functional CD8(+ cytotoxic T cells. We have recently developed a DNA vaccine encoding 18 conserved multiple HLA-DR-binding HIV-1 CD4 epitopes (HIVBr18, capable of eliciting broad CD4(+ T cell responses in multiple HLA class II transgenic mice. Here, we evaluated the breadth and functional profile of HIVBr18-induced immune responses in BALB/c mice. Immunized mice displayed high-magnitude, broad CD4(+/CD8(+ T cell responses, and 8/18 vaccine-encoded peptides were recognized. In addition, HIVBr18 immunization was able to induce polyfunctional CD4(+ and CD8(+ T cells that proliferate and produce any two cytokines (IFNγ/TNFα, IFNγ/IL-2 or TNFα/IL-2 simultaneously in response to HIV-1 peptides. For CD4(+ T cells exclusively, we also detected cells that proliferate and produce all three tested cytokines simultaneously (IFNγ/TNFα/IL-2. The vaccine also generated long-lived central and effector memory CD4(+ T cells, a desirable feature for T-cell based vaccines. By virtue of inducing broad, polyfunctional and long-lived T cell responses against conserved CD4(+ T cell epitopes, combined administration of this vaccine concept may provide sustained help for CD8(+ T cells and antibody responses- elicited by other HIV immunogens.

  6. Notch controls the survival of memory CD4+ T cells by regulating glucose uptake.

    Science.gov (United States)

    Maekawa, Yoichi; Ishifune, Chieko; Tsukumo, Shin-ichi; Hozumi, Katsuto; Yagita, Hideo; Yasutomo, Koji

    2015-01-01

    CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin κ J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake.

  7. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    Science.gov (United States)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-02-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

  8. Characterization of CD4+ T cell-mediated cytotoxicity in patients with multiple myeloma.

    Science.gov (United States)

    Zhang, Xiaole; Gao, Lei; Meng, Kai; Han, Chunting; Li, Qiang; Feng, Zhenjun; Chen, Lei

    2018-05-01

    Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38 + CD138 + plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Regulatory function of cytomegalovirus-specific CD4+CD27-CD28- T cells

    International Nuclear Information System (INIS)

    Tovar-Salazar, Adriana; Patterson-Bartlett, Julie; Jesser, Renee; Weinberg, Adriana

    2010-01-01

    CMV infection is characterized by high of frequencies of CD27 - CD28 - T cells. Here we demonstrate that CMV-specific CD4 + CD27 - CD28 - cells are regulatory T cells (T R ). CD4 + CD27 - CD28 - cells sorted from CMV-stimulated PBMC of CMV-seropositive donors inhibited de novo CMV-specific proliferation of autologous PBMC in a dose-dependent fashion. Compared with the entire CMV-stimulated CD4 + T-cell population, higher proportions of CD4 + CD27 - CD28 - T R expressed FoxP3, TGFβ, granzyme B, perforin, GITR and PD-1, lower proportions expressed CD127 and PD1-L and similar proportions expressed CD25, CTLA4, Fas-L and GITR-L. CMV-CD4 + CD27 - CD28 - T R expanded in response to IL-2, but not to CMV antigenic restimulation. The anti-proliferative effect of CMV-CD4 + CD27 - CD28 - T R significantly decreased after granzyme B or TGFβ inhibition. The CMV-CD4 + CD27 - CD28 - T R of HIV-infected and uninfected donors had similar phenotypes and anti-proliferative potency, but HIV-infected individuals had higher proportions of CMV-CD4 + CD27 - CD28 - T R . The CMV-CD4 + CD27 - CD28 - T R may contribute to the downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.

  10. CDC staging based on absolute CD4 count and CD4 percentage in an HIV-1-infected Indian population: treatment implications

    Science.gov (United States)

    Vajpayee, M; Kaushik, S; Sreenivas, V; Wig, N; Seth, P

    2005-01-01

    CD4+ T-cell levels are an important criterion for categorizing HIV-related clinical conditions according to the CDC classification system and are therefore important in the management of HIV by initiating antiretroviral therapy and prophylaxis for opportunistic infections due to HIV among HIV-infected individuals. However, it has been observed that the CD4 counts are affected by the geographical location, race, ethnic origin, age, gender and changes in total and differential leucocyte counts. In the light of this knowledge, we classified 600 HIV seropositive antiretroviral treatment (ART)-naïve Indian individuals belonging to different CDC groups A, B and C on the basis of CDC criteria of both CD4% and CD4 counts and receiver operating characteristic (ROC) curves were generated. Importantly, CDC staging on the basis of CD4% indicated significant clinical implications, requiring an early implementation of effective antiretroviral treatment regimen in HIV-infected individuals deprived of treatment when classified on the basis of CD4 counts. PMID:16045738

  11. Demonstration of strong enterobacterial reactivity of CD4+CD25- T cells from conventional and germ-free mice which is counter-regulated by CD4+CD25+ T cells

    DEFF Research Database (Denmark)

    Gad, Monika; Pedersen, Anders Elm; Kristensen, Nanna N

    2004-01-01

    Unfractionated CD4+ T cells from the gut-associated lymphoid tissue (GALT) and peripheral lymph nodes are unresponsive when exposed to enterobacterial antigens in vitro. Under similar conditions, CD4+ T cells depleted in vivo or in vitro of CD4+CD25+ T cells proliferate extensively. The CD4+CD25- T...

  12. IDENTIFICATION OF BACTERIA CAUSING DIARRHOEA IN HIV/AIDS PATIENTS AND ITS CORRELATION WITH CD4 COUNT

    Directory of Open Access Journals (Sweden)

    Anand Premanand

    2016-05-01

    Full Text Available BACKGROUND The number of HIV-positive patients is increasing in India. Data on the prevalence of diarrhoea and the spectrum of bacteria responsible for diarrhoea in HIV- positive patients is lacking in our area. The identification of enteric pathogens in patients with HIV/AIDS is important because an increasing array of therapeutic regimens is becoming available to treat many of these infections. Thus, an attempt is done to elucidate the associations between causative bacteria of acute and chronic diarrhoea and CD4 count. METHODS Stool specimens were obtained over a period of eighteen months from HIV infected adults with diarrhoea presenting to Shri B M Patil Medical College Hospital and Research Centre, Vijayapura. In all patients with diarrhoea, stool specimens were examined by microscopy and cultures to identify bacterial pathogens and blood sample was analysed for CD4 count. RESULTS A total of 80 individuals were enrolled in this study. Cases included 46 males and 34 females. Among the cases, maximum subjects were found to be in the age group of 30-40 years in which 23 (62.2% were males and 14 (37.8% were females. 56 had acute and 24 had chronic diarrhoea. The percentages of bacteria isolated were 5 (8.9% in acute and 16 (66.7% in chronic diarrhoea respectively. The most common bacteria isolated was E. Coli (17.5% followed by Klebsiella (5% and Shigella Sps (3.75%. Patients with chronic diarrhoea had lower CD4 cell counts. The maximum bacterial isolation was in the patients whose CD4 cell counts were below 200 cells/mm3. CONCLUSION Bacterial isolation was most strongly associated with low CD4 counts and chronic diarrhoea. E. coli was isolated maximum among all the bacteria in the HIV patients. Over two-thirds of diarrhoeal episodes were undiagnosed, suggesting that unidentified agents or primary HIV enteropathy are important causes of diarrhoea in this population. There is a strong negative association between duration of diarrhoea and CD4

  13. Music exposure induced prolongation of cardiac allograft survival and generated regulatory CD4⁺ cells in mice.

    Science.gov (United States)

    Uchiyama, M; Jin, X; Zhang, Q; Amano, A; Watanabe, T; Niimi, M

    2012-05-01

    In clinical practice, music has been used to decrease stress, heart rate, and blood pressure and to provide a distraction from disease symptoms. We investigated sound effects on alloimmune responses in murine heart transplantation. Naïve and eardrum-ruptured CBA/N (CBA, H2(K)) underwent transplantation of a C57BL/6 (B6, H2(b)) heart and were exposed to 1 of 3 types of music-opera (La Traviata), classical (Mozart), and New Age (Enya)-or 1 of 6 different single sound frequencies for 7 days. An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Cell-proliferation, cytokine, and flow cytometry assessments were also performed. CBA recipients of a B6 graft exposed to opera and classical music had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to 6 single sound frequencies and New Age did not (MSTs, 7, 8, 9, 8, 8, 8, and 11 days, respectively). Untreated and eardrum-ruptured CBA rejected B6 grafts acutely (MSTs, 7 and 8.5 days, respectively). Adoptive transfer of whole splenocytes, CD4(+) cells, and CD4(+)CD25(+) cells from opera-exposed primary recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and >50 days, respectively). Cell-proliferation, interleukin (IL)-2 and interferon-γ were suppressed in opera-exposed mice, whereas IL-4 and IL-10 from opera-exposed recipients were up-regulated. Flow cytometry studies showed an increased CD4(+)CD25(+)Foxp3(+) cell population in splenocytes from opera-exposed mice. In conclusion, exposure to some types of music may induce prolonged survival of fully allogeneic cardiac allografts and generate CD4(+)CD25(+)Foxp3(+) regulatory cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging.

    Science.gov (United States)

    Freise, Amanda C; Zettlitz, Kirstin A; Salazar, Felix B; Lu, Xiang; Tavaré, Richard; Wu, Anna M

    2017-08-01

    Molecular imaging of CD4 + T cells throughout the body has implications for monitoring autoimmune disease and immunotherapy of cancer. Given the key role of these cells in regulating immunity, it is important to develop a biologically inert probe. GK1.5 cys-diabody (cDb), a previously developed anti-mouse CD4 antibody fragment, was tested at different doses to assess its effects on positron emission tomography (PET) imaging and CD4 + T cell viability, proliferation, CD4 expression, and function. The effect of protein dose on image contrast (lymphoid tissue-to-muscle ratio) was assessed by administering different amounts of 89 Zr-labeled GK1.5 cDb to mice followed by PET imaging and ex vivo biodistribution analysis. To assess impact of GK1.5 cDb on T cell biology, GK1.5 cDb was incubated with T cells in vitro or administered intravenously to C57BL/6 mice at multiple protein doses. CD4 expression and T cell proliferation were analyzed with flow cytometry and cytokines were assayed. For immunoPET imaging, the lowest protein dose of 2 μg of 89 Zr-labeled GK1.5 cDb resulted in significantly higher % injected dose/g in inguinal lymph nodes (ILN) and spleen compared to the 12-μg protein dose. In vivo administration of GK1.5 cDb at the high dose of 40 μg caused a transient decrease in CD4 expression in spleen, blood, lymph nodes, and thymus, which recovered within 3 days postinjection; this effect was reduced, although not abrogated, when 2 μg was administered. Proliferation was inhibited in vivo in ILN but not the spleen by injection of 40 μg GK1.5 cDb. Concentrations of GK1.5 cDb in excess of 25 nM significantly inhibited CD4 + T cell proliferation and interferon-γ production in vitro. Overall, using low-dose GK1.5 cDb minimized biological effects on CD4 + T cells. Low-dose GK1.5 cDb yields high-contrast immunoPET images with minimal effects on T cell biology in vitro and in vivo and may be a useful tool for investigating CD4 + T cells in the context of

  15. A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV.

    Science.gov (United States)

    Triplette, Matthew; Attia, Engi F; Akgün, Kathleen M; Soo Hoo, Guy W; Freiberg, Matthew S; Butt, Adeel A; Wongtrakool, Cherry; Goetz, Matthew Bidwell; Brown, Sheldon T; Graber, Christopher J; Huang, Laurence; Crothers, Kristina

    2017-01-01

    The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio 10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era.

  16. Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy

    Directory of Open Access Journals (Sweden)

    Weihong Zeng

    2017-06-01

    Full Text Available Decidual CD4+ T (dCD4 T cells are crucial for the maternal-fetal immune tolerance required for a healthy pregnancy outcome. However, their molecular and functional characteristics are not well elucidated. In this study, we performed the first analysis of transcriptional and alternative splicing (AS landscapes for paired decidual and peripheral blood CD4+ T (pCD4 T cells in human early pregnancy using high throughput mRNA sequencing. Our data showed that dCD4 T cells are endowed with a unique transcriptional signature when compared to pCD4 T cells: dCD4 T cells upregulate 1,695 genes enriched in immune system process whereas downregulate 1,011 genes mainly related to mRNA catabolic process and the ribosome. Moreover, dCD4 T cells were observed to be at M phase, and show increased activation, proliferation, and cytokine production, as well as display an effector-memory phenotype and a heterogenous nature containing Th1, Th17, and Treg cell subsets. However, dCD4 T cells undergo a comparable number of upregulated and downregulated AS events, both of which are enriched in the genes related to cellular metabolic process. And the changes at the AS event level do not reflect measurable differences at the gene expression level in dCD4 T cells. Collectively, our findings provide a comprehensive portrait of the unique transcriptional signature and AS profile of CD4+ T cells in human decidua and help us gain more understanding of the functional characteristic of these cells during early pregnancy.

  17. McCoy cell line as a possible model containing CD4+ receptors for the study of HIV-1 replication

    Directory of Open Access Journals (Sweden)

    Nogueira Yeda L.

    2003-01-01

    Full Text Available Several studies have recently shown the use of recombinant rabies virus as potential vector-viral vaccine for HIV-1. The sequence homology between gp 120 and rabies virus glycoprotein has been reported. The McCoy cell line has therefore been used to show CD4+ or CD4+ like receptors. Samples of HIV-1 were isolated, when plasma of HIV-1 positive patients was inoculated in the McCoy cell line. The virus infection was then studied during successive virus passages. The proteins released in the extra cellular medium were checked for protein activity, by exposure to SDS Electrophoresis and blotting to nitro-cellulose filter, then reacting with sera of HIV positive and negative patients. Successive passages were performed, and showed viral replication, membrane permeabilization, the syncytium formation, and the cellular lysis (cytopathic effect. Flow cytometry analysis shows clear evidence that CD4+ receptors are present in this cell line, which enhances the likelihood of easy isolation and replication of HIV. The results observed allow the use of this cell line as a possible model for isolating HIV, as well as for carrying out studies of the dynamics of viral infection in several situations, including exposure to drugs in pharmacological studies, and possibly studies and analyses of the immune response in vaccine therapies.

  18. Inefficient Nef-mediated downmodulation of CD3 and MHC-I correlates with loss of CD4+T cells in natural SIV infection.

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    Michael Schindler

    2008-07-01

    Full Text Available Recent data suggest that Nef-mediated downmodulation of TCR-CD3 may protect SIVsmm-infected sooty mangabeys (SMs against the loss of CD4+ T cells. However, the mechanisms underlying this protective effect remain unclear. To further assess the role of Nef in nonpathogenic SIV infection, we cloned nef alleles from 11 SIVsmm-infected SMs with high (>500 and 15 animals with low (<500 CD4+ T-cells/microl in bulk into proviral HIV-1 IRES/eGFP constructs and analyzed their effects on the phenotype, activation, and apoptosis of primary T cells. We found that not only efficient Nef-mediated downmodulation of TCR-CD3 but also of MHC-I correlated with preserved CD4+ T cell counts, as well as with high numbers of Ki67+CD4+ and CD8+CD28+ T cells and reduced CD95 expression by CD4+ T cells. Moreover, effective MHC-I downregulation correlated with low proportions of effector and high percentages of naïve and memory CD8+ T cells. We found that T cells infected with viruses expressing Nef alleles from the CD4low SM group expressed significantly higher levels of the CD69, interleukin (IL-2 and programmed death (PD-1 receptors than those expressing Nefs from the CD4high group. SIVsmm Nef alleles that were less active in downmodulating TCR-CD3 were also less potent in suppressing the activation of virally infected T cells and subsequent cell death. However, only nef alleles from a single animal with very low CD4+ T cell counts rendered T cells hyper-responsive to activation, similar to those of HIV-1. Our data suggest that Nef may protect the natural hosts of SIV against the loss of CD4+ T cells by at least two mechanisms: (i downmodulation of TCR-CD3 to prevent activation-induced cell death and to suppress the induction of PD-1 that may impair T cell function and survival, and (ii downmodulation of MHC-I to reduce CTL lysis of virally infected CD4+ T cells and/or bystander CD8+ T cell activation.

  19. The influence of CD 4+t cells, hiv disease stage and zidovudine on hiv isolation in Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Carlos Brites

    1996-02-01

    Full Text Available HIV-l isolation was attempted on 72 individuais, including persons with knoum HIV infection and five without proven HIV infection but with indeterminate Western blot patterns, as well as on low-risk HIV seronegative persons. The ahility to detect HIV- 1 frorn culture supernatant by p24 antigen capture assay was evaluated by segregating patients by absolute CD4+ cell counts, clinicai stage of disease, p24 antigenemia and zidovudine use. The likelihood of a p24 positive HIV culture was highest among patients with CD4+ T-cell counts below 200/ul and patients with advanced clinical disease. Use of zidovudine did not affect the rate ofHIV positwity in cultures.Tentativa de isolamento do vírus tipo 1 da imunodeficiência adquirida (VIH-1 foi realizada em 72 indivíduos sendo 51 pacientes com sorologia positiva para o VIH-1, confirmada por Western blot; 5 doadores de sangue com padrão indeterminado ao Western blot; 3 indivíduos com diagnóstico clínico de AIDS, porém com sorologia negativa, e 13 profissionais de saúde soronegativos. Os pacientes foram estratificados de acordo com a contagem de células CD4+, estágio clínico , antigenemia (p24 e uso de zidovudine. As culturas para o VIH-1 foram positivas em 45/50 (90% tentativas. Houve uma correlação inversa entre o número de células CD4+ e a freqüência de isolamento do VIH-1. As culturas foram positivas em 84% dos indivíduos com CD4+ <200, contra 48% d positividade naqueles com contagem de célula CD4+ acima deste valor. O uso de zidovudine não interferiu na positividade das culturas. Concluímo. que a sensibilidade dos métodos de culture qualitativo e quantitativo é similar para a detecção do VIH-1. A taxa de positividade das culturas não foi afetada pelo uso prévio de zidovudine, mas foi diretamente proporcional ao grau de imunodeficiência dos pacientes.

  20. IFNγ-producing CD4+ T lymphocytes: the double-edged swords in tuberculosis.

    Science.gov (United States)

    Kumar, Pawan

    2017-12-01

    IFNγ-producing CD4 + T cells (IFNγ + CD4 + T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis (Mtb). Primarily, these cells act by enabling Mtb-infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNγ + CD4 + T cells in TB pathogenesis. High frequency of IFNγ + CD4 + T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNγ + CD4 + T cell response to mycobacterial antigens and demonstrate an IFNγ-inducible transcriptomic signature. IFNγ + CD4 + T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb-coinfected people. The pathological face of IFNγ + CD4 + T cells during mycobacterial infection is further uncovered by studies in the animal model of TB-IRIS and in Mtb-infected PD-1 -/- mice. This manuscript encompasses the evidence supporting the dual role of IFNγ + CD4 + T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis.

  1. Reactivity of naive CD4+CD25- T cells against gut microflora in healthy mice

    DEFF Research Database (Denmark)

    Gad, Monika; Lundsgaard, Dorthe; Kjellev, Stine

    2006-01-01

    We have previously shown that conventional as well as germ-free CD4+ T cells depleted of CD25+ cells from the gut-associated lymphoid tissue and the periphery proliferate specifically in response to enterobacterial antigen exposure whereas unfractionated CD4+ T cells are not reactive under...

  2. The Transcription Factor Hobit Identifies Human Cytotoxic CD4(+) T Cells

    NARCIS (Netherlands)

    Oja, Anna E.; Vieira Braga, Felipe A.; Remmerswaal, Ester B. M.; Kragten, Natasja A. M.; Hertoghs, Kirsten M. L.; Zuo, Jianmin; Moss, Paul A.; van Lier, René A. W.; van Gisbergen, Klaas P. J. M.; Hombrink, Pleun

    2017-01-01

    The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4(+) T cells that

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

    Science.gov (United States)

    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 ...

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

    Science.gov (United States)

    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...

  5. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells

    DEFF Research Database (Denmark)

    Baslund, B; Gregers, J; Nielsen, Claus Henrik

    2008-01-01

    To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.......To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells....

  6. Chronic exposure to trichloroethylene increases DNA methylation of the Ifng promoter in CD4+ T cells.

    Science.gov (United States)

    Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Li, Jingyun; Cooney, Craig A

    2016-10-17

    CD4 + T cells in female MRL+/+ mice exposed to solvent and water pollutant trichloroethylene (TCE) skew toward effector/memory CD4 + T cells, and demonstrate seemingly non-monotonic alterations in IFN-γ production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naïve CD4 + T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5mg/ml in drinking water). A time-dependent effect of TCE exposure on both Ifng gene expression and IFN-γ protein production was observed in effector/memory CD4 + T cells, with an increase after 22 weeks of exposure and a decrease after 40 weeks of exposure. No such effect of TCE was observed in naïve CD4 + T cells. A cumulative increase in DNA methylation in the CpG sites of the promoter of the Ifng gene was observed in effector/memory, but not naïve, CD4 + T cells over time. Also unique to the Ifng promoter was an increase in methylation variance in effector/memory compared to naïve CD4 + T cells. Taken together, the CpG sites of the Ifng promoter in effector/memory CD4 + T cells were especially sensitive to the effects of TCE exposure, which may help explain the regulatory effect of the chemical on this gene. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. The differentiation and protective function of cytolytic CD4 T cells in influenza infection

    Science.gov (United States)

    CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity play a role in chronic, as well as, acute infections...

