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Sample records for blood cd4 cell

  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. CD4(+)CD25 (+)CD127 (low/-) T cells: a more specific Treg population in human peripheral blood.

    Science.gov (United States)

    Yu, Ning; Li, Xiaomei; Song, Weiya; Li, Dongmei; Yu, Daliang; Zeng, Xiaofeng; Li, Mengtao; Leng, Xiaomei; Li, Xiangpei

    2012-12-01

    The quantitative identification and enrichment of viable regulatory T cells (Treg) requires reliable surface markers that are selectively expressed on Treg. Foxp3 is the accepted marker of nTreg, but it cannot be used to isolate cells for functional studies. In this study, we compared four staining profiles of Treg, including CD4(+)CD25(high) T cells, CD4(+)CD39(+) T cells, CD4(+)CD73(+) T cells, and CD4(+)CD25(+)CD127(low/-) T cells. We found that CD4(+)CD25(+)CD127(low/-) T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4(+)CD25(+)Foxp3(+) T cells, the accepted identifying characteristics for "real" nTreg cells. Moreover, functional data showed that CD4(+)CD25(+)CD127(low/-) T cells could effectively suppress the proliferation of CD4(+)CD25(-) T cells, suggesting that compared with the other three populations, CD4(+)CD25(+)CD127(low/-) T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood. Finally, we showed that CD4(+)CD25(+)CD127(low/-) can be used to quantitate Treg cells in individuals with systemic lupus erythematosus supporting the use of CD4(+)CD25(+)CD127(low/-) to identify human Treg cells. PMID:22752562

  3. Evaluation of the Effect of IL-22 on Human Cord Blood CD4+ T Cells

    Directory of Open Access Journals (Sweden)

    Javad Arasteh

    2010-06-01

    Full Text Available IL-22 is a member of IL-10 cytokine family which is believed to play an important role in inflammatory responses. IL-22 has similarities with IL-10 including conserved sequences with IL-10. IL-22 receptor is also comprised of two chains known as L-22R1 and L-10R2; supporting the speculation that the two cytokines may have similar effects. The aim of this study was to shed some light on the biological activity of IL-22 upon the cord blood CD4+CD25- T cells. In this research, cord blood T CD4+CD25- cells were cultured in presence of anti CD2/CD3/CD28 coated beads, IL-2 and IL-22 for two weeks at 37 oC and 5% CO2. Flow cytometry analysis showed that IL-22 has no effect upon CD25 and Foxp3 expression. Also, the results indicated that IL-22 is not involved in CD4+ T cell proliferation. Moreover, the results of suppression assay did not show any suppression effect on the cultured T cells. Thus, it seems that umbilical cord blood T cells probably do not express IL-22R1 on their surface.

  4. Isolation and partial characterization of peripheral blood CD4+ T cell clones expressing γδT cell receptors

    International Nuclear Information System (INIS)

    Rare T cell clones bearing both CD4 and T cell receptors (TCRγ and TCRδ) were obtained from human peripheral blood by cell sorting using anti-CD4 and anti-TCRδ1 antibodies. All the clones established were reactive with anti-TCRγδ1 antibody, whereas only about 20 % of the clones showed reactivity with anti-δTCS1 antibody. Unlike CD4+ T cells bearing TCRαβ, all the clones tested were lectin-dependent and showed CD3 antibody-redirected cytolytic activity. About 60 % exhibited natural killer cell-like activity. Immunoprecipitation analysis of TCRγδ showed that each clone expressed either a disulfide-linked or nondisulfide-linked heterodimer consisting of 37-44 kilodalton TCRγ and TCRδ chains. Southern blot analyses of TCRγ and TCRδ genes revealed some identical rearrangement patterns, suggesting the limited heterogeneity of CD4+TCRγδ+ T cells in peripheral blood. (author)

  5. Cord blood CD4+ T cells respond to self heat shock protein 60 (HSP60.

    Directory of Open Access Journals (Sweden)

    Joost A Aalberse

    Full Text Available BACKGROUND: To prevent harmful autoimmunity most immune responses to self proteins are controlled by central and peripheral tolerance. T cells specific for a limited set of self-proteins such as human heat shock protein 60 (HSP60 may contribute to peripheral tolerance. It is not known whether HSP60-specific T cells are present at birth and thus may play a role in neonatal tolerance. We studied whether self-HSP60 reactive T cells are present in cord blood, and if so, what phenotype these cells have. METHODOLOGY/PRINCIPAL FINDINGS: Cord blood mononuclear cells (CBMC of healthy, full term neonates (n = 21, were cultured with HSP60 and Tetanus Toxoid (TT to study antigen specific proliferation, cytokine secretion and up-regulation of surface markers. The functional capacity of HSP60-induced T cells was determined with in vitro suppression assays. Stimulation of CBMC with HSP60 led to CD4(+ T cell proliferation and the production of various cytokines, most notably IL-10, Interferon-gamma, and IL-6. HSP60-induced T cells expressed FOXP3 and suppressed effector T cell responses in vitro. CONCLUSION: Self-reactive HSP60 specific T cells are already present at birth. Upon stimulation with self-HSP60 these cells proliferate, produce cytokines and express FOXP3. These cells function as suppressor cells in vitro and thus they may be involved in the regulation of neonatal immune responses.

  6. Thalidomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood.

    Science.gov (United States)

    Shannon, E J; Ejigu, M; Haile-Mariam, H S; Berhan, T Y; Tasesse, G

    1992-03-01

    Thalidomide is well documented as being an effective drug in the treatment of erythema nodosum leprosum (ENL). The mechanism of action of thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully determined. Lepromatous leprosy patients experiencing ENL have been reported to have an increase in the ratio of CD4+ to CD8+ cells in their blood and ENL skin lesions. Thalidomide has been shown to cause a decrease in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males. This decrease was due to a significant reduction in the numbers of Cd4+ lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In this study, thalidomide's effectiveness in halting chronic ENL and arresting a relapse into ENL was consistently associated with a decrease in the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy patients. PMID:1569817

  7. Radiological features of pulmonary tuberculosis in human immunodeficiency virus-infected patients: correlation with the blood CD4 cell count

    International Nuclear Information System (INIS)

    To describe the radiological features of pulmonary tuberculosis (TB) in patients infected with human immunodeficiency virus (HIV) and its correlation with the blood CD4 cell count. We present 44 HIV+patients, 24 with CD4 cell counts of less than 200 cells/mm''3 (group A) and 20 in whom the CD4 counts surpassed this level (group B). We also assessed the chest x-ray images to determine whether or not there was any correlation with the blood CD4 cell counts. Fisher's exact test was used for the statistical study of the differences in the radiological findings in the two groups. The incidence of atypical features was significantly greater in the patients with CD4 cell counts of less than 200 cells/mm''3 (group A) than in those with CD4 counts of over 200 cells/mm''3 (group B). Among HIV+patients, those with a more intact immune status were more likely to present lung x-ray images typical of post-primary TB, with cavitary lesions in upper lobes. The group of patients in whom the immune deficiency was more marked showed a greater incidence of atypical pulmonary findings, more characteristics of primary TB. (Author)

  8. Clinical significance of peripheral blood CD4 + natural killer T cells in chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    JIANG Rong-long; LU Qiao-sheng; FENG Xiao-rong; LUO Kang-xian; HOU Jin-lin; FU Ning

    2001-01-01

    To understand the clinical significance of CD4+ natural killer T (NK-T) cells in chronic hepatitis B virus (HBV) infection. Methods: Peripheral blood mononuclear cells (PBMCs) from individuals with chronic HBV infection were separated routinely. After Induction with IL-12/IL-2 for 12 d, the proportion of CD4+NK-T cells in peripheral blood was determined by fluorescence activated cell sorter (FACS) analysis, and the cytotoxicity of peripheral blood lymphocytes (PBLs) was tested with a 4 h 51Cr release assay. Results: After IL-12/IL-2 induction, the proportion of CD4+ NK-T cells was (18.1±4.20)%, (6.95±2.85)% and (1.50±1.30)% in the healthy control, CAH and AsC respectively. That in the peripheral blood of chronic HBV infected individuals was lower than that in the healthy control. CD8+ NK-T cells was (2.70±1.10)%, (2.20±1.40)% and (3.10±0.70)%respectively. In vitro cytotoxicity assays against Wish cells revealed that the PBLs cytotoxicity reduced in chronic HBV infected individuals (P<0.05), and that in AsC group was significantly lower in comparison with CHB and healthy control groups. The cytotoxicity of CD4+ NK-T cells against Wish cells could be abolished by treating PBLs with either anti-CD4 Ab or anti-CD56 Ab and complement, and partially depleted by anti-CD8 Ab. Conclusion:The abnormal cellular immune function of chronic HBV infected individuals may be associated with the deficiency of CD4+ NK-T cells.