  8. Non-traditional CD4+CD25-CD69+ regulatory T cells are correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Zhao, Xiao-su; Wang, Xu-hua; Zhao, Xiang-yu; Chang, Ying-jun; Xu, Lan-ping; Zhang, Xiao-hui; Huang, Xiao-jun

    2014-07-01

    Non-traditional CD4+CD25-CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT). The frequency of CD4+CD25-CD69+ T cells among the CD4+ T cell population from the bone marrow of relapsed patients, patients with positive minimal residual disease (MRD+) and healthy donors was examined by flow cytometry. The CD4+CD25-CD69+ T cells were also stained with the intracellular markers to determine the cytokine (TGF-β, IL-2 and IL-10) secretion. The results showed that the frequency of CD4+CD25-CD69 + T cells was markedly increased in patients in the relapsed group and the MRD + group compared to the healthy donor group. The percentage of this subset of T cells was significantly decreased after effective intervention treatment. We also analyzed the reconstitution of CD4+CD25-CD69+ T cells at various time points after allo-HSCT, and the results showed that this subset of T cells reconstituted rapidly and reached a relatively higher level at +60 d in patients compared to controls. The incidence of either MRD+ or relapse in patients with a high frequency of CD4+CD25-CD69+ T cells (>7%) was significantly higher than that of patients with a low frequency of CD4+CD25-CD69+ T cells at +60 d, +90 d and +270 d after transplant. However, our preliminary data indicated that CD4+CD25-CD69+ T cells may not exert immunoregulatory function via cytokine secretion. This study provides the first clinical evidence of a correlation between non-traditional CD4+CD25-CD69+ Tregs and leukemia relapse after allo-HSCT and suggests that exploration of new methods of adoptive immunotherapy may be beneficial. Further research related to regulatory mechanism behind this phenomenon would be necessary.

  9. CD4+ and CD8+ T cells can act separately in tumour rejection after immunization with murine pneumotropic virus chimeric Her2/neu virus-like particles.

    Directory of Open Access Journals (Sweden)

    Kalle Andreasson

    Full Text Available BACKGROUND: Immunization with murine pneumotropic virus virus-like particles carrying Her2/neu (Her2MPtVLPs prevents tumour outgrowth in mice when given prophylactically, and therapeutically if combined with the adjuvant CpG. We investigated which components of the immune system are involved in tumour rejection, and whether long-term immunological memory can be obtained. METHODOLOGY AND RESULTS: During the effector phase in BALB/c mice, only depletion of CD4+ and CD8+ in combination, with or without NK cells, completely abrogated tumour protection. Depletion of single CD4+, CD8+ or NK cell populations only had minor effects. During the immunization/induction phase, combined depletion of CD4+ and CD8+ cells abolished protection, while depletion of each individual subset had no or negligible effect. When tumour rejection was studied in knock-out mice with a C57Bl/6 background, protection was lost in CD4-/-CD8-/- and CD4-/-, but not in CD8-/- mice. In contrast, when normal C57Bl/6 mice were depleted of different cell types, protection was lost irrespective of whether only CD4+, only CD8+, or CD4+ and CD8+ cells in combination were eradicated. No anti-Her2/neu antibodies were detected but a Her2/neu-specific IFNgamma response was seen. Studies of long-term memory showed that BALB/c mice could be protected against tumour development when immunized together with CpG as long as ten weeks before challenge. CONCLUSION: Her2MPtVLP immunization is efficient in stimulating several compartments of the immune system, and induces an efficient immune response including long-term memory. In addition, when depleting mice of isolated cellular compartments, tumour protection is not as efficiently abolished as when depleting several immune compartments together.

  10. Isolation and evaluation of Candida species and their association with CD4+ T cells counts in HIV patients with diarrhoea.

    Science.gov (United States)

    Awoyeni, Ayobami; Olaniran, Olarinde; Odetoyin, Babatunde; Hassan-Olajokun, Rachel; Olopade, Bolatito; Afolayan, David; Adekunle, Oluwakayode

    2017-06-01

    Gastrointestinal infection is one of the most common infections among HIV patients. Candida spp have been implicated in the aetiology of chronic diarrhoea in HIV patients, but little is known about this in Nigeria. We determined the prevalence of faecal candidiasis in HIV patients in relation to diarrhoea, CD4 counts, and other socio-demographic factors and the spectrum of Candida isolates involved. One hundred and fifty four HIV patients were investigated. Candida species were identified by standard techniques. Socio-demographic and clinical information was obtained from the patients using a structured questionnaire. The CD4 count was estimated using a single platform flow cytometer. Candida overgrowth was detected in 61 (39.5%) HIV patients, and diarrhoea was associated with candidiasis in the subjects (P=0.001). Candidiasis was commonly detected among subjects in the 29-39 years' age group. A CD4 count below 200 cells/mm 2 (62.3%) was a risk factor for acquiring candidiasis among HIV patients (P=0.001). Candida albicans (65.6%) was the most frequently recovered species followed by Candida krusei (16.4%) and Candida tropicalis (14.8%). Candidiasis is an important opportunistic infection in HIV-patients in Ile-Ife. There is need for regular checks for opportunistic infections, including candidiasis in HIV patients to monitor disease progression and prevent subsequent complications.

  11. CD4-independent use of the CCR5 receptor by sequential primary SIVsm isolates

    Directory of Open Access Journals (Sweden)

    Thorstensson Rigmor

    2007-07-01

    Full Text Available Abstract Background CD4-independence has been taken as a sign of a more open envelope structure that is more accessible to neutralizing antibodies and may confer altered cell tropism. In the present study, we analyzed SIVsm isolates for CD4-independent use of CCR5, mode of CCR5-use and macrophage tropism. The isolates have been collected sequentially from 13 experimentally infected cynomolgus macaques and have previously been shown to use CCR5 together with CD4. Furthermore, viruses obtained early after infection were neutralization sensitive, while neutralization resistance appeared already three months after infection in monkeys with progressive immunodeficiency. Results Depending whether isolated early or late in infection, two phenotypes of CD4-independent use of CCR5 could be observed. The inoculum virus (SIVsm isolate SMM-3 and reisolates obtained early in infection often showed a pronounced CD4-independence since virus production and/or syncytia induction could be detected directly in NP-2 cells expressing CCR5 but not CD4 (CD4-independent-HIGH. Conversely, late isolates were often more CD4-dependent in that productive infection in NP-2/CCR5 cells was in most cases weak and was revealed only after cocultivation of infected NP-2/CCR5 cells with peripheral blood mononuclear cells (CD4-independent-LOW. Considering neutralization sensitivity of these isolates, newly infected macaques often harbored virus populations with a CD4-independent-HIGH and neutralization sensitive phenotype that changed to a CD4-independent-LOW and neutralization resistant virus population in the course of infection. Phenotype changes occurred faster in progressor than long-term non-progressor macaques. The phenotypes were not reflected by macrophage tropism, since all isolates replicated efficiently in macrophages. Infection of cells expressing CCR5/CXCR4 chimeric receptors revealed that SIVsm used the CCR5 receptor in a different mode than HIV-1. Conclusion Our

  12. CD4 T cell knockout does not protect against kidney injury and worsens cancer.

    Science.gov (United States)

    Ravichandran, Kameswaran; Wang, Qian; Ozkok, Abdullah; Jani, Alkesh; Li, Howard; He, Zhibin; Ljubanovic, Danica; Weiser-Evans, Mary C; Nemenoff, Raphael A; Edelstein, Charles L

    2016-04-01

    Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low-dose cisplatin-induced AKI in mice with cancer. Kidney function, serum neutrophil gelatinase-associated lipocalin (NGAL), acute tubular necrosis (ATN), and tubular apoptosis score were the same in wild-type and CD4 -/- mice with AKI. The lack of protection against AKI in CD4 -/- mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38, CXCL1, and TNF-α, mediators of AKI and fibrosis, in both cisplatin-treated CD4 -/- mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and cisplatin had an impaired therapeutic effect on the tumors in CD4 -/- vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to cisplatin. In summary, in a clinically relevant model of cisplatin-induced AKI in mice with cancer, (1) CD4 -/- mice were not protected against AKI; (2) ERK, p38, CXCL1, and TNF-α, known mediators of AKI, and interstitial fibrosis were increased in CD4 -/- kidneys; and (3) CD4 -/- mice had faster tumor growth and an impaired therapeutic effect of cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer. A clinically relevant low-dose cisplatin model of AKI in mice with cancer was used. CD4 -/- mice were not functionally or histologically protected against AKI. CD4 -/- mice had faster tumor growth. CD4 -/- mice had an impaired therapeutic effect of cisplatin on the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.

  13. Detection of resistance mutations and CD4 slopes in individuals experiencing sustained virological failure

    DEFF Research Database (Denmark)

    Schultze, Anna; Paredes, Roger; Sabin, Caroline

    2014-01-01

    during the episode were included. Mutations were identified using the IAS-US (2013) list, and were presumed to be present from detection until the end of an episode. Multivariable linear mixed models with a random intercept and slope adjusted for age, baseline CD4 count, hepatitis C, drug type, RNA (log...... mutations on CD4 slopes in patients undergoing episodes of viral failure. MATERIALS AND METHODS: Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test......-scale), risk group and subtype were used to estimate CD4 slopes. Individual mutations with a population prevalence of >10% were tested for their effect on the CD4 slope. RESULTS: A total of 2731 patients experiencing a median of 1 (range 1-4) episodes were included in this analysis. The prevalence of any...

  14. Identification of IFN-gamma-producing CD4+ T cells following PMA stimulation

    DEFF Research Database (Denmark)

    Kemp, K; Bruunsgaard, H

    2001-01-01

    Treatment of T cells with phorbol esters, such as phorbol myristate acetate (PMA), induces downregulation of CD4, making unambiguous identification of this subset difficult. In this study, the kinetics of intracellular expression of interferon-gamma (IFN-gamma) and downmodulation of surface CD4...... were measured in peripheral blood mononuclear cells (PBMC) after PMA stimulation. The number of IFN-gamma-producing cells increased within a 4-h period while the fluorescence intensity of the CD4(+) cell population decreased, and the two phenomena were correlated (n = 9; p = 0.01). Our data suggest...... that intracellular staining of CD4 together with cytokine staining will make identification of CD4(+) cells possible and facilitate the procedure of intracellular staining of cytokines....

  15. Influence of Ephemeris Error on GPS Single Point Positioning Accuracy

    Science.gov (United States)

    Lihua, Ma; Wang, Meng

    2013-09-01

    The Global Positioning System (GPS) user makes use of the navigation message transmitted from GPS satellites to achieve its location. Because the receiver uses the satellite's location in position calculations, an ephemeris error, a difference between the expected and actual orbital position of a GPS satellite, reduces user accuracy. The influence extent is decided by the precision of broadcast ephemeris from the control station upload. Simulation analysis with the Yuma almanac show that maximum positioning error exists in the case where the ephemeris error is along the line-of-sight (LOS) direction. Meanwhile, the error is dependent on the relationship between the observer and spatial constellation at some time period.

  16. A novel differentiation pathway from CD4⁺ T cells to CD4⁻ T cells for maintaining immune system homeostasis.

    Science.gov (United States)

    Zhao, X; Sun, G; Sun, X; Tian, D; Liu, K; Liu, T; Cong, M; Xu, H; Li, X; Shi, W; Tian, Y; Yao, J; Guo, H; Zhang, D

    2016-04-14

    CD4(+) T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4(+) T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4(-)CD8(-)NK1.1(-) double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4(+) rather than CD8(+) T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4(+) T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases.

  17. CD4+ T cell-derived novel peptide Thp5 induces interleukin-4 production in CD4+ T cells to direct T helper 2 cell differentiation.

    Science.gov (United States)

    Khan, Mohd Moin; Chatterjee, Samit; Dwivedi, Ved Prakash; Pandey, Nishant Kumar; Singh, Yogesh; Tousif, Sultan; Bhavesh, Neel Sarovar; Van Kaer, Luc; Das, Jyoti; Das, Gobardhan

    2012-01-20

    The differentiation of naïve CD4(+) T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naïve/quiescently activated CD4(+) T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naïve T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4(+) T cells. Induction of IL-4 in CD4(+) T cells by Thp5 is independent of the transcription factor STAT6 but dependent on ERK1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation in mice. Taken together, our findings reveal that early activated CD4(+) T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype.

  18. The Differentiation and Protective Function of Cytolytic CD4 T Cells in Influenza Infection

    Directory of Open Access Journals (Sweden)

    Deborah M. Brown

    2016-03-01

    Full Text Available CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity (CD4 CTL play a role in chronic, as well as, acute infections such as influenza A virus (IAV infection. In the last couple of decades, techniques to measure the frequency and activity of these cytolytic cells has demonstrated their abundance in infections such as HIV, mouse pox, murine gamma herpes virus, CMV, EBV and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and anti-tumor immunity through their ability to acquire perforin mediated cytolytic activity and contribution to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological relevance of CD4 CTL. Here, we discuss the direct role CD4 CTL play in protection against lethal IAV infection and the factors that drive the generation of perforin mediated lytic activity in CD4 cells in vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other anti-viral and anti-tumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell mediated immune protection against heterosubtypic IAV infection.

  19. Systematic Protein-Protein Docking and Molecular Dynamics Studies of HIV-1 gp120 and CD4: Insights for New Drug Development

    Directory of Open Access Journals (Sweden)

    M. Rizman-Idid

    2011-12-01

    Full Text Available Background and the purpose of the study: The interactions between HIV-1 gp120 and mutated CD4 proteins were investigated in order to identify a lead structure for therapy based on competitive blocking of the HIV binding receptor for human T-cells. Crystal structures of HIV gp120-CD4 complexes reveal a close interaction of the virus receptor with CD4 Phe43, which is embedded in a pocket of the virus protein.Methods: This study applies computer simulations to determine the best binding of amino acid 43 CD4 mutants to HIV gp120. Besides natural CD4, three mutants carrying alternate aromatic residues His, Trp and Tyr at position 43 were investigated. Several docking programs were applied on isolated proteins based on selected crystal structures of gp120-CD4 complexes, as well as a 5 ns molecular dynamics study on the protein complexes. The initial structures were minimized in Gromacs to avoid crystal packing effects, and then subjected to docking experiments using AutoDock4, FireDock, ClusPro and ZDock. In molecular dynamics, the Gibbs free binding energy was calculated for the gp120-CD4 complexes. The docking outputs were analyzed on energy within the respective docking software.Results and conclusion: Visualization and hydrogen bonding analysis were performed using the Swiss-PdbViewer. Strong binding to HIV gp120 can be achieved with an extended aromatic group (Trp. However, the sterical demand of the interaction affects the binding kinetics. In conclusion, a ligand for an efficient blocking of HIV gp120 should involve an extended but conformational flexible aromatic group, i.e. a biphenyl. A docking study on biphenylalanine-43 confirms this expectation

  20. Diagnostic Performance of Bronchoalveolar Lavage Fluid CD4/CD8 Ratio for Sarcoidosis: A Meta-analysis.

    Science.gov (United States)

    Shen, Yongchun; Pang, Caishuang; Wu, Yanqiu; Li, Diandian; Wan, Chun; Liao, Zenglin; Yang, Ting; Chen, Lei; Wen, Fuqiang

    2016-06-01

    The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed a meta-analysis to estimate the overall diagnostic accuracy of BALF CD4/CD8 ratio based on the bulk of published evidence. Studies published prior to June 2015 and indexed in PubMed, OVID, Web of Science, Scopus and other databases were evaluated for inclusion. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Deeks's funnel plot was used to detect publication bias. Sixteen publications with 1885 subjects met our inclusion criteria and were included in this meta-analysis. Summary estimates of the diagnostic performance of the BALF CD4/CD8 ratio were as follows: sensitivity, 0.70 (95%CI 0.64-0.75); specificity, 0.83 (95%CI 0.78-0.86); PLR, 4.04 (95%CI 3.13-5.20); NLR, 0.36 (95%CI 0.30-0.44); and DOR, 11.17 (95%CI 7.31-17.07). The area under the SROC curve was 0.84 (95%CI 0.81-0.87). There was no evidence of publication bias. Measuring the BALF CD4/CD8 ratio may assist in the diagnosis of sarcoidosis when interpreted in parallel with other diagnostic factors. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts.

    Science.gov (United States)

    Wright, Edwina J; Grund, Birgit; Robertson, Kevin R; Cysique, Lucette; Brew, Bruce J; Collins, Gary L; Poehlman-Roediger, Mollie; Vjecha, Michael J; Penalva de Oliveira, Augusto César; Standridge, Barbara; Carey, Cate; Avihingsanon, Anchalee; Florence, Eric; Lundgren, Jens D; Arenas-Pinto, Alejandro; Mueller, Nicolas J; Winston, Alan; Nsubuga, Moses S; Lal, Luxshimi; Price, Richard W

    2018-05-15

    To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl. Randomized trial. The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350 cells/μl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. The 592 participants had a median age of 34 years; median baseline CD4 count was 629 cells/μl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, P = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (P < 0.001 for increase from baseline). We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/μl.

  2. Gene variation in IL-7 receptor (IL-7R)α affects IL-7R response in CD4+ T cells in HIV-infected individuals

    DEFF Research Database (Denmark)

    Hartling, Hans Jakob; Ryder, Lars P.; Ullum, Henrik

    2017-01-01

    Optimal CD4+ T cell recovery after initiating combination antiretroviral treatment (cART) in HIV infection reduces risk of morbidity and mortality. T-allele homozygosity (‘TT’) in the single nucleotide polymorphism, rs6897932(C/T), in the IL-7 receptor α (IL-7RA) is associated with faster CD4+ T...... cell recovery after cART initiation compared to C-allele homozygosity in rs6897932 (‘CC’). However, underlying mechanisms are unknown. We aimed to examine potential mechanisms explaining the association between rs6897932 and CD4+ T cell recovery. Ten ‘TT’ and 10 ‘CC’ HIV-infected individuals matched...... on gender, age, and nadir and current CD4+ T cell counts were included in a cross-sectional study. ‘TT’ individuals had higher proportion of CD4+ T cells expressing pSTAT5 compared to ‘CC’ individuals after stimulating with IL-7, especially when co-stimulated with soluble IL7-RA (sIL-7RA). Furthermore, ‘TT...

  3. Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection

    Science.gov (United States)

    Niu, Qingli; Hou, Wei; Churchyard, Gavin; Nitayaphan, Sorachai; Pitisuthithum, Punnee; Rerks-Ngarm, Supachai; Franchini, Genoveffa

    2018-01-01

    The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector-specific CD4 T cells in the HVTN204 trial. We showed that while Ad5 vector-specific CD4 T cells were readily susceptible to HIV, ALVAC-specific CD4 T cells in RV144 PBMC were substantially less susceptible to both R5 and X4 HIV in vitro. The lower HIV susceptibility of ALVAC-specific CD4 T cells was associated with the reduced surface expression of HIV entry co-receptors CCR5 and CXCR4 on these cells. Phenotypic analyses identified that ALVAC-specific CD4 T cells displayed a strong Th1 phenotype, producing higher levels of IFN-γ and CCL4 (MIP-1β) but little IL-17. Of interest, ALVAC and Ad5 vectors induced distinct profiles of vector-specific CD8 vs. CD4 T-cell proliferative responses in PBMC, with ALVAC preferentially inducing CD8 T-cell proliferation, while Ad5 vector induced CD4 T-cell proliferation. Depletion of ALVAC-, but not Ad5-, induced CD8 T cells in PBMC led to a modest increase in HIV infection of vector-specific CD4 T cells, suggesting a role of ALVAC-specific CD8 T cells in protecting ALVAC-specific CD4 T cells from HIV. Taken together, our data provide strong evidence for distinct HIV susceptibility of CD4 T cells induced by different vaccine vectors and highlight the importance of better evaluating anti-vector responses in HIV vaccination. PMID:29474461

  4. Polymorphism in interleukin-7 receptor α gene is associated with faster CD4 T-cell recovery after initiation of combination antiretroviral therapy

    DEFF Research Database (Denmark)

    Hartling, Hans J; Thørner, Lise W; Erikstrup, Christian

    2014-01-01

    OBJECTIVES: To investigate single-nucleotide polymorphisms (SNPs) in the gene encoding interleukin-7 receptor α (IL7RA) as predictors for CD4⁺ T-cell change after initiation of combination antiretroviral therapy (cART) in HIV-infected whites. DESIGN: SNPs in IL7RA were determined in the Danish HIV...

  5. Analysis of HIV disease burden by calculating the percentages of patients with CD4 counts <100 cells/µL across 52 districts reveals hot spots for intensified commitment to programmatic support

    Directory of Open Access Journals (Sweden)

    Lindi Marie Coetzee

    2017-06-01

    Full Text Available Background. South Africa (SA’s Comprehensive HIV and AIDS Care, Management and Treatment (CCMT programme has reduced new HIV infections and HIV-related deaths. In spite of progress made, 11.2% of South Africans (4.02 million were living with HIV in 2015. Objective. The National Health Laboratory Service (NHLS in SA performs CD4 testing in support of the CCMT programme and collates data through the NHLS Corporate Data Warehouse. The objective of this study was to assess the distribution of CD4 counts 500 cells/µL (as an HIV-positive ‘wellness’ indicator. Methods. CD4 data were extracted for the financial years 2010/11 and 2014/15, according to the district where the test was ordered, for predefined CD4 ranges. National and provincial averages of CD4 counts 500 cells/µL were calculated. Data were analysed using Stata 12 and mapping was done with ArcGIS software, reporting percentages of CD4 counts 500 cells/µL by district. Results. The national average percentage of patients with CD4 counts 500 cells/µL (by 57%. District-by-district analysis showed that in 2010/11, 44/52 districts had >10% of CD4 samples with counts 500 cells/µL. In contrast, in 2014/15, the highest percentages of CD4 counts 500 cells/µL were also noted. Conclusions. The percentages of CD4 counts <100 cells/µL highlighted here reveal districts with positive change suggestive of programmatic improvements, and also highlight districts requiring local interventions to achieve the UNAIDS/SA National Department of Health 90-90-90 HIV treatment goals. The study further underscores the value of using NHLS laboratory data, an underutilised national resource, to leverage laboratory test data to enable a more comprehensive understanding of programme-specific health indicators.

  6. Underwater target positioning with a single acoustic sensor

    Digital Repository Service at National Institute of Oceanography (India)

    David, M-S; Pascoal, A.M.; Joaquin, A.

    The availability of reliable underwater positioning systems to localize one or more vehicles simultaneously based on information received on-board a support ship or an autonomous surface vessel is key to the operation of some classes of AUVs...

  7. Psychopatholgy, fundamental assumptions and CD-4 T lymphocyte ...

    African Journals Online (AJOL)

    In addition, we explored whether psychopathology and negative fundamental assumptions in ... Method: Self-rating questionnaires to assess depressive symptoms, ... associated with all participants scoring in the positive range of the FA scale.

  8. Human umbilical cord mesenchymal stem cells increase interleukin-9 production of CD4+ T cells

    Science.gov (United States)

    Yang, Zhou Xin; Chi, Ying; Ji, Yue Ru; Wang, You Wei; Zhang, Jing; Luo, Wei Feng; Li, Li Na; Hu, Cai Dong; Zhuo, Guang Sheng; Wang, Li Fang; Han, Zhi-Bo; Han, Zhong Chao

    2017-01-01

    Mesenchymal stem cells (MSC) are able to differentiate into cells of multiple lineage, and additionally act to modulate the immune response. Interleukin (IL)-9 is primarily produced by cluster of differentiation (CD)4+ T cells to regulate the immune response. The present study aimed to investigate the effect of human umbilical cord derived-MSC (UC-MSC) on IL-9 production of human CD4+ T cells. It was demonstrated that the addition of UC-MSC to the culture of CD4+ T cells significantly enhanced IL-9 production by CD4+ T cells. Transwell experiments suggested that UC-MSC promotion of IL-9 production by CD4+ T cells was dependent on cell-cell contact. Upregulated expression of CD106 was observed in UC-MSC co-cultured with CD4+ T cells, and the addition of a blocking antibody of CD106 significantly impaired the ability of UC-MSC to promote IL-9 production by CD4+ T cells. Therefore, the results of the present study demonstrated that UC-MSC promoted the generation of IL-9 producing cells, which may be mediated, in part by CD106. The findings may act to expand understanding and knowledge of the immune modulatory role of UC-MSC. PMID:29042945

  9. Cell-Intrinsic Roles for Autophagy in Modulating CD4 T Cell Functions

    Directory of Open Access Journals (Sweden)

    Elise Jacquin

    2018-05-01

    Full Text Available The catabolic process of autophagy plays important functions in inflammatory and immune responses by modulating innate immunity and adaptive immunity. Over the last decade, a cell-intrinsic role for autophagy in modulating CD4 T cell functions and differentiation was revealed. After the initial observation of autophagosomes in effector CD4 T cells, further work has shown that not only autophagy levels are modulated in CD4 T cells in response to environmental signals but also that autophagy critically affects the biology of these cells. Mouse models of autophagy deletion in CD4 T cells have indeed shown that autophagy is essential for CD4 T cell survival and homeostasis in peripheral lymphoid organs. Furthermore, autophagy is required for CD4 T cell proliferation and cytokine production in response to T cell receptor activation. Recent developments have uncovered that autophagy controls CD4 T cell differentiation and functions. While autophagy is required for the maintenance of immunosuppressive functions of regulatory T cells, it restrains the differentiation of TH9 effector cells, thus limiting their antitumor and pro-inflammatory properties. We will here discuss these findings that collectively suggest that therapeutic strategies targeting autophagy could be exploited for the treatment of cancer and inflammatory diseases.

  10. Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Shicheng Su; Ling Lin; Yunjie Zeng; Nengtai Ouyang; Xiuying Cui; Herui Yao; Fengxi Su; Jian-dong Huang; Judy Lieberman; Qiang Liu; Erwei Song; Jianyou Liao; Jiang Liu; Di Huang; Chonghua He; Fei Chen; LinBing Yang; Wei Wu; Jianing Chen

    2017-01-01

    The origin of tumor-infiltrating Tregs,critical mediators of tumor immunosuppression,is unclear.Here,we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires,while hardly overlap with circulating Tregs,suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs.Furthermore,the abundance of naive CD4+ T cells and Tregs is closely correlated,both indicating poor prognosis for breast cancer patients.Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCLl8-producing macrophages.Moreover,adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner.In human breast cancer xenografts in humanized mice,blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3,a CCL18 receptor,significantly reduces intratumoral Tregs and inhibits tumor progression.These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ.Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.

  11. Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer

    Science.gov (United States)

    Su, Shicheng; Liao, Jianyou; Liu, Jiang; Huang, Di; He, Chonghua; Chen, Fei; Yang, LinBing; Wu, Wei; Chen, Jianing; Lin, Ling; Zeng, Yunjie; Ouyang, Nengtai; Cui, Xiuying; Yao, Herui; Su, Fengxi; Huang, Jian-dong; Lieberman, Judy; Liu, Qiang; Song, Erwei

    2017-01-01

    The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy. PMID:28290464

  12. Comparative study of CD4 and CD45RO T cells and CD20 B cells in cerebrospinal fluid of syphilitic meningitis and tuberculous meningitis patients.

    Science.gov (United States)

    Yu, Nian; Zhang, Qiao-Quan; Zhang, Kang; Xie, Yuan; Zhu, Hai-Qing; Lin, Xing-Jian; Di, Qing

    2016-09-01

    This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p CD4 T-cell proportion in both groups (p CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p CD45RO T cells was increased in the CSF of both group patients (p cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  13. FoxP3 mRNA splice forms in synovial CD4+ T cells in rheumatoid arthritis and psoriatic arthritis

    DEFF Research Database (Denmark)

    Ryder, L Rebekka; Bartels, Else Marie; Woetmann, Anders

    2012-01-01

    Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real-time PCR method. CD4+ T cells were isolated from 17 paired...... samples of PB and SF from RA and PsA patients, and PB from 10 controls. FoxP3fl and FoxP3Δ2 mRNA was significantly increased (6.7 and 2.1-fold, respectively) in PB CD4+ T cells from RA patients compared to controls. FoxP3fl and Δ2 mRNA in SF CD4+ T cells was increased compared to controls in sero......-negative RA and PsA, but not in sero-positive RA patients, who had a high FoxP3 expression in both PB and SF. The FoxP3Δ2Δ7 mRNA was barely detectable in patient samples, and not at all in healthy individuals. We provide evidence of an increased expression of FoxP3 splice forms in synovial CD4+ T cells from...

  14. Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent.

    Directory of Open Access Journals (Sweden)

    Christine M Freeman

    Full Text Available Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry; by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent. Aberrant lung CD4+ T cells polarization appears to be common in advanced

  15. Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.

    Science.gov (United States)

    Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie; Krauss-Etschmann, Susanne

    2017-11-01

    Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2 + CD4 + T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2 + cell populations might either increase or decrease disease pathogenesis depending on their subtype. To investigate the role of CCR2 + CD4 + T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. Pulmonary CCR2 + CD4 + T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. Frequencies of CCR2 + CD4 + T cells were increased in experimental fibrosis-specifically the CD62L - CD44 + effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2 + CD4 + T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2 + CD4 + T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3 + CD25 + cells within bronchoalveolar lavage fluid CCR2 + CD4 + T cells as compared with CCR2 - CD4 + T cells. Pulmonary CCR2 + CD4 + T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  16. IL-7 signaling imparts polyfunctionality and stemness potential to CD4+ T cells

    Science.gov (United States)

    Ding, Zhi-Chun; Liu, Chufeng; Cao, Yang; Habtetsion, Tsadik; Kuczma, Michal; Pi, Wenhu; Kong, Heng; Cacan, Ercan; Greer, Susanna F.; Cui, Yan; Blazar, Bruce R.; Munn, David H.; Zhou, Gang

    2016-01-01

    ABSTRACT The functional status of CD4+ T cells is a critical determinant of antitumor immunity. Polyfunctional CD4+ T cells possess the ability to concomitantly produce multiple Th1-type cytokines, exhibiting a functional attribute desirable for cancer immunotherapy. However, the mechanisms by which these cells are induced are neither defined nor it is clear if these cells can be used therapeutically to treat cancer. Here, we report that CD4+ T cells exposed to exogenous IL-7 during antigenic stimulation can acquire a polyfunctional phenotype, characterized by their ability to simultaneously express IFNγ, IL-2, TNFα and granzyme B. This IL-7-driven polyfunctional phenotype was associated with increased histone acetylation in the promoters of the effector genes, indicative of increased chromatin accessibility. Moreover, forced expression of a constitutively active (CA) form of STAT5 recapitulated IL-7 in inducing CD4+ T-cell polyfunctionality. Conversely, the expression of a dominant negative (DN) form of STAT5 abolished the ability of IL-7 to induce polyfunctional CD4+ T cells. These in-vitro-generated polyfunctional CD4+ T cells can traffic to tumor and expand intratumorally in response to immunization. Importantly, adoptive transfer of polyfunctional CD4+ T cells following lymphodepletive chemotherapy was able to eradicate large established tumors. This beneficial outcome was associated with the occurrence of antigen epitope spreading, activation of the endogenous CD8+ T cells and persistence of donor CD4+ T cells exhibiting memory stem cell attributes. These findings indicate that IL-7 signaling can impart polyfunctionality and stemness potential to CD4+ T cells, revealing a previously unknown property of IL-7 that can be exploited in adoptive T-cell immunotherapy. PMID:27471650

  17. DJ-1/Park7 Sensitive Na+ /H+ Exchanger 1 (NHE1) in CD4+ T Cells.

    Science.gov (United States)

    Zhou, Yuetao; Shi, Xiaolong; Chen, Hong; Zhang, Shaqiu; Salker, Madhuri S; Mack, Andreas F; Föller, Michael; Mak, Tak W; Singh, Yogesh; Lang, Florian

    2017-11-01

    DJ-1/Park7 is a redox-sensitive chaperone protein counteracting oxidation and presumably contributing to the control of oxidative stress responses and thus inflammation. DJ-1 gene deletion exacerbates the progression of Parkinson's disease presumably by augmenting oxidative stress. Formation of reactive oxygen species (ROS) is paralleled by activation of the Na + /H + exchanger 1 (NHE1). ROS formation in CD4 + T cells plays a decisive role in regulating inflammatory responses. In the present study, we explored whether DJ-1 is expressed in CD4 + T cells, and affects ROS production as well as NHE1 in those cells. To this end, DJ-1 and NHE1 transcript, and protein levels were quantified by qRT-PCR and Western blotting, respectively, intracellular pH (pH i ) utilizing bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, NHE activity from realkalinization after an ammonium pulse, and ROS production utilizing 2',7' -dichlorofluorescin diacetate (DCFDA) fluorescence. As a result DJ-1 was expressed in CD4 + T cells. ROS formation, NHE1 transcript levels, NHE1 protein, and NHE activity were higher in CD4 + T cells from DJ-1 deficient mice than in CD4 + T cells from wild type mice. Antioxidant N-acetyl-cysteine (NAC) and protein tyrosine kinase (PTK) inhibitor staurosporine decreased the NHE activity in DJ-1 deficient CD4 + T cells, and blunted the difference between DJ-1 -/- and DJ-1 +/+ CD4 + T cells, an observation pointing to a role of ROS in the up-regulation of NHE1 in DJ-1 -/- CD4 + T cells. In conclusion, DJ-1 is a powerful regulator of ROS production as well as NHE1 expression and activity in CD4 + T cells. J. Cell. Physiol. 232: 3050-3059, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Granzyme B mediated function of Parvovirus B19-specific CD4+ T cells

    Science.gov (United States)

    Kumar, Arun; Perdomo, Maria F; Kantele, Anu; Hedman, Lea; Hedman, Klaus; Franssila, Rauli

    2015-01-01

    A novel conception of CD4+ T cells with cytolytic potential (CD4+ CTL) is emerging. These cells appear to have a part in controlling malignancies and chronic infections. Human parvovirus B19 can cause a persistent infection, yet no data exist on the presence of B19-specific CD4+ CTLs. Such cells could have a role in the pathogenesis of some autoimmune disorders reported to be associated with B19. We explored the cytolytic potential of human parvovirus B19-specific T cells by stimulating peripheral blood mononuclear cell (PBMC) with recombinant B19-VP2 virus-like particles. The cytolytic potential was determined by enzyme immunoassay-based quantitation of granzyme B (GrB) and perforin from the tissue culture supernatants, by intracellular cytokine staining (ICS) and by detecting direct cytotoxicity. GrB and perforin responses with the B19 antigen were readily detectable in B19-seropositive individuals. T-cell depletion, HLA blocking and ICS experiments showed GrB and perforin to be secreted by CD4+ T cells. CD4+ T cells with strong GrB responses were found to exhibit direct cytotoxicity. As anticipated, ICS of B19-specific CD4+ T cells showed expected co-expression of GrB, perforin and interferon gamma (IFN-γ). Unexpectedly, also a strong co-expression of GrB and interleukin 17 (IL-17) was detected. These cells expressed natural killer (NK) cell surface marker CD56, together with the CD4 surface marker. To our knowledge, this is the first report on virus-specific CD4+ CTLs co-expressing CD56 antigen. Our results suggest a role for CD4+ CTL in B19 immunity. Such cells could function within both immune regulation and triggering of autoimmune phenomena such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. PMID:26246896

  19. Long-term Maintenance of CD4 T Cell Memory Responses to Malaria Antigens in Malian Children Coinfected with Schistosoma haematobium

    Directory of Open Access Journals (Sweden)

    Kirsten E. Lyke

    2018-02-01

    Full Text Available Polyparasitism is common in the developing world. We have previously demonstrated that schistosomiasis-positive (SP Malian children, aged 4–8 years, are protected from malaria compared to matched schistosomiasis-negative (SN children. The effect of concomitant schistosomiasis upon acquisition of T cell memory is unknown. We examined antigen-specific T cell frequencies in 48 Malian children aged 4–14 to a pool of malaria blood stage antigens, and a pool of schistosomal antigens, at a time point during a malaria episode and at a convalescent time point ~6 months later, following cessation of malaria transmission. CD4+ T cell-derived memory responses, defined as one or more significant cytokine (IFN-γ, TNF-α, IL-2, and/or IL-17A responses, was measured to schistoma antigens in 18/23 SP children at one or both time points, compared to 4/23 SN children (P < 0.0001. At the time of malaria infection, 12/24 SN children and 15/23 SP children (P = 0.29 stimulated with malaria antigens demonstrated memory recall as defined by CD4-derived cytokine production. This compares to 7/23 SN children and 16/23 SP children (P = 0.009 at the convalescent timepoint. 46.2% of cytokine-producing CD4+ T cells expressed a single cytokine after stimulation with malaria antigen during the malaria episode. This fell to 40.9% at follow-up with a compensatory rise of multifunctional cytokine secretion over time, a phenomenon consistent with memory maturation. The majority (53.2–59.5% of responses derived from CD45RA−CD62L− effector memory T cells with little variation in the phenotype depending upon the time point or the study cohort. We conclude that detectable T cell memory responses can be measured against both malaria and schistosoma antigens and that the presence of Schistosoma haematobium may be associated with long-term maintenance of T memory to malaria.

  20. Immune regulation in Chandipura virus infection: characterization of CD4+ T regulatory cells from infected mice

    Directory of Open Access Journals (Sweden)

    Shahir Prajakta

    2011-05-01

    Full Text Available Abstract Back ground Chandipura virus produces acute infection in mice. During infection drastic reduction of CD4+, CD8+ and CD19 + cell was noticed. Depletion of lymphocytes also noticed in spleen. The reduction may be due to the regulatory mechanism of immune system to prevent the bystander host tissue injury. There are several mechanisms like generation of regulatory cells, activation induced cell death (ACID etc were indicated to control the activation and maintain cellular homeostasis. Role of regulatory cells in homeostasis has been described in several viral diseases. This study was undertaken to characterize CD4+T regulatory cells from the infected mice. Method In this study we purified the CD4+ T cells from Chandipura virus infected susceptible Balb/c mice. CD4+ T regulatory cells were identified by expression of cell surface markers CD25, CD127 and CTLA-4 and intracellular markers Foxp3, IL-10 and TGF-beta. Antigen specificity and ability to suppress the proliferation of other lymphocytes were studied in vitro by purified CD4+CD25+T regulatory cells from infected mice. The proliferation was calculated by proliferation module of Flow Jo software. Expression of death receptors on regulatory cells were studied by flowcytometer. Results The CD4+ T cells isolated from infected mice expressed characteristic markers of regulatory phenotype at all post infective hours tested. The CD4+ T regulatory cells were proliferated when stimulated with Chandipura virus antigen. The regulatory cells did not suppress the proliferation of splenocytes stimulated with anti CD3 antibody when co cultured with them. Interesting observation was, while purification of CD4+ T cells by negative selection, the population of cells negative for CD4 also co purified along with CD4+ T cell. Flow cytometry analysis and light microscopy revealed that CD4 negative cells were of different size and shape (atypical compared to the normal lymphocytes. Greater percentage of

  1. Human umbilical cord mesenchymal stem cells increase interleukin-9 production of CD4+ T cells

    OpenAIRE

    Yang, Zhou Xin; Chi, Ying; Ji, Yue Ru; Wang, You Wei; Zhang, Jing; Luo, Wei Feng; Li, Li Na; Hu, Cai Dong; Zhuo, Guang Sheng; Wang, Li Fang; Han, Zhi-Bo; Han, Zhong Chao

    2017-01-01

    Mesenchymal stem cells (MSC) are able to differentiate into cells of multiple lineage, and additionally act to modulate the immune response. Interleukin (IL)-9 is primarily produced by cluster of differentiation (CD)4+ T cells to regulate the immune response. The present study aimed to investigate the effect of human umbilical cord derived-MSC (UC-MSC) on IL-9 production of human CD4+ T cells. It was demonstrated that the addition of UC-MSC to the culture of CD4+ T cells significantly enhance...

  2. Idiopathic CD4 lymphocytopenia with giant cell arteritis and pulmonary mucormycosis

    Directory of Open Access Journals (Sweden)

    Ryan A. Denu

    2014-10-01

    Full Text Available Idiopathic CD4 lymphocytopenia (ICL is characterized by a low CD4+ lymphocyte count in the absence of HIV or other underlying etiologies. We report a case of a 57-year old man with ICL and giant cell arteritis (GCA who developed pulmonary mucormycosis, which, to our knowledge, is the first report of these occurring in a patient with ICL. Abnormally low total lymphocyte or CD4+ cell counts occurring in patients with autoimmune disorders should alert clinicians to the possibility of ICL. Immunosuppressive treatment should be used with caution in this context.

  3. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad

    2006-01-01

    OBJECTIVE: To evaluate whether T cells expressing CCR5 and CXCR3 from multiple sclerosis (MS) patients are more resistant to apoptosis. METHODS: Expression of CD69, TNF-R1, Fas, FasL, bcl-2, and bax was investigated in 41 MS patients and 12 healthy controls by flow cytometry in CD4+ and CD8+ T...... cells expressing CCR5 and CXCR3. RESULTS: In MS patients, the percentage of CD69 was increased and Fas expression decreased in CD4+ CCR5+ T cells. INTERPRETATION: The lower Fas expression in activated CD4+ CCR5+ T cells might contribute to disease pathogenesis by prolonging cell survival and favoring...