  9. Allo-PBSCT患者CD4+CD25+调节性T细胞的体外研究%Study on post-allogeneic peripheral blood stem cell transplantation patients'CD4 + CD25 + regulatory T cells in vitro

    Institute of Scientific and Technical Information of China (English)

    翟海龙; 赖永榕

    2011-01-01

    Objective To investigate the proliferation reaction of CD4+ CD25+ Tregs in the stimulating of costimulato-ry signal, lymphocyte reactions mixed with CD4+ CD25- T cells of CD4+ CD25+ Tregs, and cytokine secretion state of the two cells in allogeneic peripheral blood stem cell transplantation ( Allo-PBSCT) patients. Methods CD4+ CD2S+ Tregs and CD4+ CD25- T cells from peripheral blood obtained from 36 patients who had undergone Allogeneic peripheral blood stem cell transplantation (Allo-PBSCT), 7 healthy volunteers as control, were isolated with magnetic cells sorting separation. Then CD4+ CD25+ Tregs and CD4+ CD25+ Tregs + CD4+ CD25- T cells were cultered for 72 hours, stimulated by an-ti-CD3-mAbs and anti-CD28-mAbs. After that the cultures added with CCK-8 solution were incubated for 1 hour. Then OD450 were detected by ELISA. IL-10, TGF-β and IFN-γ from the two above cell cultures were detected by ELISA method. Results OD450 values of CD4+ CD25+ Tregs were both extremely lower than that of CD4+ CD25- T cells and CD4+ CD25+ Tregs + CD4+ CD25- T cells( P < 0.01). IL-10, TGF-p and IFN-γ secreted by CD4 + CD25+ Tregs in vitro from patients with and without GVHD were signigicantly lower than that of CD4+ CD25- T cells( P < 0.01 ). The 3 cytokines secreted by CD4+ CD25- Tregs + CD4+ CD25- T cells group were also signigicantly lower than that of CD4+ CD25- T cells( P <0.05 ). The cytokines secretory of Allo-PBSCT group was similar with that of control group. Conclusions If the suppressive function of CD4+ CD25+ Tregs are utilized, incidence of GVHD post- Allo-PBSCT may decrease.%目的 探讨异基因外周血干细胞移植(Allo-PBSCT)患者外周血CD4+ CD25+调节性T细胞(Tregs)在协同刺激信号作用下的增殖反应、与CD4+ CD25 -T细胞混合淋巴细胞反应及上述两种培养细胞的细胞因子分泌情况.方法 对36例Allo-PBSCT患者离体CD4+ CD25+ Tregs在抗CD3-mAbs和抗CD28-mAbs的刺激下行CD4+CD25 +Tregs培养和CD4+ CD25+ Tregs、CD4

  10. 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...

  11. CD4+-T-cell counts, spontaneous apoptosis, and Fas expression in peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1-infected subjects.

    OpenAIRE

    Patki, A H; Georges, D L; Lederman, M M

    1997-01-01

    We examined the relationships among CD4+-T-cell counts, spontaneous apoptosis, and Fas expression among peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1 (HIV-1)-infected patients. After 2 days of incubation, propidium iodide DNA staining and flow cytometry revealed that peripheral blood mononuclear cells from subjects with the lowest CD4+-cell numbers (0 to 99/microl; n = 20) showed the highest frequency of apoptosis: 22.4% +/- 2.7% (mean +/- standard error...

  12. Canine CD4+CD8+ double positive T cells in peripheral blood have features of activated T cells.

    Science.gov (United States)

    Bismarck, Doris; Schütze, Nicole; Moore, Peter; Büttner, Mathias; Alber, Gottfried; Buttlar, Heiner v

    2012-10-15

    In dogs a CD4(+)CD8(+) double positive T cell subpopulation exists that has not been phenotypically defined yet. We demonstrate that canine CD4(+)CD8(+) T cells are mature CD1a(-) and TCRαβ(+) T cells. To analyse the activation potential of CD4(+)CD8(+) T cells, PBMC from dogs vaccinated against canine distemper virus (CDV) were re-stimulated with CDV. Upon antigen-specific stimulation, the CD4(+)CD8(+) T cell fraction increases and consists nearly exclusively of proliferated cells. Similarly, other features of activated effector/memory T cells such as up-regulation of CD25 and MHC-II as well as down-regulation of CD62L (L-selectin) were observed in CD4(+)CD8(+) T cells after stimulation. Canine CD4(+)CD8(+) T cells are less abundant, but more heterogeneous than porcine ones, comprising a small proportion expressing the β chain of CD8 in addition to the CD8α chain, like human CD4(+)CD8(+) T cells. In summary, this analysis provides the basis for functional characterisation of the in vivo relevance of CD4(+)CD8(+) T cells in T-cell mediated immunity. PMID:22789871

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

    Science.gov (United States)

    Lei, Yu; Hu, Tingting; Song, Xiaofei; Nie, Hong; Chen, Min; Chen, Weixian; Zhou, Zhi; Zhang, Dazhi; Hu, Huaidong; Hu, Peng; Ren, Hong

    2016-01-01

    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. PMID:27612199

  14. Analysis of CD4+CD25+ Regulatory T Cells and Foxp3 mRNA in the Peripheral Blood of Patients with Asthma

    Institute of Scientific and Technical Information of China (English)

    XUE Keying; ZHOU Yongming; XIONG Shengdao; XIONG Weining; TANG Tao

    2007-01-01

    The changes of CD4+CD25+ regulatory T cells (CD4+CD25+ Treg) and Foxp3 mRNA in peripheral blood mononuclear cells (PBMCs) from patients with asthma were investigated in order to elucidate the possible roles of CD4+CD25+ Treg in the development of asthma. The peripheral blood samples were collected from 29 healthy controls (normal control group) and 78 patients with asthma which included 30 patients in exacerbation group, 25 patients in persistent group, and 23 patients in remission group. By using flow cytometry and RT-PCR, the CD4+CD25+ Treg ratio and Foxp3 mRNA in PBMCs were detected. The CD4+CD25+ Treg ratio and Foxp3 mRNA in PBMCs of exacerbation and persistent groups were lower than that of remission and normal control groups (P<0.05). Although the CD4+CD25+ Treg ratio and Foxp3 mRNA of remission group were also lower than that of normal control group, there was no significant difference between them (P>0.05). As compared with persistent group, exacerbation group had lower CD4+CD25+ Treg ratio and Foxp3 mRNA (P<0.05). It was indicated that the decrease of CD4+CD25+Treg ratio and its function in PBMCs may be responsible for pathogenesis of asthma.