  4. Clonal expansion of CD4+ Cytotoxic T Lymphocytes in IgG4-related disease

    Science.gov (United States)

    Mattoo, Hamid; Mahajan, Vinay S.; Maehara, Takashi; Deshpande, Vikram; Della-Torre, Emanuel; Wallace, Zachary S.; Kulikova, Maria; Drijvers, Jefte M.; Daccache, Joe; Carruthers, Mollie N.; Castellino, Flavia; Stone, James R.; Stone, John H.; Pillai, Shiv

    2016-01-01

    Background IgG4-related disease (IgG4-RD) is a systemic condition of unknown etiology, characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4+ T cells constitute the major inflammatory cell population in IgG4-RD lesions. Objective We used an unbiased approach to characterize CD4+ T cell subsets in IgG4-RD subjects based on their clonal expansion and their ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4+ effector/memory T cells (TEM) in a cohort of 101 IgG4-related disease (IgG4-RD) patients. These expanded cells were characterized by gene expression analysis and flow cytometry. Next-generation sequencing of the T cell receptor β chain gene was performed on CD4+SLAMF7+ CTLs and CD4+GATA3+ TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined using quantitative multi-color imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype were expanded in IgG4-RD patients. Next-generation sequencing revealed prominent clonal expansions of these CD4+CTLs but not CD4+GATA3+ memory TH2 cells in subjects with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally-expanded CD4+CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B cell depletion was associated with a reduction in disease-associated CD4+ CTLs Conclusions IgG4-RD is prominently linked to clonally-expanded, IL-1β, and TGF- β1 secreting, CD4+ CTLs in peripheral blood as well as in inflammatory tissue lesions. These active, terminally-differentiated, cytokine-secreting effector CD4+ T cells are now linked to a human disease characterized by chronic inflammation and fibrosis. PMID:26971690

  5. Progressive multifocal leucoencephalopathy in a patient with idiopathic CD4+ lymphocytopenia.

    LENUS (Irish Health Repository)

    Moloney, F

    2012-03-01

    Progressive multifocal leucoencephalopathy (PML) is an opportunistic, demyelinating neurological disease caused by reactivation of the JC polyomavirus. PML occurs almost exclusively in immunosuppressed individuals, with only isolated case reports of PML occurring in patients without apparent immunosuppression. Idiopathic CD4+ lymohocytopenia (ICL) is a syndrome defined by the Centre for Disease Control and Prevention as a CD4+ count <300 cells\\/uL or <20% of total T cell count on >1 occasion, with no evidence of human immunodeficiency virus (HIV) infection, and the absence of other known immunodeficiency or therapy associated with lymphocytopenia. We describe a case of PML occurring in a patient with idiopathic CD4+ lymphocytopenia.

  6. In-Depth Analysis of Citrulline Specific CD4 T-Cells in Rheumatoid Arthritis

    Science.gov (United States)

    2017-01-01

    AWARD NUMBER: W81XWH-15-1-0004 TITLE: In-Depth Analysis of Citrulline-Specific CD4 T - Cells in Rheumatoid Arthritis PRINCIPAL INVESTIGATOR...2016 4. TITLE AND SUBTITLE In-Depth Analysis of Citrulline-Specific CD4 T Cells in Rheumatoid Arthritis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...NOTES 14. ABSTRACT The goal of this project is to test the hypothesis that cit-specific CD4 T cells present in rheumatoid arthritis (RA) patients

  7. CD4 T cell activation and disease activity at onset of multiple sclerosis

    DEFF Research Database (Denmark)

    Jensen, J; Langkilde, Annika Reynberg; Fenst, C

    2004-01-01

    We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease...... severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states...

  8. A pharmacogenetic study of CD4 recovery in response to HIV antiretroviral therapy in two South African population groups.

    Science.gov (United States)

    Parathyras, John; Gebhardt, Stefan; Hillermann-Rebello, Renate; Grobbelaar, Nelis; Venter, Mauritz; Warnich, Louise

    2009-05-01

    South Africa, like many other Southern African countries, has one of the highest HIV infection rates in the world and many individuals consequently receive antiretroviral therapy (ART). However, knowledge regarding (i) the prevalence of functional single nucleotide polymorphisms (SNPs) in pharmacologically relevant genes, and (ii) variance in pharmacotherapy both within and between different populations and ethnic groups is limited. The aim of this study was to determine whether selected polymorphisms in cytochrome P450 (CYP) genes (CYP2B6 and CYP3A4) and the multidrug-resistance 1 (ABCB1) gene underlie altered antiretroviral (ARV) drug response in two South African populations. DNA samples from 182 HIV-positive individuals of Mixed-Ancestry and Xhosa ethnicity on ART were genotyped for the A-392G SNP in CYP3A4, the G516T and A785G SNPs in CYP2B6, and the T-129C, C1236T, G2677T/A and C3435T SNPs in ABCB1. Univariate two-way analysis of variance (ANOVA) testing revealed no apparent effect of ethnicity on immune recovery (in terms of CD4-cell count) in response to ART. Univariate one-way ANOVA testing revealed a discernible effect of genotype on immune recovery in the cases of the T-129C (P=0.03) and G2677A (P<0.01) polymorphisms in the ABCB1 gene. This study serves as a basis for better understanding and possible prediction of pharmacogenetic risk profiles and drug response in individuals and ethnic groups in South Africa.

  9. CD3+, CD56+, CD4−, CD8−, CD20−, CD30− Peripheral T-Cell Non-Hodgkin's Lymphoma: A Rare Case Report

    Directory of Open Access Journals (Sweden)

    Ashish Jagati

    2017-01-01

    Full Text Available Cutaneous T-cell lymphoma (CTCL commonly presents as mycosis fungoides or Sezary syndrome, both having CD4 positivity. A subset of CTCL which lacks CD4 surface marker is classified as cutaneous g and d–T-cell lymphoma (CGD-TCL. Because of its rarity and inability to study large number of patients, the impact of immunophenotype on the clinical outcome of primary CTCL in patients is limited. We report a case of primary CGD-TCL in a 71-year-old male because of this rarity and to emphasize its aggressive nature.

  10. In vitro activated CD4+ T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts

    DEFF Research Database (Denmark)

    Bregenholt, S; Brimnes, J; Nissen, Mogens Holst

    1999-01-01

    To investigate the role of IFN-gamma in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild-type (WT) or IFN-gamma-deficient (IFN-gammaKO) BALB/c mice. In vitro, the two types...... of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN-gammaKO blasts induced a less severe...... intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4+ T cells positive for TNF-alpha, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the fraction of IL-4...

  11. Effect of memory CD4+ T cells' signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma.

    Science.gov (United States)

    Chen, Zhihong; Pan, Jue; Jia, Yi; Li, Dandan; Min, Zhihui; Su, Xiaoqiong; Yuan, Honglei; Shen, Geng; Cao, Shengxuan; Zhu, Lei; Wang, Xiangdong

    2017-02-01

    Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown. Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood, and cell surface staining (CD4, CD45RO, CRTH2, CD62L, and CCR7) was performed for the detection of memory CD4 + T cells in blood. After stimulation with interleukin-27 (IL-27) or IL-4 for 15 min, the STAT1/STAT6 phosphorylation of memory CD4 + T cells was measured separately by flow cytometric techniques. The cytokine-releasing profiles after 6 days of culture under neutralization, T H 2, T H 2 + lipopolysaccharide (LPS), and T H 2 + house dust mite (HDM) conditions were detected by intracellular protein (IL-5, IL-17, and interferon (IFN)-γ) staining. Correlation analyses between the profile of memory CD4 + T cells and clinical characteristics of asthma were performed. The number of circulating memory CD4 + T (CD4 + Tm) cells in asthmatics was increased compared with that in the healthy subjects (48 ± 5.7 % vs. 32 ± 4.1 %, p T H 2 memory cells but not non-T H 2 memory cells in blood. The cytokine-releasing profiles of asthmatics was unique, specifically IL-5 high , IL-17 high , and IFN-r low , compared with those of COPD patients and healthy subjects. The IL-17 production levels in CD4 + Tm cells are associated with disease severity and positively correlated with medication consumption in asthma. The long-lived, antigen-specific memory CD4 + T cells, rather than PBMCs or peripheral lymphocytes, might be the ideal T cell subset candidates for analyzing the endotype of asthma

  12. Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections

    OpenAIRE

    Qiao, Yu; Gray, Brian M.; Sofi, Mohammed H.; Bauler, Laura D.; Eaton, Kathryn A.; O'Riordan, Mary X. D.; Chang, Cheong-Hee

    2011-01-01

    We have reported a new innate-like CD4 T cell population that expresses cell surface makers of effector/memory cells and produce Th1 and Th2 cytokines immediately upon activation. Unlike conventional CD4 T cells that are selected by thymic epithelial cells, these CD4 T cells, named T-CD4 T cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of T-CD4 T cells protected mice from airway inflammation suggesting an immune regulatory role of T-CD4 T ce...

  13. Total glucosides of paeony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells.

    Science.gov (United States)

    Zhao, Ming; Liang, Gong-ping; Tang, Mei-ni; Luo, Shuang-yan; Zhang, Jing; Cheng, Wen-jing; Chan, Tak-mao; Lu, Qian-jin

    2012-05-01

    Total glucosides of paeony (TGP), an active compound extracted from Paeony root, has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the prevention of autoimmune response remains unclear. In this study, we found that TGP treatment significantly increased the percentage and number of Treg cells in lupus CD4(+) T cells. Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels. However, we couldn't observe similar results in healthy control CD4(+) T cells treated by TGP. Moreover, our results also showed that IFN-γ and IL-2 expression was enhanced in TGP-treated lupus CD4(+) T cells. These findings indicate that TGP inhibits autoimmunity in SLE patients possibly by inducing Treg cell differentiation, which may in turn be due to its ability to regulate the methylation status of the Foxp3 promoter and activate IFN-γ and IL-2 signaling. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers

    NARCIS (Netherlands)

    Almeida, Afonso R. M.; Legrand, Nicolas; Papiernik, Martine; Freitas, António A.

    2002-01-01

    We show that the lymphoid hyperplasia observed in IL-2Ralpha- and IL-2-deficient mice is due to the lack of a population of regulatory cells essential for CD4 T cell homeostasis. In chimeras reconstituted with bone marrow cells from IL-2Ralpha-deficient donors, restitution of a population of

  15. Changes of lymphocyte subsets after local irradiation for early stage breast cancer and seminoma testis: long-term increase of activated (HLA-DR+) T-cells and decrease of ''naive'' (CD4-CD45R) T lymphocytes

    International Nuclear Information System (INIS)

    De Ruysscher, D.; Aerts, R.; Vantongelen, K.; Schueren, E. van der; Waer, M.; Vandeputte, M.

    1992-01-01

    Blood lymphocyte subsets of early breast cancer patients and of men with stage I seminoma of the testis were studied up to 6 years after radiotherapy. Similar results were obtained in the two patient groups. After a temporary decrease, the CD4-w29 or ''memory'' T cells recovered completely, while the CD4-45R or ''naive'' T cells remained decreased up to 6 years after irradiation. The number of CD8 T lymphocytes did not change during or after treatment. Because of the decrease of a subset of CD4 cells, and the unchanged values of CD8 cells, the CD4/CD8 ratio decreased significantly after irradiation, and remained lower than before treatment up to 5-6 years after radiotherapy. The number of both HLA-DR positive CD4 and HLA-DR positive CD8 T cells (''activated'' T cells) increased significantly after irradiation. The natural killer (NK) cells were not affected by treatment. The authors propose that recovery of the CD4 cells is limited to the CD4-w29 (''memory'') population because of thymic dysfunction in older humans. (Author)

  16. Quantitative variations of CD4 + CD25 + cells in Peking duckwhite ...

    African Journals Online (AJOL)

    Quantitative variations of CD4 + CD25 + cells in Peking duckwhite leghorn chimeras based on bone marrow mesenchymal stem cells. ... Tropical Journal of Pharmaceutical Research. Journal Home · ABOUT THIS JOURNAL · Advanced ...

  17. Applying machine learning to predict patient-specific current CD4 ...

    African Journals Online (AJOL)

    Apple apple

    This work shows the application of machine learning to predict current CD4 cell count of an HIV- .... Pre-processing ... remaining data elements of the PR and RT datasets. ... technique based on the structure of the human brain's neuron.

  18. Pattern of CD4 T‑lymphocyte Values in Cancer Patients on Cytotoxic ...

    African Journals Online (AJOL)

    through cell surface receptors and results in replication and or mediation of one ... Keywords: Cancers, CD4 lymphocyte, Cytotoxic chemotherapy, Immunosuppression. Access this ..... of the larynx, ovaries, stomach, and urinary bladder. These.

  19. Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells

    Science.gov (United States)

    Muraro, Elena; Merlo, Anna; Martorelli, Debora; Cangemi, Michela; Dalla Santa, Silvia; Dolcetti, Riccardo; Rosato, Antonio

    2017-01-01

    CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors. PMID:28289418

  20. CD4 T Cell Responses in Latent and Chronic Viral Infections

    Science.gov (United States)

    Walton, Senta; Mandaric, Sanja; Oxenius, Annette

    2013-01-01

    The spectrum of tasks which is fulfilled by CD4 T cells in the setting of viral infections is large, ranging from support of CD8 T cells and humoral immunity to exertion of direct antiviral effector functions. While our knowledge about the differentiation pathways, plasticity, and memory of CD4 T cell responses upon acute infections or immunizations has significantly increased during the past years, much less is still known about CD4 T cell differentiation and their beneficial or pathological functions during persistent viral infections. In this review we summarize current knowledge about the differentiation, direct or indirect antiviral effector functions, and the regulation of virus-specific CD4 T cells in the setting of persistent latent or active chronic viral infections with a particular emphasis on herpes virus infections for the former and chronic lymphocytic choriomeningitis virus infection for the latter. PMID:23717308

  1. laboratory CD4 service in a rural health district in South Africa

    African Journals Online (AJOL)

    and 59 specialised labs that provide CD4 testing, gaps in service have been identified ... external quality assessment, as well as network and training support. Three new tiers .... internal data and time setting for the decentralised Disa*Lab LIS.

  2. CD4 expression on EL4 cells as an epiphenomenon of retroviral transduction and selection.

    Science.gov (United States)

    Logan, Grant J; Spinoulas, Afroditi; Alexander, Stephen I; Smythe, Jason A; Alexander, Ian E

    2004-04-01

    The EL4 murine tumour cell line, isolated from a chemically induced lymphoma over 50 years ago, has been extensively exploited in immunological research. The conclusions drawn from many of these studies have been based on the presumption that EL4 cells maintain a stable phenotype during experimental manipulation. To the contrary, we have observed 100-fold greater expression of cell surface CD4 (CD4(high)) on a subpopulation of EL4 cells following retroviral transduction and G418 selection when compared with unmodified populations. Although the mechanism responsible for this effect remains to be elucidated, the unexpected expression of CD4, a molecule that functions as both a coreceptor with the T-cell receptor and ligand for the pro-inflammatory cytokine IL-16, has the potential to influence experimental outcomes. Upregulation of CD4 should be excluded when EL4 cells are utilized in experiments requiring a consistent immuno-phenotype.

  3. CD4+ Foxp3+ T-cells contribute to myocardial ischemia-reperfusion injury.

    Science.gov (United States)

    Mathes, Denise; Weirather, Johannes; Nordbeck, Peter; Arias-Loza, Anahi-Paula; Burkard, Matthias; Pachel, Christina; Kerkau, Thomas; Beyersdorf, Niklas; Frantz, Stefan; Hofmann, Ulrich

    2016-12-01

    The present study analyzed the effect of CD4 + Forkhead box protein 3 negative (Foxp3 - ) T-cells and Foxp3 + CD4 + T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30minutes of coronary ligation followed by 24hours of reperfusion. CD4 + T-cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5±4.7% in MHCII KO versus 59.4±4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9±2.8% in MHC II KO versus 39.0±4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24hours of reperfusion. Also CD4 + T-cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4 + T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4 + T-cell activation in heart draining lymph nodes in response to 24hours of ischemia-reperfusion. Adoptive transfer of CD4 + T-cells in CD4 KO mice increased the infarct size only when including the Foxp3 + CD25 + subset. Depletion of CD4 + Foxp3 + T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. CD4 + Foxp3 + T-cells enhance myocardial ischemia-reperfusion injury. CD4 + T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM cells which expand following virulent mycobacterial challenge.

    Directory of Open Access Journals (Sweden)

    Daryan A Kaveh

    Full Text Available To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (T(EM cells in vaccinated mice. These CD4+CD44(hiCD62L(loCD27⁻ T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or 'quality of response' than single cytokine producing cells. These cells are maintained for long periods (>16 months in BCG protected mice, maintaining a vaccine-specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of T(EM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional T(EM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific T(EM in the lung may represent a new generation of TB vaccines.

  5. Conformational alterations in the CD4 binding cavity of HIV-1 gp120 influencing gp120-CD4 interactions and fusogenicity of HIV-1 envelopes derived from brain and other tissues

    Directory of Open Access Journals (Sweden)

    Ramsland Paul A

    2011-06-01

    Full Text Available Abstract Background CD4-binding site (CD4bs alterations in gp120 contribute to HIV-1 envelope (Env mediated fusogenicity and the ability of gp120 to utilize low levels of cell-surface CD4. In a recent study, we constructed three-dimensional models of gp120 to illustrate CD4bs conformations associated with enhanced fusogenicity and enhanced CD4-usage of a modestly-sized panel of blood-derived HIV-1 Envs (n = 16. These conformations were characterized by a wider aperture of the CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop. Here, we sought to provide further validation of the utility of these models for understanding mechanisms that influence Env function, by characterizing the structure-function relationships of a larger panel of Envs derived from brain and other tissues (n = 81. Findings Three-dimensional models of gp120 were generated by our recently validated homology modelling protocol. Analysis of predicted CD4bs structures showed correlations between the aperture width of the CD4bs cavity and ability of the Envs to mediate cell-cell fusion, scavenge low-levels of cell-surface CD4, bind directly to soluble CD4, and bind to the Env mAb IgG1b12 whose epitope overlaps the gp120 CD4bs. These structural alterations in the CD4bs cavity were associated with repositioning of the V5 loop. Conclusions Using a large, independent panel of Envs, we can confirm the utility of three-dimensional gp120 structural models for illustrating CD4bs alterations that can affect Env function. Furthermore, we now provide new evidence that these CD4bs alterations augment the ability of gp120 to interact with CD4 by increasing the exposure of the CD4bs.

  6. The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals

    DEFF Research Database (Denmark)

    Grarup, N; Overvad, M; Sparsø, T

    2011-01-01

    A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 va...

  7. In-Depth Analysis of Citrulline-Specific CD4 T-Cells in Rheumatoid Arthritis

    Science.gov (United States)

    2016-01-01

    be used to identify and characterize CD4+T cells specific for influenza A, West Nile, Yellow fever , Dengue and Japanese Encephalitis viruses. The...four difference species of Flavivirus using the TGEM approach. These will include: Yellow Fever Virus, West Nile Virus, Dengue Virus and Japanese...1 AWARD NUMBER: W81XWH-15-1-0004 TITLE: In-Depth Analysis of Citrulline-Specific CD4 T-Cells in Rheumatoid Arthritis PRINCIPAL INVESTIGATOR

  8. The CD4+/CD8+ Ratio in Pulmonary Tuberculosis: Systematic and Meta-Analysis Article.

    Science.gov (United States)

    Yin, Yongmei; Qin, Jie; Dai, Yaping; Zeng, Fanwei; Pei, Hao; Wang, Jun

    2015-02-01

    The ratio of CD4+/CD8+ has been used as a clinically index to evaluate patients' immunity. Numerous researchers have studied CD4+/CD8+ ratio in pulmonary tuberculosis (PTB) patients. However, the change of CD4+/CD8+ ratio remains controversial. We present a meta-analysis of 15 case-control studies to identify the change of CD4+/CD8+ ratio in PTB patients. We assessed heterogeneity of effect estimates within each group using I(2) test. Subgroup analysis was performed to explore the potential source of heterogeneity. To investigate further the potential publication bias, we visually examined the funnel plots. For robustness of results, we performed sensitivity analysis by removing studies. Data entry and analyses were carried out with RevMan 5.2 (The Nordic Cochrane Centre). Twelve peripheral blood studies were categorized into two subgroups. Eight studies presented a significant decrease of CD4+/CD8+ ratio in PTB cases compared to healthy subjects (SMD: -0.45; 95% CI -0.65--0.25; I(2) = 7%). Other four studies researched on the newly diagnosed patients presented a more seriously and significantly decrease (SMD: -2.17; 95% CI -2.61--1.74; I(2) = 37%). The pooled analysis of bronchoalveolar lavage fluid (BALF) studies showed a significant increase of CD4+/CD8+ ratio using Flow Cytometry (FCM) (SMD: 4.75; 95% CI 3.44-6.05; I(2) =0%). The present meta-analysis indicated that there was a synthetic evidence for the reduced CD4+/CD8+ ratio in peripheral blood of PTB patients, especially newly diagnosed cases. However, the CD4+/CD8+ ratio in BALF was increased using method of FCM.

  9. CD4+ T cell mediated chronic intestinal disease : immune regulation versus inflammation

    OpenAIRE

    Westendorf, Astrid Maria

    2004-01-01

    Die Ätiologie von chronisch entzündlichen Darmerkrankungen ist weitgehend ungeklärt. Nach derzeitiger Auffassung liegt der Schwerpunkt in der Dysregulation lokaler immunologischer Reaktionen in der Darmmukosa. Zur Untersuchung der chronisch entzündlichen Darmerkrankungen wurde ein CD4+ T Zell basiertes doppelt-transgenes Mausmodell entwickelt. Die gleichzeitige Expression eines Modellantigens in Darmepithelzellen und antigenspezifischen CD4+ T Zellen führten zu einer chronischen Entzündungsre...

  10. Reactive Oxygen Species and Their Implications on CD4+ T Cells in Type 1 Diabetes.

    Science.gov (United States)

    Previte, Dana M; Piganelli, Jon D

    2017-11-28

    Previous work has indicated that type 1 diabetes (T1D) pathology is highly driven by reactive oxygen species (ROS). One way in which ROS shape the autoimmune response demonstrated in T1D is by promoting CD4 + T cell activation and differentiation. As CD4 + T cells are a significant contributor to pancreatic β cell destruction in T1D, understanding how ROS impact their development, activation, and differentiation is critical. Recent Advances: CD4 + T cells themselves generate ROS via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and electron transport chain activity. Moreover, T cells can also be exposed to exogenous ROS generated by other immune cells (e.g., macrophages and dendritic cells) and β cells. Genetically modified animals and ROS inhibitors have demonstrated that ROS blockade during activation results in CD4 + T cell hyporesponsiveness and reduced diabetes incidence. Critical Issues and Future Directions: Although the majority of studies with regard to T1D and CD4 + T cells have been done to examine the influence of redox on CD4 + T cell activation, this is not the only circumstance in which a T cell can be impacted by redox. ROS and redox have also been shown to play roles in CD4 + T cell-related tolerogenic mechanisms, including thymic selection and regulatory T cell-mediated suppression. However, the effect of these mechanisms with respect to T1D pathogenesis remains elusive. Therefore, pursuing these avenues may provide valuable insight into the global role of ROS and redox in autoreactive CD4 + T cell formation and function. Antioxid. Redox Signal. 00, 000-000.

  11. Cell-contact-dependent activation of CD4+ T cells by adhesion molecules on synovial fibroblasts.

    Science.gov (United States)

    Mori, Masato; Hashimoto, Motomu; Matsuo, Takashi; Fujii, Takao; Furu, Moritoshi; Ito, Hiromu; Yoshitomi, Hiroyuki; Hirose, Jun; Ito, Yoshinaga; Akizuki, Shuji; Nakashima, Ran; Imura, Yoshitaka; Yukawa, Naoichiro; Yoshifuji, Hajime; Ohmura, Koichiro; Mimori, Tsuneyo

    2017-05-01

    To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4 +  T cells. Naïve CD4 +  T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4 +  T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4 +  T cells, CD161 +  or CD161 - naïve CD4 +  T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. SF enhanced naïve CD4 +  T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4 +  T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161 +  naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CD4 +  T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.

  12. Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects.

    Science.gov (United States)

    Abana, Chike O; Pilkinton, Mark A; Gaudieri, Silvana; Chopra, Abha; McDonnell, Wyatt J; Wanjalla, Celestine; Barnett, Louise; Gangula, Rama; Hager, Cindy; Jung, Dae K; Engelhardt, Brian G; Jagasia, Madan H; Klenerman, Paul; Phillips, Elizabeth J; Koelle, David M; Kalams, Spyros A; Mallal, Simon A

    2017-11-01

    Select CMV epitopes drive life-long CD8 + T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4 + T cells specific for human CMV (HCMV) are elevated in HIV + HCMV + subjects. To determine whether HCMV epitope-specific CD4 + T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4 + T cells in coinfected HLA-DR7 + long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4 + T cells were inflated among these HIV + subjects compared with those from an HIV - HCMV + HLA-DR7 + cohort or with HLA-DR7-restricted CD4 + T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4 + T cells consisted of effector memory or effector memory-RA + subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX 3 CR1, CD38, or HLA-DR but less often coexpressed CD38 + and HLA-DR + The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4 + T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease. Copyright © 2017 by The American Association of Immunologists, Inc.

  13. Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM) cells in cattle naturally infected with bovine tuberculosis.

    Science.gov (United States)

    Whelan, Adam O; Villarreal-Ramos, Bernardo; Vordermeier, H Martin; Hogarth, Philip J

    2011-01-01

    Gaining a better understanding of the T cell mechanisms underlying natural immunity to bovine tuberculosis would help to identify immune correlates of disease progression and facilitate the rational design of improved vaccine and diagnostic strategies. CD4 T cells play an established central role in immunity to TB, and recent interest has focussed on the potential role of multifunctional CD4 T cells expressing IFN-γ, IL-2 and TNF-α. Until now, it has not been possible to assess the contribution of these multifunctional CD4 T cells in cattle due to the lack of reagents to detect bovine IL-2 (bIL-2). Using recombinant phage display technology, we have identified an antibody that recognises biologically active bIL-2. Using this antibody, we have developed a polychromatic flow cytometric staining panel that has allowed the investigation of multifunctional CD4 T-cells responses in cattle naturally infected with M. bovis. Assessment of the frequency of antigen specific CD4 T cell subsets reveals a dominant IFN-γ(+)IL-2(+)TNF-α(+) and IFN-γ(+) TNF-α(+) response in naturally infected cattle. These multifunctional CD4 T cells express a CD44(hi)CD45RO(+)CD62L(lo) T-effector memory (T(EM)) phenotype and display higher cytokine median fluorescence intensities than single cytokine producers, consistent with an enhanced 'quality of response' as reported for multifunctional cells in human and murine systems. Through our development of these novel immunological bovine tools, we provide the first description of multifunctional T(EM) cells in cattle. Application of these tools will improve our understanding of protective immunity in bovine TB and allow more direct comparisons of the complex T cell mediated immune responses between murine models, human clinical studies and bovine TB models in the future. © 2011 Whelan et al.

  14. Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM cells in cattle naturally infected with bovine tuberculosis.

    Directory of Open Access Journals (Sweden)

    Adam O Whelan

    Full Text Available Gaining a better understanding of the T cell mechanisms underlying natural immunity to bovine tuberculosis would help to identify immune correlates of disease progression and facilitate the rational design of improved vaccine and diagnostic strategies. CD4 T cells play an established central role in immunity to TB, and recent interest has focussed on the potential role of multifunctional CD4 T cells expressing IFN-γ, IL-2 and TNF-α. Until now, it has not been possible to assess the contribution of these multifunctional CD4 T cells in cattle due to the lack of reagents to detect bovine IL-2 (bIL-2. Using recombinant phage display technology, we have identified an antibody that recognises biologically active bIL-2. Using this antibody, we have developed a polychromatic flow cytometric staining panel that has allowed the investigation of multifunctional CD4 T-cells responses in cattle naturally infected with M. bovis. Assessment of the frequency of antigen specific CD4 T cell subsets reveals a dominant IFN-γ(+IL-2(+TNF-α(+ and IFN-γ(+ TNF-α(+ response in naturally infected cattle. These multifunctional CD4 T cells express a CD44(hiCD45RO(+CD62L(lo T-effector memory (T(EM phenotype and display higher cytokine median fluorescence intensities than single cytokine producers, consistent with an enhanced 'quality of response' as reported for multifunctional cells in human and murine systems. Through our development of these novel immunological bovine tools, we provide the first description of multifunctional T(EM cells in cattle. Application of these tools will improve our understanding of protective immunity in bovine TB and allow more direct comparisons of the complex T cell mediated immune responses between murine models, human clinical studies and bovine TB models in the future.

  15. A dominant EV71-specific CD4+ T cell epitope is highly conserved among human enteroviruses.

    Directory of Open Access Journals (Sweden)

    Ruicheng Wei

    Full Text Available CD4+ T cell-mediated immunity plays a central role in determining the immunopathogenesis of viral infections. However, the role of CD4+ T cells in EV71 infection, which causes hand, foot and mouth disease (HFMD, has yet to be elucidated. We applied a sophisticated method to identify promiscuous CD4+ T cell epitopes contained within the sequence of the EV71 polyprotein. Fifteen epitopes were identified, and three of them are dominant ones. The most dominant epitope is highly conserved among enterovirus species, including HFMD-related coxsackieviruses, HFMD-unrelated echoviruses and polioviruses. Furthermore, the CD4+ T cells specific to the epitope indeed cross-reacted with the homolog of poliovirus 3 Sabin. Our findings imply that CD4+ T cell responses to poliovirus following vaccination, or to other enteroviruses to which individuals may be exposed in early childhood, may have a modulating effect on subsequent CD4+ T cell response to EV71 infection or vaccine.

  16. CD4 cells can be more efficient at tumor rejection than CD8 cells.

    Science.gov (United States)

    Perez-Diez, Ainhoa; Joncker, Nathalie T; Choi, Kyungho; Chan, William F N; Anderson, Colin C; Lantz, Olivier; Matzinger, Polly

    2007-06-15

    Researchers designing antitumor treatments have long focused on eliciting tumor-specific CD8 cytotoxic T lymphocytes (CTL) because of their potent killing activity and their ability to reject transplanted organs. The resulting treatments, however, have generally been surprisingly poor at inducing complete tumor rejection, both in experimental models and in the clinic. Although a few scattered studies suggested that CD4 T "helper" cells might also serve as antitumor effectors, they have generally been studied mostly for their ability to enhance the activity of CTL. In this mouse study, we compared monoclonal populations of tumor-specific CD4 and CD8 T cells as effectors against several different tumors, and found that CD4 T cells eliminated tumors that were resistant to CD8-mediated rejection, even in cases where the tumors expressed major histocompatibility complex (MHC) class I molecules but not MHC class II. MHC class II expression on host tissues was critical, suggesting that the CD4 T cells act indirectly. Indeed, the CD4 T cells partnered with NK cells to obtain the maximal antitumor effect. These findings suggest that CD4 T cells can be powerful antitumor effector cells that can, in some cases, outperform CD8 T cells, which are the current "gold standard" effector cell in tumor immunotherapy.

  17. CD4+ T cell effects on CD8+ T cell location defined using bioluminescence.

    Directory of Open Access Journals (Sweden)

    Mitra Azadniv

    2011-01-01

    Full Text Available T lymphocytes of the CD8+ class are critical in delivering cytotoxic function and in controlling viral and intracellular infections. These cells are "helped" by T lymphocytes of the CD4+ class, which facilitate their activation, clonal expansion, full differentiation and the persistence of memory. In this study we investigated the impact of CD4+ T cells on the location of CD8+ T cells, using antibody-mediated CD4+ T cell depletion and imaging the antigen-driven redistribution of bioluminescent CD8+ T cells in living mice. We documented that CD4+ T cells influence the biodistribution of CD8+ T cells, favoring their localization to abdominal lymph nodes. Flow cytometric analysis revealed that this was associated with an increase in the expression of specific integrins. The presence of CD4+ T cells at the time of initial CD8+ T cell activation also influences their biodistribution in the memory phase. Based on these results, we propose the model that one of the functions of CD4+ T cell "help" is to program the homing potential of CD8+ T cells.

  18. Understanding the slow depletion of memory CD4+ T cells in HIV infection.

    Directory of Open Access Journals (Sweden)

    Andrew Yates

    2007-05-01

    Full Text Available The asymptomatic phase of HIV infection is characterised by a slow decline of peripheral blood CD4(+ T cells. Why this decline is slow is not understood. One potential explanation is that the low average rate of homeostatic proliferation or immune activation dictates the pace of a "runaway" decline of memory CD4(+ T cells, in which activation drives infection, higher viral loads, more recruitment of cells into an activated state, and further infection events. We explore this hypothesis using mathematical models.Using simple mathematical models of the dynamics of T cell homeostasis and proliferation, we find that this mechanism fails to explain the time scale of CD4(+ memory T cell loss. Instead it predicts the rapid attainment of a stable set point, so other mechanisms must be invoked to explain the slow decline in CD4(+ cells.A runaway cycle in which elevated CD4(+ T cell activation and proliferation drive HIV production and vice versa cannot explain the pace of depletion during chronic HIV infection. We summarize some alternative mechanisms by which the CD4(+ memory T cell homeostatic set point might slowly diminish. While none are mutually exclusive, the phenomenon of viral rebound, in which interruption of antiretroviral therapy causes a rapid return to pretreatment viral load and T cell counts, supports the model of virus adaptation as a major force driving depletion.

  19. HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

    Directory of Open Access Journals (Sweden)

    Nathan Erdmann

    2015-08-01

    Full Text Available Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1 exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE or its non-adapted (NAE version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001. However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001. CD4+ T cell responses in patients with acute HIV infection (AHI demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

  20. In situ depletion of CD4(+) T cells in human skin by Zanolimumab

    DEFF Research Database (Denmark)

    Villadsen, L.S.; Skov, L.; Dam, T.N.

    2007-01-01

    CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease......-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis......(+), but not CD8(+) CD3(+) T cells. The capacity of Zanolimumab to deplete the CD4(+) T cells in the skin may be of importance in diseases where CD4(+) T cells play a central role. Indeed, in a phase II clinical trial Zanolimumab has shown a dose-dependent clinical response in patients with CTCL and the antibody...

  1. Impact of nicotine on the interplay between human periodontal ligament cells and CD4+ T cells.

    Science.gov (United States)

    Ge, Xin; Liu, Ying-Feng; Wong, Yong; Wu, Li-Zheng; Tan, Ling; Liu, Fen; Wang, Xiao-Jing

    2016-09-01

    Periodontitis is a common infectious disease associated with destruction of periodontal ligaments and alveolar bones. CD4(+) T cell-mediated immune response is involved in the progression of periodontitis. Tobacco consumption increases the risk of periodontal disease. However, the impact of nicotine on the interaction between human periodontal ligament (PDL) cells and CD4(+) T cells remains unrevealed. Our study aims to investigate the effect of nicotine on PDL cells and the cocultured CD4(+) T cells. The PDL cell cultures were established by explants from healthy individuals, exposed to nicotine or α-bungarotoxin (α-BTX), and incubated solely or in combination with CD4(+) T cells. Afterwards, cell viability, secreted cytokines, and matrix metalloproteinases (MMPs) were evaluated. In monoculture of PDL cells, nicotine dramatically repressed cell viability and increased apoptosis. Meanwhile, α-BTX largely reversed the nicotine-induced apoptosis and increased viability of PDL cells. Compared with the monoculture, MMP-1, MMP-3, interleukin (IL)-1β, IL-6, IL-17, and IL-21 in supernatant of cocultures were markedly elevated after treatment with nicotine. Moreover, α-BTX significantly attenuated nicotine-triggered production of these components either in mono- or co-cultures. In addition, PDL cell-derived CXCL12 following nicotine treatment recruited CD4(+) T cells. Above all, nicotine deteriorated periodontitis partially by promoting PDL cell-CD4(+) T cell-mediated inflammatory response and matrix degradation. © The Author(s) 2015.

  2. A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease

    Science.gov (United States)

    Zhou, Vivian; Agle, Kimberle; Chen, Xiao; Beres, Amy; Komorowski, Richard; Belle, Ludovic; Taylor, Carolyn; Zhu, Fenlu; Haribhai, Dipica; Williams, Calvin B.; Verbsky, James; Blumenschein, Wendy; Sadekova, Svetlana; Bowman, Eddie; Ballantyne, Christie; Weaver, Casey; Serody, David A.; Vincent, Benjamin; Serody, Jonathan; Cua, Daniel J.; Drobyski, William R.

    2016-01-01

    Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell–mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin–expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non–Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10–regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers. PMID:27500496

  3. Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes.

    Science.gov (United States)

    Westhorpe, Clare L V; Norman, M Ursula; Hall, Pam; Snelgrove, Sarah L; Finsterbusch, Michaela; Li, Anqi; Lo, Camden; Tan, Zhe Hao; Li, Songhui; Nilsson, Susan K; Kitching, A Richard; Hickey, Michael J

    2018-02-21

    Although effector CD4 + T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown. Here we show the process of intravascular antigen recognition using intravital multiphoton microscopy of glomeruli. CD4 + T cells undergo intravascular migration within uninflamed glomeruli. Similarly, while MHCII is not expressed by intrinsic glomerular cells, intravascular MHCII-expressing immune cells patrol glomerular capillaries, interacting with CD4 + T cells. Following intravascular deposition of antigen in glomeruli, effector CD4 + T-cell responses, including NFAT1 nuclear translocation and decreased migration, are consistent with antigen recognition. Of the MHCII + immune cells adherent in glomerular capillaries, only monocytes are retained for prolonged durations. These cells can also induce T-cell proliferation in vitro. Moreover, monocyte depletion reduces CD4 + T-cell-dependent glomerular inflammation. These findings indicate that MHCII + monocytes patrolling the glomerular microvasculature can present intravascular antigen to CD4 + T cells within glomerular capillaries, leading to antigen-dependent inflammation.

  4. Establishment and characterization of Epstein-Barr virus-specific human CD4+ T lymphocyte clones

    International Nuclear Information System (INIS)

    Honda, S.; Okuno, K.; Yasutomi, M.; Takasaki, T.; Kurane, I.

    1998-01-01

    We developed a simple method for establishing Epstein-Barr virus (EBV)-specific, human CD4+ T cell clones. The method originates from our experience that the regression of cell growth in in vitro EBV transformation of B cells occurs when round lymphoid cells appear in the culture. Peripheral blood mononuclear cells were cultured with EBV; and IL-2 (20 U/ml) was added to the culture on day 17 after the virus addition. The phenotype of the growing cells was CD3+ , CD4+ , and CD8-. The cells were cytotoxic for autologous lymphoblastoid B cell line (LCL) and EBV-super-infected autologous LCL. The cytotoxic T lymphocytes (CTLs) were confirmed to be CD4+ T cells but not CD8+ T cells in the culture. CTL clones were established by a limiting dilution method. All the CTL clones had the phenotype of CD3+ , CD4+ and CD8-, and proliferated in response to autologous LCL. They produced interferon (IFN)-gamma, interleukin 2 (IL-2) and tumour necrosis factor (TNF)-beta but not IL-4. All but one clone responded to both autologous, EBV-super-infected and non-super-infected LCLs. Proliferative and cytotoxic responses to allogeneic LCLs were heterogeneous. These results suggest that this method induces heterogeneous, EBV-specific CD4+ CTL clones and is useful for analysis of CD4+ T cells in EBV infections. (authors)

  5. Scaffold protein JLP mediates TCR-initiated CD4+T cell activation and CD154 expression.

    Science.gov (United States)

    Yan, Qi; Yang, Cheng; Fu, Qiang; Chen, Zhaowei; Liu, Shan; Fu, Dou; Rahman, Rahmat N; Nakazato, Ryota; Yoshioka, Katsuji; Kung, Sam K P; Ding, Guohua; Wang, Huiming

    2017-07-01

    CD4 + T-cell activation and its subsequent induction of CD154 (CD40 ligand, CD40L) expression are pivotal in shaping both the humoral and cellular immune responses. Scaffold protein JLP regulates signal transduction pathways and molecular trafficking inside cells, thus represents a critical component in maintaining cellular functions. Its role in regulating CD4 + T-cell activation and CD154 expression, however, is unclear. Here, we demonstrated expression of JLP in mouse tissues of lymph nodes, thymus, spleen, and also CD4 + T cells. Using CD4+ T cells from jlp-deficient and jlp-wild-type mice, we demonstrated that JLP-deficiency impaired T-cell proliferation, IL-2 production, and CD154 induction upon TCR stimulations, but had no impacts on the expression of other surface molecules such as CD25, CD69, and TCR. These observed impaired T-cell functions in the jlp-/- CD4 + T cells were associated with defective NF-AT activation and Ca 2 + influx, but not the MAPK, NF-κB, as well as AP-1 signaling pathways. Our findings indicated that, for the first time, JLP plays a critical role in regulating CD4 + T cells response to TCR stimulation partly by mediating the activation of TCR-initiated Ca 2+ /NF-AT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Increased Aqueous Humor CD4+/CD8+ Lymphocyte Ratio in Sarcoid Uveitis.

    Science.gov (United States)

    Dave, Namita; Chevour, Priyanka; Mahendradas, Padmamalini; Venkatesh, Anitha; Kawali, Ankush; Shetty, Rohit; Ghosh, Arkasubhra; Sethu, Swaminathan

    2018-02-08

    To determine aqueous humor CD4+/CD8+ T-lymphocyte ratio changes in sarcoid and non-sarcoid uveitis with anterior chamber involvement. The case-control study includes 61 patients with either anterior uveitis, intermediate uveitis with anterior spill, or panuveitis. A total of 21 of them were categorized as sarcoid uveitis and 40 as non-sarcoid uveitis according to diagnostic criteria. CD4+/CD8+ ratio in the aqueous humor was determined using flow cytometry. Significantly higher CD4+/CD8+ ratio in the aqueous humor was observed in patients with sarcoid uveitis (6.3 ± 1.4; mean ± SEM) compared to non-sarcoid uveitis (1.6 ± 0.1; mean ± SEM). Whole blood CD4+/CD8+ ratio was not elevated in subjects with sarcoid and non-sarcoid uveitis. Aqueous humor CD4+/CD8+ ratio >3.5 was observed to be associated with sarcoid uveitis (OR 38, 95% CI 7.0-205.2). Increased aqueous humor CD4+/CD8+ ratio in sarcoid uveitis. Immunophenotyping of localized lymphocytosis in aqueous humor could be utilized as an additional confirmatory marker for ocular sarcoidosis.