  15. Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion

    Science.gov (United States)

    Morita, Rimpei; Schmitt, Nathalie; Bentebibel, Salah-Eddine; Ranganathan, Rajaram; Bourdery, Laure; Zurawski, Gerard; Foucat, Emile; Dullaers, Melissa; Oh, SangKon; Sabzghabaei, Natalie; Lavecchio, Elizabeth M; Punaro, Marilynn; Pascual, Virginia; Banchereau, Jacques; Ueno, Hideki

    2011-01-01

    Although a fraction of human blood memory CD4+ T cells expresses chemokine (C-X-C motif) receptor 5 (CXCR5), their relationship to T follicular helper (Tfh) cells is not well-established. Here we show that human blood CXCR5+ CD4+ T cells share functional properties with Tfh cells, and appear to represent their circulating memory compartment. Blood CXCR5+ CD4+ T cells comprised three subsets; T helper 1 (Th1), Th2 and Th17 cells. Th2 and Th17 cells within CXCR5+, but not within CXCR5−, compartment efficiently induced naïve B cells to produce immunoglobulins via interleukin-21 (IL-21). In contrast, Th1 cells from both CXCR5+ and CXCR5− compartments lacked the capacity to help B cells. Patients with juvenile dermatomyositis, a systemic autoimmune disease, displayed a profound skewing of blood CXCR5+ Th subsets towards Th2 and Th17 cells. Importantly, the skewing of subsets correlated with disease activity and frequency of blood plasmablasts. Collectively, our study suggests that an altered balance of Tfh subsets contributes to human autoimmunity. PMID:21215658

  16. The Detection and Significance of CD4+CD25+CD127lo/-Tregs in Peripheral Blood CD4+T Cells of Healthy and Asthma Patients during Exacerbation and Remission%急性发作期和缓解期哮喘患者外周血CD4+CD25+CD127lo/-Treg的检测和意义

    Institute of Scientific and Technical Information of China (English)

    上官文姬; 沈惠风; 王利民; 叶人诵

    2011-01-01

    目的:通过检测健康人、急性发作期和缓解期哮喘患者外周血CD4+CD25+CD127lo/-Treg细胞的表达水平,探讨该细胞表达水平的变化与哮喘患者病情严重程度的关系.方法:采集急性发作期、缓解期哮喘患者及健康人外周抗凝血,用流式细胞术检测其外周血中CD4+CD25+CD127lo/-Treg细胞占CD4+T细胞的比例.结果:哮喘急性发作组和缓解组患者外周血中CD4+CD25+CD127lo/-Treg细胞占CD4+T细胞的百分比低于健康对照组(P<0.05);哮喘急性发作期组CD4+CD25+CD127lo/-Treg细胞占CD4+T细胞的百分比低于哮喘缓解组(P<0.05).结论:CD4+CD25+ CD127lo/-Treg细胞数量减少可能参与了哮喘的发病过程.%Objective:To investigate the relationship between the expression levels of CD4 + CD25 + CD127lo/-Tregs in peripheral blood of asthma patients during exacerbation or remission. Methods: A total of 2 ml peripheral blood were collected in healthy or asthma patients during exacerbation and remission. The percentage of CD4+ CD25 + CDl27lo/-Tregs in CD4+ T cells by flow cytometry were detected. Results: A significant decrease of the percentage of CD4+ CD25+ CD127lo/- Tregs in CD4+ T cells was observed in exacerbation and remission groups compared with control group (P<0.05). This was also detected in exacerbation group compared with remission group (P<0.05). Conclusions: The CD4+ CD25+ CD127lo/-Tregs play a key role in the pathogenesis of asthma and its decrease,which may lead to immune dysfunction, may be involved in the mechanisms of asthma.

  17. Role of the frequency of blood CD4+ CXCR5+ CCR6+ T cells in autoimmunity in patients with Sjögren’s syndrome

    International Nuclear Information System (INIS)

    Highlights: ► The frequency of CD4+ CXCR5+ CCR6+ T cells increased in pSS patients and positively correlated with autoantibodies in the blood. ► CD4+ CXCR5+ CCR6+ T cells in blood invariably coexpressed PD-1, ICOS, CD40L, Bcl-6 and secreted IL-21 after stimulated by PHA. ► CD4+ CXCR5+ CCR6+ Tfh cells in blood may be suitable biomarkers for the evaluation of the active immune stage of pSS patients. -- Abstract: The blood CD4+ CXCR5+ T cells, known as “circulating” Tfh, have been shown to efficiently induce naïve 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+ CXCR5+ T cells is increased in pSS patients and positively correlated with autoantibodies in the blood. The concentration of Th17-like subsets (CD4+ CXCR5+ CCR6+) 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+ CXCR5+ T cells in the blood may participate in the antibody-related immune responses and that high frequency of CD4+ CXCR5+ CCR6+ 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.

  18. 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.

  19. Decreased number of CD4+ and CD8+ T cells that express the interleukin-7 receptor in blood and tissues of SIV-infected macaques

    International Nuclear Information System (INIS)

    Acute HIV/SIV (human/simian immunodeficiency virus) infection results in severe CD4+ T cell depletion in lymphoid compartments. During the chronic phase of infection, CD4+ T cell numbers rebound in blood but remain low in the gut-associated lymphoid tissue (GALT), even when viral replication is suppressed by antiretroviral therapy (ART). Thus, strategies to repopulate lymphoid compartments may ameliorate the clinical outcome of HIV/SIV infection. Interleukin (IL)-7 is a key cytokine for the maintenance of homeostatic proliferation of T cells. In HIV/SIV infection, IL-7 expression is increased, likely to compensate for T cell loss, suggesting that supraphysiological administration of IL-7 could provide additional benefit. However, the ability of T cells to respond to IL-7 is dependent on the level of expression of the IL-7 receptor (IL-7R) in T cells in various body compartments. In here, we investigated the proportion of IL-7R+ T cells in blood, spleen, gut, and genitourinary tract of healthy and SIV-infected macaques with various degrees of CD4+ T cell depletion. We found that the percentage of T cells expressing IL-7R was significantly lower in both CD4+ and CD8+ T cell subsets in SIV-infected macaques than in healthy animals and this decrease directly correlated with the CD4+ T cell number. Importantly, the proportion of CD4+ and CD8+ T cells expressing IL-7R in blood paralleled that found in tissues. IL-7R+ T cells within the SIV-specific CD8+ T cells varied and were lowest in most tissues of viremic macaques, likely reflecting continuous antigen stimulation of effector cells

  20. Abnormality and significance of interleukin-9 and CD4~+ interleukin-9~+ T-cells in peripheral blood of patients with systemic lupus erythematosus

    Institute of Scientific and Technical Information of China (English)

    欧阳涵

    2013-01-01

    Objective To examine the protein and mRNA levels of interleukin-9(IL-9) and the frequencies of CD4+ IL-9+ T-cells in peripheral blood of patients with systemic lupus erythematosus(SLE) and explore the roles of double positive T cells and IL-9 in the pathogenesis of

  1. 吸毒人员外周血CD4+CD25+Foxp3调节性T细胞表达%Expression of CD4+CD25+Foxp3 regulatory T cells in the blood of drug abuse population

    Institute of Scientific and Technical Information of China (English)

    庞惠勇; 葛恒明; 陈晓芹; 刘小林; 李忠典; 张振宇; 张健

    2011-01-01

    Objective:This study was designed to investigate the effect of drug abuse on human immune function by examining the blood CD4+ CD25 + Foxp3 regulatory T cell expression. Methods: Blood samples were collected in 114 different drug taken route and period people. Flow cytometry was employed to examine the expression of CD4 + CD25 + Foxp3 regulatory T cells. Results: The expression of CD4 + CD25 + Foxp3 regulatory T cells was different among different taken route groups (Oral, 49.07% ± 14.88% > intravenous injection, 34.96% ± 13.41% > mixed routes, 26.72% ± 8.49% ). There were significant differences (P<0. 01) between any of the above two groups. We also examined the effect of drug taken period on the expression of CD4+ CD25 + Foxp3 regulatory T cells. For oral taken people, the expression was much lower in the people with taken period longer than 10 years (37. 14% ± 12.29%) compared with those people with shorter drug taken period ( ≤ 10 years) (51.79% ± 10.44%, P < 0. 01 ). For mixed taken route patients, however, the expression increased from 27.06% ± 8.99% in people with ≤ 10 - year drug taken period to 35.47% ± 11.02% in people with > 10 - year drug taken period( P < 0.01 ). There was no significant difference in the intravenous injection group( P >0.05 ). Conclusion: By examining the blood CD4 + CD25 + Foxp3 regulatory T cell expression in the drug abuse population, it was found that different drug taken routes and periods may induce different extents of injury to the body immune function. Our results provide not only an accurate, reliable monitoring index, but also a new approach to examine the immune function in drug abuse population.%目的:探讨外周血CD4+CD25+Foxp3调节性T细胞与吸毒人员机体免疫的关系.方法:采集114名吸毒人员外周血,根据不同吸毒方式和吸毒年限进行分组,应用流式细胞仪检测外周血中CD4+CD25+Foxp3调节性T细胞表达.结果:不同吸毒方式的吸毒人员外周血CD