  7. IL-17-Expressing CD4+ and CD8+ T Lymphocytes in Human Toxoplasmosis

    Directory of Open Access Journals (Sweden)

    Jéssica Líver Alves Silva

    2014-01-01

    Full Text Available This study aimed to measure the synthesis of Th1 and Th2 cytokines by mononuclear cells after culture with live T. gondii and identified Th17 (CD4+ and Tc17 (CD8+ cells in toxoplasma-seronegative and toxoplasma-seropositive parturient and nonpregnant women. Cytometric bead arrays were used to measure cytokine levels (IL-2, TNF-α, IFN-γ, IL-4, IL-5, and IL-10; immunophenotyping was used to characterize Th17 and Tc17 cells, and the cells were stained with antibodies against CD4+ and CD8+ T cells expressing IL-17. The addition of tachyzoites to cell cultures induced the synthesis of IL-5, IL-10, and TNF-α by cells from seronegative parturient women and of IL-5 and IL-10 by cells from seropositive, nonpregnant women. We observed a lower level of IL-17-expressing CD4+ and CD8+ T lymphocytes in cultures of cells from seronegative and seropositive parturient and nonpregnant women that were stimulated with tachyzoites, whereas analysis of the CD4+ and CD8+ T cell populations showed a higher level of CD4+ T cells compared with CD8+ T cells. These results suggest that the cytokine pattern and IL-17-expressing CD4+ and CD8+ T lymphocytes may have important roles in the inflammatory response to T. gondii, thus contributing to the maintenance of pregnancy and control of parasite invasion and replication.

  8. Lymphoid tissue inducer cells: pivotal cells in the evolution of CD4 immunity and tolerance?

    Directory of Open Access Journals (Sweden)

    Peter John Lane

    2012-02-01

    Full Text Available Phylogeny suggests that the evolution of placentation in mammals was accompanied by substantial changes in the mammalian immune system: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi are members of an emerging family of innate lymphoid cells (ILCs that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3-dependent regulatory T cells (Tregs that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the Tregs that under normal circumstances are absolutely required to regulate CD4 effector cells.

  9. Operational challenges in delivering CD4 diagnostics in sub-Saharan Africa.

    Science.gov (United States)

    Thairu, L; Katzenstein, D; Israelski, D

    2011-07-01

    Access to reliable and low cost CD4 T-cell enumeration to stage illness and monitor anti-retroviral therapy remains elusive in resource-limited settings. We report challenges in delivering CD4 testing using the microcapillary Fluorescence-Activated Cell Sorter (FACS) methodology (Guava EasyCD4 instrument Guava Technologies, Hayward) in Burkina Faso and Zimbabwe. Resources, instruments, reagents, and training were provided to local laboratories within the existing infrastructure and data on CD4 were collected from routine laboratory testing. Challenges encountered included frequent instrument breakdown; poor manufacturer maintenance; difficulties in managing reagent stocks; high technician turnover; reliance on antiquated data management systems; redundant service provision; and lack of repeat testing in male HIV+ patients and in patients with higher CD4 counts after initial staging. While adopting newer, less expensive technologies such as fluorescent platforms and point of care tests can facilitate access to lower cost CD4 testing, our experience suggests that supply chain, corporate commitment to implementation, and community factors also require consideration.

  10. Create positive contraceptive images for strongest impact in single lesson.

    Science.gov (United States)

    1987-05-01

    Health educators attempting to deliver contraceptive information to adolescents in the classroom must seek ways to make a major impact in a very short period of time. A Planned Parenthood professional from New Jersey has developed a single-shot birth control lesson that, rather than presenting the pros and cons of various contraceptive methods, has teenagers identify themselves as at high, low, or no risk of pregnancy. Students estimate the number of classmates who are in each category and then assess whether they personally are at risk of an unintended pregnancy. In general, teens overestimate the number of classmates who are sexually active. This approach seems to make the ensuing discussion of contraceptive methods more meaningful. This discussion presents the condom and foam, the sponge, and visiting a family planning clinic. After this 40 minute presentation, fewer adolescents report being afraid of contraceptive side effects; they also have more knowledge about the efficacy and availability of different methods. A lesson in preparation is centered around a videotape entitled "Swept Away is Not Okay." It shows a teen couple going to a family planning clinic before they ever have intercourse. This strategy of encouraging adolescents to seek contraception before sexual involvement begins is considered more realistic than pressuring teens to abstain from sex. School officials and teachers have been receptive to this educational approach, viewing it as presenting important public health information.

  11. Role of the frequency of blood CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells in autoimmunity in patients with Sjoegren's syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xue-yi; Wu, Zhen-biao; Ding, Jin; Zheng, Zhao-hui [Department of Clinical Immunology, State key Discipline of Cell Biology, Xi-jing Hospital, Fourth Military Medical University, Shaanxi Province (China); Li, Xiao-yan [Department of Endocrine and Metabolic Diseases, Shaanxi Provincial People' s Hospital, Xi' an, Shaanxi Province (China); Chen, Li-na [Department of Clinical Immunology, State key Discipline of Cell Biology, Xi-jing Hospital, Fourth Military Medical University, Shaanxi Province (China); Zhu, Ping, E-mail: zhuping@fmmu.edu.cn [Department of Clinical Immunology, State key Discipline of Cell Biology, Xi-jing Hospital, Fourth Military Medical University, Shaanxi Province (China)

    2012-06-01

    Highlights: Black-Right-Pointing-Pointer The frequency of CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells increased in pSS patients and positively correlated with autoantibodies in the blood. Black-Right-Pointing-Pointer CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells in blood invariably coexpressed PD-1, ICOS, CD40L, Bcl-6 and secreted IL-21 after stimulated by PHA. Black-Right-Pointing-Pointer CD4{sup +} CXCR5{sup +} CCR6{sup +} Tfh cells in blood may be suitable biomarkers for the evaluation of the active immune stage of pSS patients. -- Abstract: The blood CD4{sup +} CXCR5{sup +} T cells, known as 'circulating' Tfh, have been shown to efficiently induce naieve B cells to produce immunoglobulin. They play an important role in certain autoimmune diseases. In the present study, we show for the first time that the frequency of CD4{sup +} CXCR5{sup +} T cells is increased in pSS patients and positively correlated with autoantibodies in the blood. The concentration of Th17-like subsets (CD4{sup +} CXCR5{sup +} CCR6{sup +}) in pSS patients was found to be significantly higher than in healthy controls. Functional assays showed that activated Th17-like subtypes in the blood display the key features of Tfh cells, including invariably coexpressed PD-1, ICOS, CD40L and IL-21. Th17 subsets were found to highly express Bcl-6 protein and Th1 and Th2 were not. Bcl-6 is believed to be a master transforming factor for Tfh cell differentiation and facilitate B cell proliferation and somatic hypermutation within the germinal center. These data indicate that Th17 subsets of CD4{sup +} CXCR5{sup +} T cells in the blood may participate in the antibody-related immune responses and that high frequency of CD4{sup +} CXCR5{sup +} CCR6{sup +} Tfh cells in blood may be suitable biomarkers for the evaluation of the active immune stage of pSS patients. It might provide insights into the pathogenesis and perhaps help researchers identify novel therapeutic targets for pSS.

  12. Minimal contribution of cell-bound antibodies to the immunoscintigraphy of inflamed joints with 99mTc-anti-CD4 monoclonal antibodies

    International Nuclear Information System (INIS)

    Kinne, R.W.; Palombo-Kinne, E.; Wolski, A.; Wolf, F.; Emmrich, F.; Becker, W.

    2002-01-01

    Aim: The cellular joint infiltrate in rheumatoid arthritis patients is rich in CD4-positive T-helper lymphocytes and macrophages, rendering anti-CD4 monoclonal antibodies (mAbs) suitable for specific immunoscintigraphy of human/experimental arthritis. Following intravenous injection, however, mAbs are present both in the free form and bound to CD4-positive, circulating monocytes and T-cells. Thus, the present study aimed at analyzing the relative contribution of the free and the cell-bound component to the imaging of inflamed joints in experimental adjuvant arthritis (AA). Methods: AA rat pertioneal macrophages or lymph node T-cells were incubated in vitro with saturating amounts of 99mTc-anti-CD4 mAb (W3/25) and injected i.v. into rats with AA. Results: In vitro release of 99m Tc-anti-CD4 mAb from the cells was limited (on average 1.57%/h for macrophages and 0.84%/h for T-cells). Following i.v. injection, whole body/joints scans and tissue measurements showed only negligible accumulation of radioactivity in inflamed ankle joints (tissue: 0.22 and 0.34% of the injected activity, respectively), whereas the radioactivity was concentrated in liver (tissue: 79% and 71%, respectively), kidney, and urinary bladder. Unlike macrophages, however, anti-CD4 mAb-coated T-cells significantly accumulated in lymphoid organs, the inflamed synovial membrane of the ankle joints, as well as in elbow and knee joints. Conclusion: While the overall contribution of cell-bound mAbs to the imaging of arthritic joints with anti-CD4 mAbs is minimal, differential accumulation of macrophages and T-cells in lymphoid organs and the inflamed synovial membrane indicates preferential migration patterns of these 2 cell populations in arthritic rats. Although only validated for 99m Tc-anti-CD4 mAbs, extrapolation of the results to other anticellular mAbs with similar affinity for their antigen may be possible. (orig.) [de

  13. Trends in CD4 Count Testing, Retention in Pre-ART Care, and ART Initiation Rates over the First Decade of Expansion of HIV Services in Haiti.

    Directory of Open Access Journals (Sweden)

    Serena P Koenig

    Full Text Available High attrition during the period from HIV testing to antiretroviral therapy (ART initiation is widely reported. Though treatment guidelines have changed to broaden ART eligibility and services have been widely expanded over the past decade, data on the temporal trends in pre-ART outcomes are limited; such data would be useful to guide future policy decisions.We evaluated temporal trends and predictors of retention for each step from HIV testing to ART initiation over the past decade at the GHESKIO clinic in Port-au-Prince Haiti. The 24,925 patients >17 years of age who received a positive HIV test at GHESKIO from March 1, 2003 to February 28, 2013 were included. Patients were followed until they remained in pre-ART care for one year or initiated ART.24,925 patients (61% female, median age 35 years were included, and 15,008 (60% had blood drawn for CD4 count within 12 months of HIV testing; the trend increased over time from 36% in Year 1 to 78% in Year 10 (p500 cells/mm3, respectively. The trend increased over time for each CD4 strata, and in Year 10, 94%, 95%, 79%, and 74% were retained in pre-ART care or initiated ART for each CD4 strata. Predictors of pre-ART attrition included male gender, low income, and low educational status. Older age and tuberculosis (TB at HIV testing were associated with retention in care.The proportion of patients completing assessments for ART eligibility, remaining in pre-ART care, and initiating ART have increased over the last decade across all CD4 count strata, particularly among patients with CD4 count ≤350 cells/mm3. However, additional retention efforts are needed for patients with higher CD4 counts.

  14. Glycosylphosphatidylinositol-Anchored Anti-HIV scFv Efficiently Protects CD4 T Cells from HIV-1 Infection and Deletion in hu-PBL Mice

    Science.gov (United States)

    Ye, Chaobaihui; Wang, Weiming; Cheng, Liang; Li, Guangming; Wen, Michael; Wang, Qi; Zhang, Qing; Li, Dan

    2016-01-01

    ABSTRACT Despite success in viral inhibition and CD4 T cell recovery by highly active antiretroviral treatment (HAART), HIV-1 is still not curable due to the persistence of the HIV-1 reservoir during treatment. One patient with acute myeloid leukemia who received allogeneic hematopoietic stem cell transplantation from a homozygous CCR5 Δ32 donor has had no detectable viremia for 9 years after HAART cessation. This case has inspired a field of HIV-1 cure research focusing on engineering HIV-1 resistance in permissive cells. Here, we employed a glycosylphosphatidylinositol (GPI)-scFv X5 approach to confer resistance of human primary CD4 T cells to HIV-1. We showed that primary CD4 T cells expressing GPI-scFv X5 were resistant to CCR5 (R5)-, CXCR4 (X4)-, and dual-tropic HIV-1 and had a survival advantage compared to control cells ex vivo. In a hu-PBL mouse study, GPI-scFv X5-transduced CD4 T cells were selected in peripheral blood and lymphoid tissues upon HIV-1 infection. Finally, GPI-scFv X5-transduced CD4 T cells, after being cotransfused with HIV-infected cells, showed significantly reduced viral loads and viral RNA copy numbers relative to CD4 cells in hu-PBL mice compared to mice with GPI-scFv AB65-transduced CD4 T cells. We conclude that GPI-scFv X5-modified CD4 T cells could potentially be used as a genetic intervention against both R5- and X4-tropic HIV-1 infections. IMPORTANCE Blocking of HIV-1 entry is one of most promising approaches for therapy. Genetic disruption of the HIV-1 coreceptor CCR5 by nucleases in T cells is under 2 clinical trials and leads to reduced viremia in patients. However, the emergence of viruses using the CXCR4 coreceptor is a concern for therapies applying single-coreceptor disruption. Here, we report that HIV-1-permissive CD4 T cells engineered with GPI-scFv X5 are resistant to R5-, X4-, or dual-tropic virus infection ex vivo. In a preclinical study using hu-PBL mice, we show that CD4 T cells were protected and that GPI-scFv X5

  15. The frequencies of IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+ T-cells correlate with the magnitude of the QuantiFERON® gold in-tube response in a prospective study of healthy indian adolescents.

    Science.gov (United States)

    Jenum, Synne; Grewal, Harleen M S; Hokey, David A; Kenneth, John; Vaz, Mario; Doherty, Timothy Mark; Jahnsen, Frode Lars

    2014-01-01

    QuantiFERON-TB Gold In-Tube (QFT) is an IFNγ-release assay used in the diagnosis of Mycobacterium tuberculosis (MTB) infection. The risk of TB progression increases with the magnitude of the MTB-specific IFNγ-response. QFT reversion, also associated with low Tuberculin Skin Test responses, may therefore represent a transient immune response with control of M. tuberculosis infection. However, studies at the single cell level have suggested that the quality (polyfunctionality) of the T-cell response is more important than the quantity of cytokines produced. To explore the quality and/or magnitude of mycobacteria-specific T-cell responses associated with QFT reversion and persistent QFT-positivity. Multi-color flowcytometry on prospectively collected peripheral blood mononuclear cells was applied to assess mycobacteria-specific T-cell responses in 42 QFT positive Indian adolescents of whom 21 became QFT negative (reverters) within one year. Ten QFT consistent negatives were also included as controls. There was no difference in the qualitative PPD-specific CD4+ T-cell response between QFT consistent positives and reverters. However, compared with QFT consistent positives, reverters displayed lower absolute frequencies of polyfunctional (IFNγ+IL2+TNFα+) CD4+ T-cells at baseline, which were further reduced to the point where they were not different to QFT negative controls one year later. Moreover, absolute frequencies of these cells correlated well with the magnitude of the QFT-response. Whereas specific polyfunctional CD4+ T-cells have been suggested to protect against TB progression, our data do not support that higher relative or absolute frequencies of PPD-specific polyfunctional CD4+ T-cells in peripheral blood can explain the reduced risk of TB progression observed in QFT reverters. On the contrary, absolute frequencies of these cells correlated with the QFT-response, suggesting that this readout reflects antigenic load.

  16. Predicting CD4 count changes among patients on antiretroviral treatment: Application of data mining techniques.

    Science.gov (United States)

    Kebede, Mihiretu; Zegeye, Desalegn Tigabu; Zeleke, Berihun Megabiaw

    2017-12-01

    To monitor the progress of therapy and disease progression, periodic CD4 counts are required throughout the course of HIV/AIDS care and support. The demand for CD4 count measurement is increasing as ART programs expand over the last decade. This study aimed to predict CD4 count changes and to identify the predictors of CD4 count changes among patients on ART. A cross-sectional study was conducted at the University of Gondar Hospital from 3,104 adult patients on ART with CD4 counts measured at least twice (baseline and most recent). Data were retrieved from the HIV care clinic electronic database and patients` charts. Descriptive data were analyzed by SPSS version 20. Cross-Industry Standard Process for Data Mining (CRISP-DM) methodology was followed to undertake the study. WEKA version 3.8 was used to conduct a predictive data mining. Before building the predictive data mining models, information gain values and correlation-based Feature Selection methods were used for attribute selection. Variables were ranked according to their relevance based on their information gain values. J48, Neural Network, and Random Forest algorithms were experimented to assess model accuracies. The median duration of ART was 191.5 weeks. The mean CD4 count change was 243 (SD 191.14) cells per microliter. Overall, 2427 (78.2%) patients had their CD4 counts increased by at least 100 cells per microliter, while 4% had a decline from the baseline CD4 value. Baseline variables including age, educational status, CD8 count, ART regimen, and hemoglobin levels predicted CD4 count changes with predictive accuracies of J48, Neural Network, and Random Forest being 87.1%, 83.5%, and 99.8%, respectively. Random Forest algorithm had a superior performance accuracy level than both J48 and Artificial Neural Network. The precision, sensitivity and recall values of Random Forest were also more than 99%. Nearly accurate prediction results were obtained using Random Forest algorithm. This algorithm could be

  17. Downregulation of cathepsin G reduces the activation of CD4+ T cells in murine autoimmune diabetes.

    Science.gov (United States)

    Zou, Fang; Lai, Xiaoyang; Li, Jing; Lei, Shuihong; Hu, Lei

    2017-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease due to progressive injury of islet cells mediated by T lymphocytes (T cells). Our previous studies have shown that only cathepsin G (CatG), not other proteases, is involved in the antigen presentation of proinsulin, and if the presentation is inhibited, the activation of CD4+ T cells induced by proinsulin is alleviated in T1DM patients, and CatG-specific inhibitor reduces the activation of CD4+ cells induced by proinsulin in T1DM patients. Therefore, we hypothesize that CatG may play an important role in the activation of CD4+ T cells in T1DM. To this end, mouse studies were conducted to demonstrate that CatG impacts the activation of CD4+ T cells in non-obese diabetic (NOD) mice. CatG gene expression and the activation of CD4+ T cells were examined in NOD mice. The effect of CatG inhibitor was investigated in NOD mice on the activation of CD4+ T cells, islet β cell function, islet inflammation and β-cell apoptosis. Furthermore, NOD mice were injected with CatG siRNA in early stage to observe the effect of CatG knockdown on the activation status of CD4+ T cells and the progression of diabetes. During the pathogenesis of diabetes, the expression level of CatG in NOD mice gradually increased and the CD4+ T cells were gradually activated, resulting in more TH1 cells and less TH2 and Treg cells. Treatment with CatG-specific inhibitor reduced the blood glucose level, improved the function of islet β cells and reduced the activation of CD4+ T cells. Early application of CatG siRNA improved the function of islet β cells, reduced islet inflammation and β cell apoptosis, and lowered the activation level of CD4+ T cells, thus slowing down the progression of diabetes.

  18. Analysis of HIV disease burden by calculating the percentages of patients with CD4 counts <100 cells/µL across 52 districts reveals hot spots for intensified commitment to programmatic support.

    Science.gov (United States)

    Coetzee, Lindi Marie; Cassim, Naseem; Glencross, Deborah Kim

    2017-05-24

    South Africa (SA)'s Comprehensive HIV and AIDS Care, Management and Treatment (CCMT) programme has reduced new HIV infections and HIV-related deaths. In spite of progress made, 11.2% of South Africans (4.02 million) were living with HIV in 2015. The National Health Laboratory Service (NHLS) in SA performs CD4 testing in support of the CCMT programme and collates data through the NHLS Corporate Data Warehouse. The objective of this study was to assess the distribution of CD4 counts <100 cells/µL (defining severely immunosuppressed HIV-positive patients) and >500 cells/µL (as an HIV-positive 'wellness' indicator). CD4 data were extracted for the financial years 2010/11 and 2014/15, according to the district where the test was ordered, for predefined CD4 ranges. National and provincial averages of CD4 counts <100 and >500 cells/µL were calculated. Data were analysed using Stata 12 and mapping was done with ArcGIS software, reporting percentages of CD4 counts <100 and >500 cells/µL by district. The national average percentage of patients with CD4 counts <100 cells/µL showed a marked decrease (by 22%) over the 5-year study period, with a concurrent increase in CD4 counts >500 cells/µL (by 57%). District-by-district analysis showed that in 2010/11, 44/52 districts had >10% of CD4 samples with counts <100 cells/µL, decreasing to only 17/52 districts by 2014/15. Overall, districts in the Western Cape and KwaZulu-Natal had the lowest percentages of CD4 counts <100 cells/µL, as well as the highest percentages of counts >500 cells/µL. In contrast, in 2014/15, the highest percentages of CD4 counts <100 cells/µL were noted in the West Rand (Gauteng), Vhembe (Limpopo) and Nelson Mandela Bay (Eastern Cape) districts, where the lowest percentages of counts >500 cells/µL were also noted. The percentages of CD4 counts <100 cells/µL highlighted here reveal districts with positive change suggestive of programmatic improvements, and also highlight districts requiring local

  19. Failure of pulmonary clearance of Rhodococcus equi infection in CD4+ T-lymphocyte-deficient transgenic mice.

    OpenAIRE

    Kanaly, S T; Hines, S A; Palmer, G H

    1993-01-01

    Pulmonary clearance of Rhodococcus equi requires functional T lymphocytes. In this study, CD8+ T-lymphocyte-deficient transgenic mice cleared virulent R. equi from the lungs while infection in CD4+ T-lymphocyte-deficient transgenic mice persisted. Although both CD4+ and CD8+ T cells function early in pulmonary defense against R. equi, clearance is dependent on CD4+ T lymphocytes.