  2. Canine CD4(+)CD8(+) double-positive T cells can develop from CD4(+) and CD8(+) T cells.

    Science.gov (United States)

    Bismarck, Doris; Moore, Peter F; Alber, Gottfried; von Buttlar, Heiner

    2014-12-15

    For a long time the expression of the CD4 and CD8 receptor on peripheral blood T cells was thought to be mutually exclusive. However, in canine peripheral blood, similar to other species as swine or human for example, mature CD4(+)CD8(+) double-positive (dp) T cells exist which simultaneously express both surface receptors and have features of activated T cells. Canine CD4(+)CD8(+)dp T cells are heterogeneous and can be divided into three subpopulations by their intensity of CD4 and CD8α expression: CD4(bright)CD8α(bright), CD4(dim)CD8α(bright) and CD4(dim)CD8α(dim). The number of CD4(+)CD8α(+)dp T cells increases after in vitro stimulation of canine peripheral blood mononuclear cells (PBMC) raising the question of their progenitor(s). Thus, the aim of our study was to characterize the progenitor(s) of canine CD4(+)CD8α(+)dp T cells. By cell tracing experiments we identified both CD4(+) single-positive (sp) and also CD8α(+)sp T cells as progenitors of canine CD4(+)CD8α(+)dp T cells after in vitro stimulation. CD4(+)sp T cells almost exclusively upregulate a CD8αα homodimer, whereas CD8α(+)sp T cells can become CD4(+)CD8αβ(+) or CD4(+)CD8αα(+). Even in the absence of other cells, highly purified CD4(+)sp T cells can become double-positive upon in vitro stimulation, whereas highly purified CD8α(+)sp T cells fail to do so. However, CD8α(+)sp T cells can additionally express CD4 when stimulated in the presence of CD4(-)CD8α(-) double-negative (dn) cells or more efficiently when stimulated in the presence of CD4(+)sp T cells. Soluble factors secreted by CD4(+)sp T cells are sufficient for the upregulation of CD4 on CD8α(+)sp T cells, but direct cell-cell contact between CD4(+)sp and CD8α(+)sp T cells is more efficient. mRNA analysis shows that additional CD4 expression on CD8α(+)sp T cells results from de novo synthesis. Thus, uptake of soluble CD4 or trogocytosis is less likely as mechanism for generation of canine double-positive T cells. CD4(+)CD

  3. Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria.

    Directory of Open Access Journals (Sweden)

    Michelle J Boyle

    2015-07-01

    Full Text Available FoxP3+ regulatory CD4 T cells (Tregs help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.

  4. Different distribution of CD4 and CD8 T cells in synovial membrane and peripheral blood of rheumatoid arthritis and osteoarthritis patients.

    Directory of Open Access Journals (Sweden)

    J M Witkowski

    2010-05-01

    Full Text Available Rheumatoid arthritis (RA and osteoarthritis (OA are chronic diseases associated with morphological joint changes. Synovial membrane (SM involvement was established for RA, but the data for OA are limited, because OA is usually regarded as noninflammatory disease. Changes in immune system in RA are not limited to joints, and the significant role of T cells of peripheral blood (PB is not disputable. However, there is still an open debate about PB immunological profile in OA. Therefore, we decided to measure the distribution of CD4+ and CD8+ T cells, regarding CD28 expression, both in PB and SM of RA and OA patients, on the same day. Altogether, eleven RA patients, 11 OA patients and similar numbers of age-matched healthy controls were included into the study. Flow cytometry was used for T cells subpopulation distinguishing and quantification; monoclonal antibodies against CD3, CD4, CD8 and CD28 with different fluorochromes were used for stainings. The RA patients had significantly higher percentage of CD3+4+ cells in PB as compared to OA patients and relevant control group. Both within the CD4+ and CD8+ compartments, significantly lower percentages of cells bearing the CD28 marker were found in the PB of OA as compared to RA patients. The proportion of CD3+CD4+ cells in SM was dependent on age of OA patients, older OA patients had significantly higher value of their SM/blood ratio than RA patients. Older OA subjects were also characterized by higher values of the SM/blood ratio of both CD4+CD28+ and CD8+CD28+ subpopulations than RA or younger OA patients. In conclusion, in contrast to the traditional view of OA disease, our results give support to the hypothesis that OA may also (like RA be a disease with a local immunological involvement.

  5. Increased expression of inducible co-stimulator on CD4+ T-cells in the peripheral blood and synovial fluid of patients with failed hip arthroplasties

    Science.gov (United States)

    Matharu, G. S.; Mittal, S.; Pynsent, P. B.; Buckley, C. D.; Revell, M. P.

    2016-01-01

    Objectives T-cells are considered to play an important role in the inflammatory response causing arthroplasty failure. The study objectives were to investigate the composition and distribution of CD4+ T-cell phenotypes in the peripheral blood (PB) and synovial fluid (SF) of patients undergoing revision surgery for failed metal-on-metal (MoM) and metal-on-polyethylene (MoP) hip arthroplasties, and in patients awaiting total hip arthroplasty. Methods In this prospective case-control study, PB and SF were obtained from 22 patients (23 hips) undergoing revision of MoM (n = 14) and MoP (n = 9) hip arthroplasties, with eight controls provided from primary hip osteoarthritis cases awaiting arthroplasty. Lymphocyte subtypes in samples were analysed using flow cytometry. Results The percentages of CD4+ T-cell subtypes in PB were not different between groups. The CD4+ T-cells in the SF of MoM hips showed a completely different distribution of phenotypes compared with that found in the PB in the same patients, including significantly decreased CD4+ T-central memory cells (p DOI: 10.1302/2046-3758.52.2000574 PMID:26868893

  6. Cytokine responses of CD4+ T cells during a Plasmodium chabaudi chabaudi (ER blood-stage infection in mice initiated by the natural route of infection

    Directory of Open Access Journals (Sweden)

    Butcher Geoffrey

    2007-06-01

    Full Text Available Abstract Background Investigation of host responses to blood stages of Plasmodium spp, and the immunopathology associated with this phase of the life cycle are often performed on mice infected directly with infected red blood cells. Thus, the effects of mosquito bites and the pre-erythrocytic stages of the parasite, which would be present in natural infection, are ignored In this paper, Plasmodium chabaudi chabaudi infections of mice injected directly with infected red blood cells were compared with those of mice infected by the bites of infected mosquitoes, in order to determine whether the courses of primary infection and splenic CD4 T cell responses are similar. Methods C57Bl/6 mice were injected with red blood cells infected with P. chabaudi (ER or infected via the bite of Anopheles stephensi mosquitoes. Parasitaemia were monitored by Giemsa-stained thin blood films. Total spleen cells, CD4+ T cells, and cytokine production (IFN-γ, IL-2, IL-4, IL-10 were analysed by flow cytometry. In some experiments, mice were subjected to bites of uninfected mosquitoes prior to infectious bites in order to determine whether mosquito bites per se could affect a subsequent P. chabaudi infection. Results P. chabaudi (ER infections initiated by mosquito bite were characterized by lower parasitaemia of shorter duration than those observed after direct blood challenge. However, splenomegaly was comparable suggesting that parasitaemia alone does not account for the increase in spleen size. Total numbers of CD4 T cells and those producing IFN-γ, IL-10 and IL-2 were reduced in comparison to direct blood challenge. By contrast, the reduction in IL-4 producing cells was less marked suggesting that there is a proportionally lower Th1-like response in mice infected via infectious mosquitoes. Strikingly, pre-exposure to bites of uninfected mosquitoes reduced the magnitude and duration of the subsequent mosquito-transmitted infection still further, but enhanced the

  7. [Dendritic Cells Promote the Proliferation of Peripheral Blood CRTH2 Cells (CD4(+)CD294(+)Th2) and Help B Cells to Secrete Immunoglobulin].