  20. Cytotoxic reactivity of gut lamina propria CD4+ alpha beta T cells in SCID mice with colitis

    DEFF Research Database (Denmark)

    Bonhagen, K; Thoma, S; Bland, P

    1996-01-01

    Polyclonal, mucosa-seeking memory/effector CD4+ T cells containing a large fraction of blasts activated in situ accumulate in the gut lamina propria of severe-combined immunodeficient (SCID) mice developing colitis after CD4+ T cell transplantation. CD4+ T cells isolated from different repopulated...

  1. Preferential infection and depletion of Mycobacterium tuberculosis-specific CD4 T cells after HIV-1 infection

    NARCIS (Netherlands)

    Geldmacher, Christof; Ngwenyama, Njabulo; Schuetz, Alexandra; Petrovas, Constantinos; Reither, Klaus; Heeregrave, Edwin J.; Casazza, Joseph P.; Ambrozak, David R.; Louder, Mark; Ampofo, William; Pollakis, Georgios; Hill, Brenna; Sanga, Erica; Saathoff, Elmar; Maboko, Leonard; Roederer, Mario; Paxton, William A.; Hoelscher, Michael; Koup, Richard A.

    2010-01-01

    HIV-1 infection results in the progressive loss of CD4 T cells. In this study, we address how different pathogen-specific CD4 T cells are affected by HIV infection and the cellular parameters involved. We found striking differences in the depletion rates between CD4 T cells to two common

  2. Normal telomere lengths in naive and memory CD4+ T cells in HIV type 1 infection: a mathematical interpretation

    NARCIS (Netherlands)

    Wolthers, K. C.; Noest, A. J.; Otto, S. A.; Miedema, F.; de Boer, R. J.

    1999-01-01

    To study CD4+ T cell productivity during HIV-1 infection, CD4+ T cell telomere lengths were measured. Cross-sectional and longitudinal analysis of HIV-1-infected individuals with CD4+ T cells counts >300 cells/mm3 showed normal average telomeric restriction fragment (TRF) length and normal

  3. Normal telomere lengths in naive and memory CD4 T cells in HIV type 1 infection : a mathematical interpretation

    NARCIS (Netherlands)

    Wolthers, K.C.; Noest, A.J.; Otto, S.A.; Miedema, F.; Boer, R.J. de

    1999-01-01

    To study CD4+ T cell productivity during HIV-1 infection, CD4+ T cell telomere lengths were measured. Cross-sectional and longitudinal analysis of HIV-1-infected individuals with CD4+ T cells counts >300 cells/mm3 showed normal average telomeric restriction fragment (TRF) length and normal

  4. Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy.

    Science.gov (United States)

    ElAlfy, Mohsen Saleh; Adly, Amira Abdel Moneam; Ebeid, Fatma Soliman ElSayed; Eissa, Deena Samir; Ismail, Eman Abdel Rahman; Mohammed, Yasser Hassan; Ahmed, Manar Elsayed; Saad, Aya Sayed

    2018-06-20

    Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4 + CD28 null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4 + CD28 null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4 + CD28 null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4 + CD28 null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4 + CD28 null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4 + CD28 null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4 + CD28 null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

  5. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

    International Nuclear Information System (INIS)

    Wirsdörfer, Florian; Cappuccini, Federica; Niazman, Muska; Leve, Simone de; Westendorf, Astrid M; Lüdemann, Lutz; Stuschke, Martin; Jendrossek, Verena

    2014-01-01

    Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg). C57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry. Whole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice. The response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease

  6. Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bingfen Yang

    Full Text Available CD244 (2B4 is a member of the signaling lymphocyte activation molecule (SLAM family of immune cell receptors and it plays an important role in modulating NK cell and CD8(+ T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4(+ T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4(+ T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen-specific CD4(+ T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4(+ T cells, CD244/2B4-bright CD4(+ T cell subset had significantly reduced expression of IFN-γ, suggesting that CD244/2B4 expression may modulate IFN-γ production in M. tuberculosis antigen-responsive CD4(+ T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-γ. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-γ, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4(+ T cell function.

  7. Quorum sensing in CD4+ T cell homeostasis: a hypothesis and a model.

    Directory of Open Access Journals (Sweden)

    Afonso R.M. Almeida

    2012-05-01

    Full Text Available Homeostasis of lymphocyte numbers is believed to be due to competition between cellular populations for a common niche of restricted size, defined by the combination of interactions and trophic factors required for cell survival. Here we propose a new mechanism: homeostasis of lymphocyte numbers could also be achieved by the ability of lymphocytes to perceive the density of their own populations. Such a mechanism would be reminiscent of the primordial quorum sensing systems used by bacteria, in which some bacteria sense the accumulation of bacterial metabolites secreted by other elements of the population, allowing them to count the number of cells present and adapt their growth accordingly. We propose that homeostasis of CD4+ T cell numbers may occur via a quorum-sensing-like mechanism, where IL-2 is produced by activated CD4+ T cells and sensed by a population of CD4+ Treg cells that expresses the high-affinity IL-2Rα-chain and can regulate the number of activated IL-2-producing CD4+ T cells and the total CD4+T cell population. In other words, CD4+ T cell populations can restrain their growth by monitoring the number of activated cells, thus preventing uncontrolled lymphocyte proliferation during immune responses. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled T cell activation and autoimmunity. Finally, we present a mathematical model that describes the role of IL-2 and quorum-sensing mechanisms in CD4+ T cell homeostasis during an immune response.

  8. Diagnostic utility of CD4%:CD8 low% T-lymphocyte ratio to differentiate feline immunodeficiency virus (FIV)-infected from FIV-vaccinated cats.

    Science.gov (United States)

    Litster, Annette; Lin, Jui-Ming; Nichols, Jamieson; Weng, Hsin-Yi

    2014-06-04

    Antibody testing based on individual risk assessments is recommended to determine feline immunodeficiency virus (FIV) status, but ELISA and Western blot tests cannot distinguish between anti-FIV antibodies produced in response to natural infection and those produced in response to FIV vaccination. The aim of this cross-sectional study was to test the hypothesis that FIV-infected cats could be differentiated from FIV-vaccinated uninfected cats using lymphocyte subset results, specifically the CD4%:CD8(low)% T-lymphocyte ratio. Comparisons of the CD4%:CD8(low)% T-lymphocyte ratio were made among the following four groups: Group 1 - FIV-infected cats (n=61; FIV-antibody positive by ELISA and FIV PCR positive); Group 2 - FIV-uninfected cats (n=96; FIV-antibody negative by ELISA); Group 3 - FIV-vaccinated uninfected cats (n=31; FIV-antibody negative by ELISA before being vaccinated against FIV, after which they tested FIV ELISA positive); and Group 4 - FIV-uninfected but under chronic/active antigenic stimulation (n=16; FIV-antibody negative by ELISA; all had active clinical signs of either upper respiratory tract disease or gingival disease for ≥ 21 days). The median CD4%:CD8(low)% T-lymphocyte ratio was lower in Group 1 (1.39) than in each of the other three groups (Group 2 - 9.77, Group 3 - 9.72, Group 4 - 5.64; P<0.05). The CD4%:CD8(low)% T-lymphocyte ratio was also the most effective discriminator between FIV-infected cats and the other three groups, and areas under ROC curves ranged from 0.91 (compared with Group 4) to 0.96 (compared with Group 3). CD4%:CD8(low)% shows promise as an effective test to differentiate between FIV-infected cats and FIV-vaccinated uninfected cats. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Dynamic Changes in Fetal Microchimerism in Maternal Peripheral Blood Mononuclear Cells, CD4+ and CD8+ Cells in Normal Pregnancy

    Science.gov (United States)

    Adams Waldorf, Kristina M.; Gammill, Hilary S.; Lucas, Joëlle; Aydelotte, Tessa M.; Leisenring, Wendy M.; Lambert, Nathalie C.; Nelson, J. Lee

    2010-01-01

    Objective Cell trafficking during pregnancy results in persistence of small populations of fetal cells in the mother, known as fetal microchimerism (FMc). Changes in cell-free fetal DNA during gestation have been well-described, however, less is known about dynamic changes in fetal immune cells in maternal blood. We investigated FMc in maternal peripheral blood mononuclear cells (PBMC) longitudinally across gestation. Study Design Thirty-five women with normal pregnancies were studied. FMc was identified in PBMC, CD4+ and CD8+ subsets employing quantitative PCR assays targeting fetal-specific genetic polymorphisms. FMc quantities were reported as fetal genome equivalents (gEq) per 1,000,000 gEq mother’s cells. Poisson regression modeled the rate of FMc detection. Main Outcome Measure FMc in PBMC Results The probability of detecting one fetal cell equivalent increased 6.2-fold each trimester [Incidence Rate Ratio (IRR) 95% CI: 1.73, 21.91; p=0.005]. Although FMC in PBMC was not detected for the majority of time points, 7 of 35 women had detectable FMc during pregnancy at one or more time points, with the majority of positive samples being from the third trimester. There was a suggestion of greater HLA-sharing in families where women had FMc in PBMC. FMc was detected in 9% of CD4+ (2/23) and 18% of CD8+ (3/25) subsets. Conclusions FMc in PBMC increased as gestation progressed and was found within CD4+ and CD8+ subsets in some women in the latter half of gestation. A number of factors could influence cellular FMc levels including subclinical fetal-maternal interface changes and events related to parturition. Whether FMc during pregnancy predicts persistent FMc and/or correlates with fetal-maternal HLA-relationships also merits further study. PMID:20569981

  10. Casp8p41: The Protean Mediator of Death in CD4 T-cells that Replicate HIV

    Directory of Open Access Journals (Sweden)

    Rahul Sampath

    2016-01-01

    Full Text Available HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound–-that occurs within weeks of combination anti retroviral therapy (cART interruption. Modalities to engineer transcriptional stimulation (reactivation of this dormant integrated HIV provirus, leading to expression of cytotoxic viral proteins, are thought to be a specific way to eradicate the latently infected CD4 pool and are becoming increasingly relevant in the era of HIV cure. HIV protease is one such protein produced after HIV reactivation that cleaves procaspase-8 to generate a novel protein Casp8p41. Casp8p41 then binds to the BH3 domain of BAK, leading to BAK oligomerization, mitochondrial depolarization, and apoptosis. In central memory T cells (TCMs from HIV-infected patients, an elevated Bcl-2/procaspase-8 ratio was observed, and Casp8p41 binding to Bcl-2 was associated with a lack of reactivation-induced cell death. This was reversed by priming cells with a specific Bcl-2 antagonist prior to reactivation, resulting in increased cell death and decreased HIV DNA in a Casp8p41-dependent pathway. This review describes the biology, clinical relevance, and implications of Casp8p41 for a potential cure.

  11. The Ixodes scapularis Salivary Protein, Salp15, Prevents the Association of HIV-1 gp120 and CD4

    OpenAIRE

    Juncadella, Ignacio J.; Garg, Renu; Bates, Tonya C.; Olivera, Elias R.; Anguita, Juan

    2007-01-01

    Ixodes scapularis salivary protein, Salp15, inhibits CD4+ T cell activation by binding to the most-extracellular domains of the CD4 molecule, potentially overlapping with the gp120-binding region. We now show that Salp15 inhibits the interaction of gp120 and CD4. Furthermore, Salp15 prevents syncytia formation between HL2/3 (a stable HeLa cell line expressing the envelope protein) and CD4-expressing cells. Salp15 prevented gp120-CD4 interaction at least partially through its direct interactio...

  12. Intestinal Parasitosis in Relation to Anti-Retroviral Therapy, CD4(+) T-cell Count and Diarrhea in HIV Patients.

    Science.gov (United States)

    Khalil, Shehla; Mirdha, Bijay Ranjan; Sinha, Sanjeev; Panda, Ashutosh; Singh, Yogita; Joseph, Anju; Deb, Manorama

    2015-12-01

    Intestinal parasitic infections are one of the major causes of diarrhea in human immunodeficiency virus (HIV) seropositive individuals. Antiretroviral therapy has markedly reduced the incidence of many opportunistic infections, but parasite-related diarrhea still remains frequent and often underestimated especially in developing countries. The present hospital-based study was conducted to determine the spectrum of intestinal parasitosis in adult HIV/AIDS (acquired immunodeficiency syndrome) patients with or without diarrhea with the levels of CD4(+) T-cell counts. A total of 400 individuals were enrolled and were screened for intestinal parasitosis. Of these study population, 200 were HIV seropositives, and the remaining 200 were HIV uninfected individuals with or without diarrhea. Intestinal parasites were identified by using microscopy as well as PCR assay. A total of 130 (32.5%) out of 400 patients were positive for any kinds of intestinal parasites. The cumulative number of parasite positive patients was 152 due to multiple infections. A significant association of Cryptosporidium (P<0.001) was detected among individuals with CD4(+) T-cell counts less than 200 cells/μl.

  13. Primary brain tumors treated with steroids and radiotherapy: Low CD4 counts and risk of infection

    International Nuclear Information System (INIS)

    Hughes, Michael A.; Parisi, Michele; Grossman, Stuart; Kleinberg, Lawrence

    2005-01-01

    Purpose: Patients with primary brain tumors are often treated with high doses of corticosteroids for prolonged periods to reduce intracranial swelling and alleviate symptoms such as headaches. This treatment may lead to immunosuppression, placing the patient at risk of life-threatening opportunistic infections, such as Pneumocystis carinii pneumonia. The risk of contracting some types of infection may be reduced with prophylactic antibiotics. The purpose of this study was to determine the occurrence of low CD4 counts and whether monitoring CD4 counts during and after radiotherapy (RT) is warranted. Methods and Materials: CD4 counts were measured during RT in 70 of 76 consecutive patients with newly diagnosed Grade III and IV astrocytoma and anaplastic oligodendroglioma treated with corticosteroids and seen at the Johns Hopkins Hospital. Weekly CD4 measurements were taken in the most recent 25 patients. Prophylactic trimethoprim-sulfamethoxazole (160 mg/800 mg p.o. every Monday, Wednesday, and Friday) or dapsone (100 mg p.o. daily) in those with sulfa allergy was prescribed only if patients developed a low CD4 count. Carmustine chemotherapy wafers were placed at surgery in 23% of patients, evenly distributed between the groups. No patient received any other chemotherapy concurrent with RT. Results: CD4 counts decreased to 3 in 17 (24%) of 70 patients. For the 25 patients with weekly CD4 counts, all CD4 counts were >450/mm 3 before RT, but 6 (24%) of 25 fell to 3 during RT. Patients with counts 3 were significantly more likely to be hospitalized (41% vs. 9%, p <0.01) and be hospitalized for infection (23% vs. 4%, p <0.05) during RT. Overall survival was not significantly different between the groups. All patients with low CD4 counts were treated with prophylactic antibiotics, and no patient developed Pneumocystis carinii pneumonia. No patients developed a serious adverse reaction to antibiotic therapy. The mean dose of steroids, mean minimal white blood cell count

  14. CLINICAL AND LABORATORY PROFILE OF PATIENTS WITH IDIOPATHIC CD4 LYMPHOCYTOPENIA- A RARE CLINICAL ENTITY

    Directory of Open Access Journals (Sweden)

    Vijayashree Thyagaraj

    2017-01-01

    Full Text Available BACKGROUND Since 1989, several investigators have reported unusual cases of severe opportunistic infections associated with CD4 lymphocytopenia in the absence of human immunodeficiency virus infection. The cause of this condition is unknown. The Centres for Disease Control and Prevention (CDC defines Idiopathic CD4 T Lymphocytopenia (ICL as a clinical condition in which patients with depressed numbers of circulating CD4+ T-cell lymphocytes (<300 cells/μL or <20% of total T cells at a minimum of two separate time points at least 6 weeks apart, have no laboratory evidence of infection with human HIV-1 or HIV-2, or any defined immunodeficiency or therapy associated with depressed levels of CD4 T cells. The aim of the study is to analyse the clinical profile, opportunistic infections, laboratory parameters and outcome in terms of survival of patients diagnosed with ICL. MATERIALS AND METHODS Eight HIV negative patients who presented with opportunistic infections and who were diagnosed with ICL from 2007 to 2015 were included in the study. A detailed history was taken; physical examination was performed and the nature of illness with which they presented was documented. Then, CD4 and CD8 counts were done and CD4 count was repeated after a 6-week interval. The patients were followed up until discharge or death. RESULTS The mean age was 37.50±9.55 years. There were six males (75% and two females (25%. Fever was a presenting symptom among six (75% of them. Two were diagnosed to have cutaneous cryptococcosis (25%, two with invasive aspergillosis (25% and four with tuberculosis (50%. Absolute lymphocyte count was less than 1200 in seven patients (87.5%, which roughly correlates with a CD4 count of less than 200 cells/μL, among PLWHIV. The mean CD4 count was 183.63±63.74 cells/μL during the first measurement and 214.43±103.98 cells/μL during the second one. Two patients died (37.5%. None of the patients were recorded to have any form of malignancy

  15. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    International Nuclear Information System (INIS)

    Kim, Kyung-Chang; Kim, Hyeon Guk; Roh, Tae-Young; Park, Jihwan; Jung, Kyung-Min; Lee, Joo-Shil; Choi, Sang-Yun; Kim, Sung Soon; Choi, Byeong-Sun

    2011-01-01

    Research highlights: → CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. → CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. → HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. → H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. → HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56 Lck , ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56 Lck , ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.

  16. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung-Chang [National Institute of Health, Chungbuk (Korea, Republic of); School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Hyeon Guk [National Institute of Health, Chungbuk (Korea, Republic of); Roh, Tae-Young [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Park, Jihwan [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Jung, Kyung-Min; Lee, Joo-Shil [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Sang-Yun [School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Sung Soon [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Byeong-Sun, E-mail: byeongsun@korea.kr [National Institute of Health, Chungbuk (Korea, Republic of)

    2011-01-14

    Research highlights: {yields} CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. {yields} CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. {yields} HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. {yields} H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. {yields} HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56{sup Lck}, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56{sup Lck}, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new

  17. Transmitted drug resistance in the CFAR network of integrated clinical systems cohort: prevalence and effects on pre-therapy CD4 and viral load.

    Directory of Open Access Journals (Sweden)

    Art F Y Poon

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL and CD4+ cell count (CD4 at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184 were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (-1.7 log₁₀pVL and D67N/G (-2.1[³√CD4] and 0.4 log₁₀pVL were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1

  18. Mitofusin 2 Promotes Apoptosis of CD4+ T Cells by Inhibiting Autophagy in Sepsis

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    Lan Ying

    2017-01-01

    Full Text Available Apoptosis of CD4+ T cells is a primary pathophysiological mechanism of immune dysfunction in the pathogenesis of sepsis. Mitofusin 2 (Mfn2, an integral mitochondrial outer membrane protein, has been confirmed to be associated with cellular metabolism, proliferation, and apoptosis. The function of Mfn2 in CD4+ T cell apoptosis in sepsis is poorly understood. Here, we discovered increased in vivo Mfn2 expression, autophagy deficiency, and elevated cell apoptosis in murine splenic CD4+ T cells after cecal ligation and puncture (CLP. We also observed almost identical results in splenic CD4+ T cells upon lipopolysaccharide (LPS stimulation in vitro. Furthermore, overexpression of Mfn2 resulted in impaired autophagy and increased apoptosis in Jurkat cells. Pharmacological inhibition of autophagy with 3-methyladenine enhanced Mfn2 overexpression-induced cell apoptosis. In addition, overexpression of Mfn2 downregulated phorbol myristate acetate (PMA/ionomycin-, rapamycin- and starvation-induced autophagy in Jurkat T cells. Taken together, these data indicate a critical role of Mfn2 in CD4+ T cell apoptosis in sepsis and the underlying mechanism of autophagy deficiency.

  19. Profiling calcium signals of in vitro polarized human effector CD4+ T cells.

    Science.gov (United States)

    Kircher, Sarah; Merino-Wong, Maylin; Niemeyer, Barbara A; Alansary, Dalia

    2018-06-01

    Differentiation of naïve CD4 + T cells into effector subtypes with distinct cytokine profiles and physiological roles is a tightly regulated process, the imbalance of which can lead to an inadequate immune response or autoimmune disease. The crucial role of Ca 2+ signals, mainly mediated by the store operated Ca 2+ entry (SOCE) in shaping the immune response is well described. However, it is unclear if human effector CD4 + T cell subsets show differential Ca 2+ signatures in response to different stimulation methods. Herein, we provide optimized in vitro culture conditions for polarization of human CD4 + effector T cells and characterize their SOCE following both pharmacological store depletion and direct T-cell receptor (TCR) activation. Moreover, we measured whole cell Ca 2+ release activated Ca 2+ currents (I CRAC ) and investigated whether the observed differences correlate to the expression of CRAC genes. Our results show that Ca 2+ profiles of helper CD4 + Th1, Th2 and Th17 are distinct and in part shaped by the intensity of stimulation. Regulatory T cells (Treg) are unique being the subtype with the most prominent SOCE response. Analysis of in vivo differentiated Treg unraveled the role of differential expression of ORAI2 in fine-tuning signals in Treg vs. conventional CD4 + T cells. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

  20. Specific interaction of aurintricarboxylic acid with the human immunodeficiency virus/CD4 cell receptor

    International Nuclear Information System (INIS)

    Schols, D.; Baba, M.; Pauwels, R.; Desmyter, J.; De Clercq, E.

    1989-01-01

    The triphenylmethane derivative aurintricarboxylic acid (ATA), but not aurin, selectively prevented the binding of OKT4A/Leu-3a monoclonal antibody (mAb) and, to a lesser extent, OKT4 mAb to the CD4 cell receptor for human immunodeficiency virus type 1 (HIV-1). The effect was seen within 1 min at an ATA concentration of 10 μM in various T4 + cells (MT-4, U-937, peripheral blood lymphocytes, and monocytes). It was dose-dependent and reversible. ATA prevented the attachment of radiolabeled HIV-1 particles to MT-4 cells, which could be expected as the result of its specific binding to the HIV/CD4 receptor. Other HIV inhibitors such as suramin, fuchsin acid, azidothymidine, dextran sulfate, heparin, and pentosan polysulfate did not affect OKT4A/Leu-3a mAb binding to the CD4 receptor, although the sulfated polysaccharides suppressed HIV-1 adsorption to the cells at concentrations required for complete protection against HIV-1 cytopathogenicity. Thus, ATA is a selective marker molecule for the CD4 receptor. ATA also interfered with the staining of membrane-associated HIV-1 glycoprotein gp120 by a mAb against it. These unusual properties of a small molecule of nonimmunological origin may have important implications for the study of CD4/HIV/AIDS pathogenesis and possibly treatment

  1. Computational modeling of heterogeneity and function of CD4+ T cells

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    Adria eCarbo

    2014-07-01

    Full Text Available The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation.

  2. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow.

    Science.gov (United States)

    Tokoyoda, Koji; Zehentmeier, Sandra; Hegazy, Ahmed N; Albrecht, Inka; Grün, Joachim R; Löhning, Max; Radbruch, Andreas

    2009-05-01

    CD4(+) T lymphocytes are key to immunological memory. Here we show that in the memory phase of specific immune responses, most of the memory CD4(+) T lymphocytes had relocated into the bone marrow (BM) within 3-8 weeks after their generation-a process involving integrin alpha2. Antigen-specific memory CD4(+) T lymphocytes highly expressed Ly-6C, unlike most splenic CD44(hi)CD62L(-) CD4(+) T lymphocytes. In adult mice, more than 80% of Ly-6C(hi)CD44(hi)CD62L(-) memory CD4(+) T lymphocytes were in the BM. In the BM, they associated to IL-7-expressing VCAM-1(+) stroma cells. Gene expression and proliferation were downregulated, indicating a resting state. Upon challenge with antigen, they rapidly expressed cytokines and CD154 and efficiently induced the production of high-affinity antibodies by B lymphocytes. Thus, in the memory phase of immunity, memory helper T cells are maintained in BM as resting but highly reactive cells in survival niches defined by IL-7-expressing stroma cells.

  3. Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

    Science.gov (United States)

    Nishida, Atsushi; Nagahama, Kiyotaka; Imaeda, Hirotsugu; Ogawa, Atsuhiro; Lau, Cindy W; Kobayashi, Taku; Hisamatsu, Tadakazu; Preffer, Frederic I; Mizoguchi, Emiko; Ikeuchi, Hiroki; Hibi, Toshifumi; Fukuda, Minoru; Andoh, Akira; Blumberg, Richard S; Mizoguchi, Atsushi

    2012-12-17

    Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

  4. Exogenous and endogenous hyaluronic acid reduces HIV infection of CD4+ T cells

    Science.gov (United States)

    Li, Peilin; Fujimoto, Katsuya; Bourguingnon, Lilly; Yukl, Steven; Deeks, Steven; Wong, Joseph K

    2014-01-01

    Preventing mucosal transmission of HIV is critical to halting the HIV epidemic. Novel approaches to preventing mucosal transmission are needed. Hyaluronic acid (HA) is a major extracellular component of mucosa and the primary ligand for the cell surface receptor CD44. CD44 enhances HIV infection of CD4+ T cells, but the role of HA in this process is not clear. To study this, virions were generated with CD44 (HIVCD44) or without CD44 (HIVmock). Exogenous HA reduced HIV infection of unstimulated CD4+ T cells in a CD44-dependent manner. Conversely, hyaluronidase-mediated reduction of endogenous HA on the cell surface enhanced HIV binding to and infection of unstimulated CD4+ T cells. Exogenous HA treatment reduced activation of protein kinase C alpha via CD44 on CD4+ T cells during infection with HIVCD44. These results reveal new roles for HA during the interaction of HIV with CD4+ T cells that may be relevant to mucosal HIV transmission and could be exploitable as a future strategy to prevent HIV infection. PMID:24957217

  5. Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

    Science.gov (United States)

    Juno, Jennifer A.; van Bockel, David; Kent, Stephen J.; Kelleher, Anthony D.; Zaunders, John J.; Munier, C. Mee Ling

    2017-01-01

    CD4 T cells with cytotoxic function were once thought to be an artifact due to long-term in vitro cultures but have in more recent years become accepted and reported in the literature in response to a number of viral infections. In this review, we focus on cytotoxic CD4 T cells in the context of human viral infections and in some infections that affect mice and non-human primates. We examine the effector mechanisms used by cytotoxic CD4 cells, the phenotypes that describe this population, and the transcription factors and pathways that lead to their induction following infection. We further consider the cells that are the predominant targets of this effector subset and describe the viral infections in which CD4 cytotoxic T lymphocytes have been shown to play a protective or pathologic role. Cytotoxic CD4 T cells are detected in the circulation at much higher levels than previously realized and are now recognized to have an important role in the immune response to viral infections. PMID:28167943

  6. IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells

    DEFF Research Database (Denmark)

    Skov, S; Bonyhadi, M; Odum, Niels

    2000-01-01

    The cellular and humoral immune system is critically dependent upon CD40-CD154 (CD40 ligand) interactions between CD40 expressed on B cells, macrophages, and dendritic cells, and CD154 expressed primarily on CD4 T cells. Previous studies have shown that CD154 is transiently expressed on CD4 T cells...... after T cell receptor engagement in vitro. However, we found that stimulation of PBLs with maximal CD28 costimulation, using beads coupled to Abs against CD3 and CD28, led to a very prolonged expression of CD154 on CD4 cells (>4 days) that was dependent upon autocrine IL-2 production. Previously...... activated CD4 T cells could respond to IL-2, or the related cytokine IL-15, by de novo CD154 production and expression without requiring an additional signal from CD3 and CD28. These results provide evidence that CD28 costimulation of CD4 T cells, through autocrine IL-2 production, maintains high levels...

  7. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

    Science.gov (United States)

    Doitsh, Gilad; Galloway, Nicole L. K.; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

    2014-01-01

    The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of `anti-AIDS' therapeutics targeting the host rather than the virus.

  8. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

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    Verhoef Adrienne

    2005-01-01

    Full Text Available Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

  9. Role of distinct CD4(+) T helper subset in pathogenesis of oral lichen planus.

    Science.gov (United States)

    Wang, Hui; Zhang, Dunfang; Han, Qi; Zhao, Xin; Zeng, Xin; Xu, Yi; Sun, Zheng; Chen, Qianming

    2016-07-01

    Oral lichen planus (OLP) is one of the most common chronic inflammatory oral mucosal diseases with T-cell-mediated immune pathogenesis. In subepithelial and lamina propria of OLP local lesions, the presence of CD4(+) T helper (CD4(+) Th) cells appeared as the major lymphocytes. These CD4(+) T lymphocytes can differentiate into distinct Th cell types such as Th1, Th2, Treg, Th17, Th22, Th9, and Tfh within the context of certain cytokines environment. Growing evidence indicated that Th1/Th2 imbalance may greatly participate into the cytokine network of OLP immunopathology. In addition, Th1/Th2 imbalance can be regulated by the Treg subset and also greatly influenced by the emerging novel CD4(+) Th subset Th17. Furthermore, the presence of novel subsets Th22, Th9 and Tfh in OLP patients is yet to be clarified. All these Th subsets and their specific cytokines may play a critical role in determining the character, extent and duration of immune responses in OLP pathogenesis. Therefore, we review the roles of distinct CD4(+) Th subsets and their signature cytokines in determining disease severity and susceptibility of OLP and also reveal the novel therapeutic strategies based on T lymphocytes subsets in OLP treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Glutamic acid decarboxylase-derived epitopes with specific domains expand CD4(+CD25(+ regulatory T cells.

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    Guojiang Chen

    Full Text Available BACKGROUND: CD4(+CD25(+ regulatory T cell (Treg-based immunotherapy is considered a promising regimen for controlling the progression of autoimmune diabetes. In this study, we tested the hypothesis that the therapeutic effects of Tregs in response to the antigenic epitope stimulation depend on the structural properties of the epitopes used. METHODOLOGY/PRINCIPAL FINDINGS: Splenic lymphocytes from nonobese diabetic (NOD mice were stimulated with different glutamic acid decarboxylase (GAD-derived epitopes for 7-10 days and the frequency and function of Tregs was analyzed. We found that, although all expanded Tregs showed suppressive functions in vitro, only p524 (GAD524-538-expanded CD4(+CD25(+ T cells inhibited diabetes development in the co-transfer models, while p509 (GAD509-528- or p530 (GAD530-543-expanded CD4(+CD25(+ T cells had no such effects. Using computer-guided molecular modeling and docking methods, the differences in structural characteristics of these epitopes and the interaction mode (including binding energy and identified domains in the epitopes between the above-mentioned epitopes and MHC class II I-A(g7 were analyzed. The theoretical results showed that the epitope p524, which induced protective Tregs, possessed negative surface-electrostatic potential and bound two chains of MHC class II I-A(g7, while the epitopes p509 and p530 which had no such ability exhibited positive surface-electrostatic potential and bound one chain of I-A(g7. Furthermore, p524 bound to I-A(g7 more stably than p509 and p530. Of importance, we hypothesized and subsequently confirmed experimentally that the epitope (GAD570-585, p570, which displayed similar characteristics to p524, was a protective epitope by showing that p570-expanded CD4(+CD25(+ T cells suppressed the onset of diabetes in NOD mice. CONCLUSIONS/SIGNIFICANCE: These data suggest that molecular modeling-based structural analysis of epitopes may be an instrumental tool for prediction of

  11. Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events.

    Science.gov (United States)

    Ho, Hsu-Tso; Fan, Li; Nowicka-Sans, Beata; McAuliffe, Brian; Li, Chang-Ben; Yamanaka, Gregory; Zhou, Nannan; Fang, Hua; Dicker, Ira; Dalterio, Richard; Gong, Yi-Fei; Wang, Tao; Yin, Zhiwei; Ueda, Yasutsugu; Matiskella, John; Kadow, John; Clapham, Paul; Robinson, James; Colonno, Richard; Lin, Pin-Fang

    2006-04-01

    BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.

  12. Dynamic transcription of long non-coding RNA genes during CD4+ T cell development and activation.

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    Fei Xia

    Full Text Available BACKGROUND: Recent evidence shows that long non-coding RNA (LncRNA play important regulatory roles in many biology process, including cell development, activation and oncogenesis. However, the roles of these LncRNAs in the development and activation of CD4+ T cells, which is an important component of immune response, remain unknown. RESULTS: To predict the function of LncRNA in the development and activation of CD4+ T cells, first, we examined the expression profiles of LncRNAs and mRNAs in CD4-CD8- (DN, CD4+CD8+ (DP, CD4+CD8-, and activated CD4+CD8- T cells in a microarray analysis and verified these results by real time PCRs (qPCR. We found that the expression of hundreds of LncRNAs significantly changed in each process of developmental transition, including DN into DP, DP into CD4+CD8-, and CD4+CD8- into activated CD4+ T cells. A Kendall distance analysis suggested that the expression of LncRNAs in DN, DP, CD4+CD8- T cells and activated CD4+ T cells were correlated with the expression of mRNAs in these T cells. The Blat algorithm and GO analysis suggested that LncRNAs may exert important roles in the development and activation of CD4+ T cells. These roles included proliferation, homeostasis, maturation, activation, migration, apoptosis and calcium ion transportation. CONCLUSION: The present study found that the expression profiles of LncRNAs in different stages of CD4+ T cells are distinguishable. LncRNAs are involved in the key biological process in CD4+ T cell development and activation.

  13. The effect of a 12-week combinational exercise program on CD4 count and mental health among HIV infected women: A randomized control trial

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    Mostafa Dianatinasab

    2018-04-01

    Full Text Available Background/objective: There are conflicting results regarding the effects of exercise on immune function of HIV positive patients. Exercise can also be beneficial to psychological functioning of the patients. The purpose of this study was to determine the impact of a 12-week aerobic and resistance exercise training program on mental health and CD4 counts among female HIV+ patients. Methods: This clinical trial was conducted between September and December 2013. Forty participants (women age range 20–40 were carefully selected from 240 HIV-positive women referred to Voluntary Counseling and Treatment Center (VCT and randomly assigned to either exercise (80 min of aerobic and strength training while receiving the VCT's routine services group (n = 20 or control (received the VCT's routine services only group (n = 20. To assess their mental health status, all participants completed GHQ28 questionnaire. Blood samples were collected to measure CD4 and T-cell counts at baseline and at the end of the 12-week intervention. Results: From a sample of 40 women with HIV infection, the data of 30 participants [experimental group (14 and control group (16] were analyzed (participation rate 75%. The results indicated that after the intervention program, a significant difference in CD4 cell counts was found between the two groups (P = 0.01. With regard to mental health, after performing intervention, significant improvement in all subscales including anxiety disorder, social function, depression and mental health's total score was observed in the exercise compared to the control groups (P < 0.001. Conclusion: Exercise training can be included in health care services in order to improve the mental health status of women with HIV infection. No effect on CD4 count was detected. Keywords: Exercises training, Mental health, CD4 count, HIV infected women

  14. Inflammation in disseminated lesions: an analysis of CD4+, CD20+, CD68+, CD31+ and vW+ cells in non-ulcerated lesions of disseminated leishmaniasis

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    Dayana Santos Mendes

    2013-02-01

    Full Text Available Disseminated leishmaniasis (DL differs from other clinical forms of the disease due to the presence of many non-ulcerated lesions (papules and nodules in non-contiguous areas of the body. We describe the histopathology of DL non-ulcerated lesions and the presence of CD4-, CD20-, CD68-, CD31- and von Willebrand factor (vW-positive cells in the inflamed area. We analysed eighteen biopsies from non-ulcerated lesions and quantified the inflamed areas and the expression of CD4, CD20, CD68, CD31 and vW using Image-Pro software (Media Cybernetics. Diffuse lymphoplasmacytic perivascular infiltrates were found in dermal skin. Inflammation was observed in 3-73% of the total biopsy area and showed a significant linear correlation with the number of vW+ vessels. The most common cells were CD68+ macrophages, CD20+ B-cells and CD4+ T-cells. A significant linear correlation between CD4+ and CD20+ cells and the size of the inflamed area was also found. Our findings show chronic inflammation in all DL non-ulcerated lesions predominantly formed by macrophages, plasmacytes and T and B-cells. As the inflamed area expanded, the number of granulomas and extent of the vascular framework increased. Thus, we demonstrate that vessels may have an important role in the clinical evolution of DL lesions.

  15. Effect of Natalizumab on Circulating CD4(+) T-Cells in Multiple Sclerosis

    DEFF Research Database (Denmark)

    Börnsen, Lars; Christensen, Jeppe Romme; Ratzer, Rikke

    2012-01-01

    in general or myelin-reactive T-cells in particular showed signs of increased immune activation. Furthermore we examined the effects of natalizumab on CD4(+) T-cell responses to myelin in vitro. Natalizumab-treated MS patients had significantly increased numbers of effector-memory T-cells in the blood. In T-cells......(HIGH) T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26(HIGH)CD4(+) T-cells in vitro. Otherwise CD4(+) T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. In conclusion natalizumab treatment selectively increased...... transmigration of circulating immune-cells across the vascular endothelium into the CNS. Recent studies suggested that natalizumab treated MS patients have an increased T-cell pool in the blood compartment which may be selectively enriched in activated T-cells. Proposed causes are sequestration of activated T-cells...

  16. Rapid and sustained CD4(+) T-cell-independent immunity from adenovirus-encoded vaccine antigens

    DEFF Research Database (Denmark)

    Holst, Peter J; Bartholdy, Christina; Buus, Anette Stryhn

    2007-01-01

    -linked lymphocytic choriomeningitis virus (LCMV)-derived epitopes was long-lived and protective. Notably, in contrast to full-length protein, the response elicited with the beta(2)-microglobulin-linked LCMV-derived epitope was CD4(+) T-cell independent. Furthermore, virus-specific CD8(+) T cells primed...... in the absence of CD4(+) T-cell help were sustained in the long term and able to expand and control a secondary challenge with LCMV. Our results demonstrate that modifications to the antigen used in adenovirus vaccines may be used to improve the induced T-cell response. Such a strategy for CD4(+) T-cell...... to that elicited with an adenovirus-encoded minimal epitope covalently linked to beta(2)-microglobulin. We demonstrate that the beta(2)-microglobulin-linked epitope induced an accelerated and augmented CD8(+) T-cell response. Furthermore, the immunity conferred by vaccination with beta(2)-microglobulin...

  17. Detection of circulating tumor lysate-reactive CD4+ T cells in melanoma patients

    DEFF Research Database (Denmark)

    Ladekarl, Morten; Agger, Ralf; Fleischer, Charlotte C

    2004-01-01

    PURPOSE: We wanted to study whether an allogeneic melanoma lysate would be a feasible stimulatory antigen source for detection of a peripheral CD4+ T-cell immune response in patients with medically untreated malignant melanoma. The lysate was produced from a melanoma cell line (FM3.29) which...... was found in 1 of 4 patients radically operated for localized disease, whereas no responders were seen among 7 healthy donors. The fraction of circulating lysate-activated T cells ranged from 0.0037% to 0.080% of the CD4+ population. A negative result of the assay was found occasionally, especially...... expresses high amounts of melanoma antigens. METHODS: Fresh peripheral blood was incubated with and without lysate for 6 h in the presence of anti-CD28/anti-CD49d MoAb (for costimulation). After flow cytometric estimation of the frequency of CD69+/IFN-gamma+ cells in the CD4+ population, the response...

  18. Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.

    Science.gov (United States)

    Chen, Li; Liu, Dan; Zhang, Yang; Zhang, Huan; Cheng, Hua

    2015-10-23

    The retroviral Tax proteins of human T cell leukemia virus type 1 and 2 (HTLV-1 and -2) are highly homologous viral transactivators. Both viral proteins can immortalize human primary CD4+ memory T cells, but when expressed alone they rarely transform T cells. In the present study, we found that the Tax proteins displayed a differential ability to immortalize human CD4+Foxp3+ T cells with characteristic expression of CTLA-4 and GITR. Because epidermal growth factor receptor (EGFR) was reportedly expressed and activated in a subset of CD4+Foxp3+ T cells, we introduced an activated EGFR into Tax-immortalized CD4+Foxp3+ T cells. We observed that these modified cells were grown independently of exogenous IL-2, correlating with a T cell transformation phenotype. In Tax-immortalized CD4+Foxp3- T cells, ectopic expression of Foxp3 was a prerequisite for Tax transformation of T cells. Accordingly, treatment of the transformed T cells with erlotinib, a selective inhibitor of EGFR, induced degradation of EGFR in lysosome, consequently causing T cell growth inhibition. Further, we identified autophagy as a crucial cellular survival pathway for the transformed T cells. Silencing key autophagy molecules including Beclin1, Atg5 and PI3 kinase class III (PI3KC3) resulted in drastic impairment of T cell growth. Our data, therefore, unveiled a previously unidentified role of Foxp3 in T cell transformation, providing a molecular basis for HTLV-1 transformation of CD4+Foxp3+ T cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Necroptosis takes place in human immunodeficiency virus type-1 (HIV-1-infected CD4+ T lymphocytes.

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    Ting Pan

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection is characterized by progressive depletion of CD4+ T lymphocytes and dysfunction of the immune system. The numbers of CD4+ T lymphocytes in the human body are maintained constantly by homeostatic mechanisms that failed during HIV-1 infection, resulting in progressive loss of CD4+ T cells mainly via apoptosis. Recently, a non-apoptotic form of necrotic programmed cell death, named necroptosis, has been investiga