    Science.gov (United States)

    Tian, Fa-Qing; Li, Juan; Li, Ju-Heng; Tang, Mei-Qin; Cheng, Xiao-Hui; Huang, Ying-Cai; Li, Hui-Qing

    2016-08-01

    Objective:To investigate the promotive effect of dendritic cells(DCs) on proliferation of CRTH2 (CD4(+)CD294(+)Th2) cells and the influence of CRTH2 cells on secretion of immunoglobulin from B cells so as to provide a new approach for amplification and sorting of Th2 cells. Methods:DCs were induced from peripheral blood mononuclear cells, then the loaded-BCGV-Ag-DCs were cocultured with T cells, and the mixed lymphocyte reaction(MLR) was performed by CCK8 method. The phenotypes of DCs and CRTH2 cells were detected by flow cytometry. CRTH2 cells sorted by MACS were co-cultured with B cells for 5 days to detect the secretion of immunoglobulin. Results:The subsets and absolute number CRTH2 cells were significantly increased by loaded-BCGV-Ag-DCs. The levels of IgG, IgA and IgE were higher increased in supernatant of CRTH2 and B cell co-culture system than that in control group or that in transwell group(Pcells can be greatly promoted by loaded-BCGV-Ag-DCs, and the CRTH2 cells can help B cells to secrete IgG, IgA and IgE. PMID:27531793

  8. Blood feeding by the Rocky Mountain spotted fever vector, Dermacentor andersoni, induces interleukin-4 expression by cognate antigen responding CD4+ T cells

    Directory of Open Access Journals (Sweden)

    Wikel Stephen K

    2009-10-01

    Full Text Available Abstract Background Tick modulation of host defenses facilitates both blood feeding and pathogen transmission. Several tick species deviate host T cell responses toward a Th2 cytokine profile. The majority of studies of modulation of T cell cytokine expression by ticks were performed with lymphocytes from infested mice stimulated in vitro with polyclonal T cell activators. Those reports did not examine tick modulation of antigen specific responses. We report use of a transgenic T cell receptor (TCR adoptive transfer model reactive with influenza hemagglutinin peptide (110-120 to examine CD4+ T cell intracellular cytokine responses during infestation with the metastriate tick, Dermacentor andersoni, or exposure to salivary gland extracts. Results Infestation with pathogen-free D. andersoni nymphs or administration of an intradermal injection of female or male tick salivary gland extract induced significant increases of IL-4 transcripts in skin and draining lymph nodes of BALB/c mice as measured by quantitative real-time RT-PCR. Furthermore, IL-10 transcripts were significantly increased in skin while IL-2 and IFN-γ transcripts were not significantly changed by tick feeding or intradermal injection of salivary gland proteins, suggesting a superimposed Th2 response. Infestation induced TCR transgenic CD4+ T cells to divide more frequently as measured by CFSE dilution, but more notably these CD4+ T cells also gained the capacity to express IL-4. Intracellular levels of IL-4 were significantly increased. A second infestation administered 14 days after a primary exposure to ticks resulted in partially reduced CFSE dilution with no change in IL-4 expression when compared to one exposure to ticks. Intradermal inoculation of salivary gland extracts from both male and female ticks also induced IL-4 expression. Conclusion This is the first report of the influence of a metastriate tick on the cytokine profile of antigen specific CD4+ T cells. Blood feeding

  9. Effects of active bufadienolide compounds on human cancer cells and CD4+CD25+Foxp3+ regulatory T cells in mitogen-activated human peripheral blood mononuclear cells.

    Science.gov (United States)

    Yuan, Bo; He, Jing; Kisoh, Keishi; Hayashi, Hideki; Tanaka, Sachiko; Si, Nan; Zhao, Hai-Yu; Hirano, Toshihiko; Bian, Baolin; Takagi, Norio

    2016-09-01

    The growth inhibitory effects of bufadienolide compounds were investigated in two intractable cancer cells, a human glioblastoma cell line U-87 and a pancreatic cancer cell line SW1990. Among four bufadienolide compounds, a dose-dependent cytotoxicity was observed in these cancer cells after treatment with gamabufotalin and arenobufagin. The IC50 values of the two compounds were 3-5 times higher in normal peripheral blood mononuclear cells (PBMCs) than these values for both cancer cell lines. However, similar phenomena were not observed for two other bufadienolide compounds, telocinobufagin and bufalin. These results thus suggest that gamabufotalin and arenobufagin possess selective cytotoxic activity against tumor cells rather than normal cells. Moreover, a clear dose-dependent lactate dehydrogenase (LDH) release, a well-known hallmark of necrosis, was observed in both cancer cells treated with gamabufotalin, suggesting that gamabufotalin-mediated cell death is predominantly associated with a necrosis-like phenotype. Of most importance, treatment with as little as 8 ng/ml of gamabufotalin, even an almost non-toxic concentration to PBMCs, efficiently downregulated the percentages of CD4+CD25+Foxp3+ regulator T (Treg) cells in mitogen-activated PBMCs. Given that Treg cells play a critical role in tumor immunotolerance by suppressing antitumor immunity, these results suggest that gamabufotalin may serve as a promising candidate, as an adjuvant therapeutic agent by manipulating Treg cells to enhance the efficacy of conventional anticancer drugs and lessen their side-effects. These findings provide insights into the clinical application of gamabufotalin for cancer patients with glioblastoma/pancreatic cancer based on its cytocidal effect against tumor cells as well as its depletion of Treg cells. PMID:27431260

  10. Coexpression of CD4 and CD8 on peripheral blood T cells and lamina propria T cells in inflammatory bowel disease by two colour immunofluorescence and flow cytometric analysis.

    OpenAIRE

    Senju, M; Wu, K C; Mahida, Y R; Jewell, D P

    1991-01-01

    Using two colour immunofluorescence with fluorescein isothiocyanate and phycoerythrin labelled monoclonal antibodies and multiparameter flow cytometry, we investigated the coexpression of CD4 and CD8 antigens on peripheral blood lymphocytes and lamina propria lymphocytes of patients with ulcerative colitis and Crohn's disease and normal control subjects. Both the absolute number and the proportion of peripheral blood CD4+, CD8+ cells in inflammatory bowel disease were small but significantly ...

  11. Increased frequency of CD4-8-T cells bearing T-cell receptor αβ chains in peripheral blood of atomic bomb survivors exposed to high doses

    International Nuclear Information System (INIS)

    A rare T-cell subpopulation, CD4-z8-αβ cells, may be differentiated through a pathway (or pathways) different from the pathway(s) of conventional CD4+ or CD8+ cells. In the present study, the frequencies of CD4-8- T cells in peripheral-blood αβ T cells in 409 atomic bomb survivors were determined to investigate late effects of radiation on the composition of human T-cell subpopulations. The frequency of CD4-8-αβ T-cell decreased significantly with the subject's age and was higher in females than males. A significant increase in the frequency was found in the survivors exposed to more than 1.5Gy, suggesting that the previous radiation exposure altered differentiation and development of T cells. 25 refs., 4 figs., 3 tabs

  12. CD4-regulatory cells in COPD patients

    DEFF Research Database (Denmark)

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

    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, smo...

  13. Novel Teleost CD4-Bearing Cell Populations Provide Insights into the Evolutionary Origins and Primordial Roles of CD4+ Lymphocytes and CD4+ Macrophages.

    Science.gov (United States)

    Takizawa, Fumio; Magadan, Susana; Parra, David; Xu, Zhen; Korytář, Tomáš; Boudinot, Pierre; Sunyer, J Oriol

    2016-06-01

    Tetrapods contain a single CD4 coreceptor with four Ig 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 Ig domains, whereas CD4-2 contains only two. Because CD4-2 is reminiscent of the prototypic two-domain CD4 coreceptor, we hypothesized that by characterizing the cell types bearing CD4-1 and CD4-2, we would shed light into the evolution and primordial roles of CD4-bearing cells. Using newly established mAbs against CD4-1 and CD4-2, we identified two bona-fide CD4(+) T cell populations: a predominant lymphocyte population coexpressing surface CD4-1 and CD4-2 (CD4 double-positive [DP]), and a minor subset expressing only CD4-2 (CD4-2 single-positive [SP]). Although both subsets produced equivalent levels of Th1, Th17, and regulatory T cell cytokines upon bacterial infection, CD4-2 SP lymphocytes were less proliferative and displayed a more restricted TCRβ repertoire. These data suggest that CD4-2 SP cells represent a functionally distinct population and may embody a vestigial CD4(+) T cell subset, the roles of which reflect those of primeval CD4(+) T cells. Importantly, we also describe the first CD4(+) monocyte/macrophage population in a nonmammalian species. Of all myeloid subsets, we found the CD4(+) population to be the most phagocytic, whereas CD4(+) lymphocytes lacked this capacity. This study fills in an important gap in the knowledge of teleost CD4-bearing leukocytes, thus revealing critical insights into the evolutionary origins and primordial roles of CD4(+) lymphocytes and CD4(+) monocytes/macrophages. PMID:27183628

  14. Pollution of mycological surfaces in hospital emergency departments correlates positively with blood NKT CD3(+) 16(+) 56(+) and negatively with CD4(+) cell levels of their staff.

    Science.gov (United States)

    Suska, Milena; Lewicki, Sławomir; Kiepura, Anna; Winnicka, Izabela; Leszczyński, Paweł; Bielawska-Drózd, Agata; Cieślik, Piotr; Kubiak, Leszek; Depczyńska, Daria; Brewczyńska, Aleksandra; Skopińska-Różewska, Ewa; Kocik, Janusz

    2016-01-01

    The aim of the present study was the assessment of the putative influence of yeast and filamentous fungi in healthcare and control (office) workplaces (10 of each kind) on immune system competence measured by NK (natural killer), CD4(+), and NKT (natural killer T lymphocyte) cell levels in the blood of the personnel employed at these workplaces. Imprints from floors and walls were collected in winter. The blood was taken in spring the following year, from 40 men, 26 to 53 years old, healthcare workers of hospital emergency departments (HED), who had been working for at least five years in their current positions, and from 36 corresponding controls, working in control offices. Evaluation of blood leukocyte subpopulations was done by flow cytometry. The qualitative analysis of the surface samples revealed a prevalence of strains belonging to Aspergillus spp. and Penicillium spp. genus. There was no statistically significant difference between the level of NKT; however, the percentage of NK cells was lower in the blood of HED workers than in the blood of offices personnel. Spearman analysis revealed the existence of positive correlation (r = 0.4677, p = 0.002) between the total CFU/25 cm(2) obtained by imprinting method from walls and floors of HED and the percentage of NKT (CD3(+)16(+)56(+)) lymphocytes collected from the blood of their personnel, and negative correlation (r = -0. 3688, p = 0.019) between this parameter of fungal pollution and the percentage of CD4(+) lymphocytes in the blood of HED staff. No other correlations were found. PMID:27095925

  15. Self-reactive CD4+ T cells and B cells in the blood in health and autoimmune disease: increased frequency of thyroglobulin-reactive cells in Graves' disease

    DEFF Research Database (Denmark)

    Nielsen, Claus H; Moeller, Ane Christine; Hegedüs, Laszlo;

    2006-01-01

    with autoimmune thyroiditis. In Hashimoto's thyroiditis, B cells bound increased amounts of thyroglobulin in a complement- and autoantibody-dependent manner, and the thyroglobulin-elicited proliferation of CD4(+) T cells and B cells was complement dependent. Increased proportions of Tg-responsive CD4......(+) T cells and B cells were found in patients with Graves' disease. Notably, both patient groups and healthy controls exhibited higher proliferative responses to thyroglobulin than to a foreign recall antigen, tetanus toxoid. Our results suggest that self-tolerance can be broken by exposure of...... circulating lymphocytes to high local concentrations of self-antigen, and that complement plays a role in the maintenance of autoimmune processes, at least in Hashimoto's thyroiditis....

  16. Radiological features of pulmonary tuberculosis in human immunodeficiency virus-infected patients: correlation with the blood CD4 cell count; Patrones radiologicos de la tuberculosis pulmonar en pacientes con infeccion VIH: correlacion con el indice de linfocitos CD4 en sangre

    Energy Technology Data Exchange (ETDEWEB)

    Isusi, M.; Eguidazu, J.; Oleaga, L.; Grande, D. [Hospital de Basurto. Bilbao (Spain)

    2000-07-01

    To describe the radiological features of pulmonary tuberculosis (TB) in patients infected with human immunodeficiency virus (HIV) and its correlation with the blood CD4 cell count. We present 44 HIV+patients, 24 with CD4 cell counts of less than 200 cells/mm''3 (group A) and 20 in whom the CD4 counts surpassed this level (group B). We also assessed the chest x-ray images to determine whether or not there was any correlation with the blood CD4 cell counts. Fisher's exact test was used for the statistical study of the differences in the radiological findings in the two groups. The incidence of atypical features was significantly greater in the patients with CD4 cell counts of less than 200 cells/mm''3 (group A) than in those with CD4 counts of over 200 cells/mm''3 (group B). Among HIV+patients, those with a more intact immune status were more likely to present lung x-ray images typical of post-primary TB, with cavitary lesions in upper lobes. The group of patients in whom the immune deficiency was more marked showed a greater incidence of atypical pulmonary findings, more characteristics of primary TB. (Author)

  17. Proliferation and Apoptosis of Bone Marrow CD4~+ T Cells in Patients with Aplastic Anemia and Impacts of the Secreted Cytokines on Hematopoietic Stem Cells from Umbilical Cord Blood

    Institute of Scientific and Technical Information of China (English)

    郑邈; 孙汉英; 周剑峰; 徐慧珍; 黄丽芳; 刘文励

    2010-01-01

    Recent studies indicate that immune-associated aplastic anemia(AA)resembles such autoimmune diseases as insulin-dependent diabetes and chronic autoimmune thyroiditis that belong to organ-specific autoimmune diseases.Many independent investigation groups have successfully isolated the pathopoiesis-associated T cell clone causing hematopoiesis failure with a CD4 phenotype from peripheral blood and bone marrow(BM)in AA patients.In the current study,BM CD4+ T cells were isolated from AA patients and healthy con...

  18. In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.

    Directory of Open Access Journals (Sweden)

    Henrique Borges da Silva

    2015-02-01

    Full Text Available Dendritic cells (DCs are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip, with Plasmodium chabaudi AS (Pc parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.

  19. Investigation of CD4~+ CXCR5~+ follicular helper T cell frequency and expression of related functional molecules in peripheral blood of hepatitis C virus patients

    Institute of Scientific and Technical Information of China (English)

    王宇

    2013-01-01

    Objective To determine whether hepatitis C virus (HCV) infection is associated with increased frequency of the CD4+follicular helper T (Tfh) subset in peripheral blood and to investigate their potential function contribution to the HCV-induced immune response by

  20. Effect of methylprednisolone on CD4 + CD25 + T regulator cells in peripheral blood with asthmatic patients in vitro%甲泼尼龙对哮喘患者外周血CD4+CD25+调节性T细胞影响的体外研究

    Institute of Scientific and Technical Information of China (English)

    鞠云飞; 孙立锋; 胡华; 杨燕; 滕格玲

    2011-01-01

    目的 观察哮喘患者外周血中CD4+ CD25+调节性T细胞(Treg)功能状态及甲泼尼龙对其的影响.方法 清晨取静脉血5 mL,常规分离外周血单个核细胞,分为健康组、哮喘组及1×10-7 mol·L-1甲泼尼龙哮喘干预组,刺激培养48 h,用ELISA法测定IL - 10及TGF - β1的浓度;流式细胞仪检测CD4+ CD25+Treg的比例及细胞内Foxp3表达,用SPSS 17.0进行分析.结果 哮喘组,外周血CD4+ CD25+ Treg细胞比例降低,CD4+ CD25+ Foxp3+ Treg细胞减少,TGF -β1分泌减少,IL - 10分泌有增高趋势,但与健康组比较无统计学意义;甲泼尼龙可以明显增加哮喘急性发作期患者CD4+ CD25+ Treg比例,Foxp3表达明显增强;但未能增加TGF -β1及IL-10的分泌.结论 哮喘患者CD4+ CD25+ Treg功能低下,可能是哮喘发病机制之一;甲泼尼龙可能通过上调CD4+ CD25+ Treg数量,起到控制哮喘急性发作的作用.%Objective To observe the state of CD4+ CD25 + T regulator ( Treg ) cells and the effect of methylprednisolone ( MP) on it in peripheral blood with asthmatic patients. Methods Thirty patients with asthma and 20 healthy controls who visited the Chest Hospital of Shandong Province from Jan, 2010 to Dec, 2010 were included. Five mL fasting blood samples were collected and peripheral blood mononuclear cells ( PBMCs) were isolated using Ficoll - Hypaque density gradient centrifugation. PBMCs were incubated with phytohemagglutinin ( PHA) . The samples were divided into three groups, including healthy control, asthma group, 1 x 10-7 mol · L-1 MP group. After 48 h incubation, supernatant was harvested to determine levels of IL - 10 and TGF - β1 by ELISA. Intracellular 3 - colour flow cytometry were used to assess the expression of Foxp3. All data were analyzed using SPSS 17.0. Results The ratio of CD4+ CD25 + Treg cells and CD4 + CD25 + Foxp3 + Treg cells declined in asthmatic patients compared with healthy control. The secretion of TGF - β1 weaked . The secretion of

  1. Detection and Quantification of CD4+ T Cells with Specificity for a New Major Histocompatibility Complex Class II-Restricted Influenza A Virus Matrix Protein Epitope in Peripheral Blood of Influenza Patients

    OpenAIRE

    Linnemann, Thomas; Jung, Günther; Walden, Peter

    2000-01-01

    FVFTLTVPS was identified as the core sequence of a new major histocompatibility complex class II-restricted T-cell epitope of influenza virus matrix protein. Epitope-specific CD4+ T cells were detected in the peripheral blood of patients with frequencies of up to 0.94%, depending on the number of additional terminal amino acids.

  2. Towards Developing a Malaria Vaccine Based on CD4 T Cell Mediated Immunity in Blood Stage of Malaria Infection

    Institute of Scientific and Technical Information of China (English)

    徐沪济

    2004-01-01

    Twenty-one years after malaria antigens were first cloned a vaccine still appears to be a long way off. There have been periods of great excitement and in model systems subunit vaccine homologues can induce robust protection. However, significant challenges exist concerning antigenic variation and polymorphism, immunological non-respons-iveness to individual vaccine antigens, parasite-induced apoptosis of immune effector and memory cells and immune deviation as a result of maternal immtmity and alterations of dendritic cell function.

  3. CD4+CD25highCD127low Regulatory T Cells in Peripheral Blood Are Not an Independent Factor for Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

    Science.gov (United States)

    Perz, Jolanta B.; Gürel, Selma; Schonland, Stefan O.; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter

    2012-01-01

    Background. The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (HSCT) largely relies on the graft-versus-leukemia (GVL) effect. Uncontrolled graft-versus-host disease (GVHD) is a feared complication of HSCT. Regulatory T cells (Treg) are a subset of CD4+ T-helper cells believed to maintain tolerance after HSCT. It remains unclear whether low peripheral blood Treg have an impact on the risk for acute (aGVHD) and chronic GVHD (cGVHD). Methods. In this paper we enumerated the CD4+CD25highCD127low Treg in the peripheral blood of 84 patients after at least 150 days from HSCT and in 20 healthy age-matched controls. Results. Although similar mean lymphocyte counts were found in patients and controls, CD3+CD4+ T-cell counts were significantly lower in patients. Patients also had significantly lower Treg percentages among lymphocytes as compared to controls. Patients with cGVHD had even higher percentages of Treg if compared to patients without cGVHD. In multivariate analysis, Treg percentages were not an independent factor for cGVHD. Conclusions. This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity. PMID:22666141

  4. Effect of rapamycin and ciclosporin on proliferation of human periheral blood CD4+CD2+5 regulatory T cells%雷帕霉素及环孢素对人类外周血 CD4+CD2+5调节性T细胞体外增殖的影响

    Institute of Scientific and Technical Information of China (English)

    赵冰清; 朱志军; 王永磊

    2015-01-01

    Objective To observe the influence of rapamycin and ciclosporin on the proliferation of human periheral blood CD4+CD2+5 regulatory T cells.Methods The CD4+CD2+5 regulatory T cells ( Treg cells) from human peripheral blood were isolated by immunomagnetic bead separation, the purity of CD4+CD2+5 Treg was measured by flow cytometry.We divid-ed the CD4+CD2+5 Treg into the groups A, B and C, which were added with 100 nmol/L rapamycin, 410 nmol/L cyclospo-rine and the blank culture medium.After 7 days′culture, we calculated the percentage of primary Treg cells of different groups by flow cytometry.Results The percentage of primary Treg cells in the groups A, B and C were 8.8%±3.2%, 48.9%±7.0%and 33.2%±4.3%, respectively.Significant difference was found when we compared groups A and B with group C, respectively ( all P <0.05).Conclusion Rapamycin can significantly promote the proliferation of CD4+CD2+5 Treg in vitro, and it promotes the formation of immune tolerance in patients after transplantation;but cyclosporine inhibits the proliferation of CD4+CD2+5 Treg and hampers the progression.%目的:观察雷帕霉素与环孢素对人类外周血CD4+CD2+5调节性T细胞( Treg)体外增殖的影响。方法利用免疫磁珠法提取健康成人外周血CD4+CD2+5 Treg,流式细胞仪检测CD4+CD2+5 Treg纯度;将羧基荧光素乙酰乙酸进行标记的CD4+CD2+5 Treg分为A、B、C组,分别加入100 nmol/L雷帕霉素、410 nmol/L环孢素及空白培养基;培养7 d后上流式细胞仪,计算原代细胞所占比例。结果 A组原代细胞所占比例为8.8%±3.2%,B组为48.9%±7.0%,C组为33.2%±4.3%;A、B组分别与C组比较,P均<0.05。结论雷帕霉素可促进CD4+CD2+5 Treg的体外增殖,有利于移植后患者免疫耐受的形成;而环孢素则抑制CD4+CD2+5 Treg的体外增殖,不利于免疫耐受的形成。

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

    International Nuclear Information System (INIS)

    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

  6. The ratio between CD4+ and CD8+ cells in the peripheral blood of patients with hematological malignancies is not altered by thalidomide.

    Science.gov (United States)

    Strupp, C; Germing, U; Aivado, M; Kündgen, A; Fenk, R; Hünerlitürkoglu, A; Kobbe, G; Haas, R; Gattermann, N

    2005-07-01

    Thalidomide is thought to have anti-angiogenic and immunomodulatory properties, including suppression of tumor necrosis factor-alpha, effects on interleukins and interferons, down-regulation of some cell adhesion molecules, and changes in the proportion of lymphocyte subsets. It is unclear whether the clinical response to thalidomide in patients with multiple myeloma (MM), idiopathic myelofibrosis (IM), and myelodysplastic syndromes (MDS) is related to its ability to inhibit angiogenesis or its immunomodulatory effects. We examined the effect of thalidomide on T-lymphocyte subsets in 18 patients with MDS, 6 patients with MM, 4 patients with IM, and 3 patients with angioimmunoblastic lymphoma (AILD). These patients had either a relapse or progressive disease following cytotoxic chemotherapy including high-dose chemotherapy with autologous stem cell support. Thalidomide was first administered at 100 mg/day p.o. and increased to 400 mg/day. T-lymphocyte subsets (CD4+, CD8+) were measured by fluorescence-activated cell sorter (FACS) before and during treatment with thalidomide. Twenty-six of 31 patients responded to thalidomide, most of them achieving partial remission. The median concentration of CD4+ cells was 443/microl, the median of CD8+ cells was 359/microl (CD3 992/microl). In our cohort, no significant changes in absolute numbers or proportions of CD3+ (P = 0.12), CD4+ (P = 0.668), or CD8+ (P = 0.143) cells were observed following the treatment with thalidomide. Although the CD4/CD8 ratio declined from 1.6 to 1.0 during 3 months of thalidomide treatment, this had no statistical significance (P = 0.1). Our findings show that an effect of thalidomide on the T lymphocytes studied is unlikely to be of major importance for the clinical effects. PMID:16019550

  7. CD4 T cell activation and disease activity at onset of multiple sclerosis

    DEFF Research Database (Denmark)

    Jensen, J; Langkilde, Annika Reynberg; Fenst, C; Nicolaisen, M. S.; Roed, H. G.; Christensen, M; Sellebjerg, F

    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...

  8. Increased percentage of L-selectin+ and ICAM-1+ peripheral blood CD4+/CD8+ T cells in active Graves' ophthalmopathy.

    Directory of Open Access Journals (Sweden)

    Alina Bakunowicz-Lazarczyk

    2009-05-01

    Full Text Available The purpose of the study was to evaluate the percentage of CD4+/CD8+ peripheral T cells expressing CD62L+ and CD54+ in patients with Graves' disease and to assess if these estimations could be helpful as markers of active ophthalmopathy. The study was carried out in 25 patients with Graves' disease (GD divided into 3 groups: 1/ 8 patients with active Graves' ophthalmopathy (GO (CAS 3-6, GO complaints pound 1 year, 2/ 9 patients with hyperthyroid GD without symptoms of ophthalmopathy (GDtox and 3/ 8 patients with euthyroid GD with no GO symptoms (GDeu. The control group consisted of 15 healthy volunteers age and sex matched to groups 1-3. The expression of lymphocyte adhesion molecules was evaluated by using three-color flow cytometry. In GO group the percentage of CD8+CD54+, CD8+CD62L+, CD4+CD54+ and CD4+CD62L+ T cells was significantly higher as compared to controls (p<0.001, p<0.05, p<0.01, p<0.001 respectively. The percentage of CD8+CD54+ T lymphocytes was also elevated in GO group in comparison to hyperthyroid GD patients (p< 0.05. CD4+CD62L+ and CD8+CD54+ percentages were also increased in GDtox and GDeu as compared to controls. We found a positive correlation between the TSHRab concentration and the percentage of CD8+CD62L+ T cells in all studied groups (r= 0.39, p<0.05 and between the TSHRab level and CAS (r= 0.77, p<0.05. The increased percentage of CD8+CD54+ and CD8+CD62L+ T cells in patients with Graves' ophthalmopathy may be used as a marker of immune inflammation activity.

  9. Changes of Th17 cells and CD4+CD25+ regulatory T cells in peripheral blood of asthmatic children and their relationship with the situation of asthma.%哮喘患儿外周血Th17细胞CD4+CD25+调节性细胞变化及其与病情相关分析

    Institute of Scientific and Technical Information of China (English)

    马秋莉; 彭韶; 梁鹏; 李会娟; 张曼

    2011-01-01

    Objective To observe the levels of Thl7 cells, CD4+CD25+ regulatory T cells in the asthmatic children and relationship between the two types of cells and children' s condition. Methods Flow cytometry was used to detect the percentages of the Thl7 cells and CD4+CD25+ regulatory T cells in the peripheral blood of acute asthma children (asthma group, n - 60) .alleviated period asthma children (n = 30) and healthy children (healthy control group, n = 30).Acute asthma children were divided into 3 groups: mild, moderate and severe asthmatic patients. Results Compared with the healthy control group (1.02% ± 0.28%) and alleviated period asthma children (1.65% ± 0.38%), the numbers of CD4+ cells (Thl7) expressing IL-17 in peripheral blood of acute asthma(2.24% ± 1.02%) were increased, and the differences were statistically significant (P<0.05). The levels of CD4+CD25+T cells in peripheral blood of acute asthma and alleviated period asthma children (5.37% ± 0.80% ; 6.05% ± 0.87%) were significantly lower than those of healthy children (7.11% ± 0.89%) (P < 0.05). Thl7 cells were positively correlated with the course of childhood asthma(r = 0.649, P < 0.05).CD4+CD25+ regulatory T cells were negatively correlated with the course of childhood asthma (r =-0.599, P < 0.05). Conclusion The immunization response of Thl7 cells in peripheral blood of asthmatic children is strengthened, but the immune function of CD4+CD25+regulatory T cells is decresed. The severity of asthma is closely related to the inbal-ance of Th71ATreg cellular immunity.%目的 探讨支气管哮喘患儿外周血中辅助T细胞(Th) 17细胞和CD4+ CD25+调节性T细胞(Treg)的变化与儿童哮喘病情的相关性.方法 收集2009年月5月至2010年4月于郑州大学第一附属医院就诊的患儿,均为首次确诊哮喘或规范吸入激素停用>3个月后复发及近1个月内无明显感染者.采用流式细胞仪测定患儿外周血中Th17细胞及CD4+CD25+Treg比例的变化.结果 Th

  10. Correlation between State of Bronchial Asthma Children and Peripheral Blood Th17 and CD4+ CD2+5 Regulatory T Cells Changes%外周血Th17和CD4+ CD2+5调节性T细胞变化与患儿支气管哮喘活动状态的相关性研究

    Institute of Scientific and Technical Information of China (English)

    陈啸洪; 李华浚; 姚欢银; 朱芹; 张佩红; 章杭湖; 刘小群; 周国中

    2015-01-01

    Objective To investigate the correlation of the active state of asthma with the peripheral blood Th17 and CD4+ CD2+5 regulatory T cells(Treg)change on children. Methods From January 2010 to December 2013,98 cases of children with asthma in shaoxing Peopleˊs Hospital specialist outpatient clinic were selected for chronic duration group,meanwhile 40 cases of remission asthma children in the same hospital were selected as remission group. 40 cases of healthy children in child health clinic were selected as healthy control group. Using flow cytometry to measure childrenˊs peripheral blood Th17 and CD4+CD2+5 Treg. Results In three groups comparison,there were significant differences among Th17,CD4+CD2+5 Treg and Th17/CD4+CD2+5Treg(F =5. 274,7. 813,3. 526,P <0. 05). There was positive relationship between the score of Th17 cells, Th17/CD4+CD2+5Treg and C-ACT(r=0. 823,0. 485,P<0. 05). CD4+CD2+5Treg was negatively related with C-ACT(r= -0. 562,P<0. 05). Th17 cells was negatively related with CD4+CD2+5Treg(r= -0. 273,P<0. 05). Conclusion Children with chronic asthma duration,Th17 immune response enhanced,and CD4+ CD2+5 Treg immune function declined,the severity of asthma and peripheral blood Th17 /Treg of the immune imbalances are closely related.%目的:探讨外周血Th17和CD4+CD2+5调节性T细胞( CD4+CD2+5 Treg)变化与患儿支气管哮喘活动状态的相关性。方法选取2010年1月—2013年12月于绍兴市人民医院哮喘专科门诊就诊的慢性持续期支气管哮喘患儿98例为慢性持续期组,选择同期在本院治疗的缓解期支气管哮喘患儿40例为缓解期组,选择同期在本院儿童保健门诊体检健康的儿童40例作为健康对照组。采用流式细胞仪测定受试者外周血中Th17及CD4+CD2+5 Treg。结果三组间Th17、CD4+CD2+5Treg和Th17/CD4+CD2+5Treg 比较,差异均有统计学意义(F 值分别为5.274、7.813和3.526,P <0.05)。Th17、Th17/CD4+CD2+5Treg与儿

  11. Label Free Detection of CD4+ and CD8+ T Cells Using the Optofluidic Ring Resonator

    Directory of Open Access Journals (Sweden)

    John T. Gohring

    2010-06-01

    Full Text Available We have demonstrated label free detection of CD4+ and CD8+ T-Lymphocyte whole cells and CD4+ T-Lymphocyte cell lysis using the optofluidic ring resonator (OFRR sensor. The OFRR sensing platform incorporates microfluidics and photonics in a setup that utilizes small sample volume and achieves a fast detection time. In this work, white blood cells were isolated from healthy blood and the concentrations were adjusted to match T-Lymphocyte levels of individuals infected with HIV. Detection was accomplished by immobilizing CD4 and CD8 antibodies on the inner surface of the OFRR. Sensing results show excellent detection of CD4+ and CD8+ T-Lymphocyte cells at medically significant concentrations with a detection time of approximately 30 minutes. This work will lead to a rapid and low-cost sensing device that can provide a CD4 and CD8 count as a measure of HIV progression.

  12. Allergen-Specific CD4(+) T Cells in Human Asthma.

    Science.gov (United States)

    Ling, Morris F; Luster, Andrew D

    2016-03-01

    In allergic asthma, aeroallergen exposure of sensitized individuals mobilizes robust innate and adaptive airway immune responses, stimulating eosinophilic airway inflammation and the activation and infiltration of allergen-specific CD4(+) T cells into the airways. Allergen-specific CD4(+) T cells are thought to be central players in the asthmatic response as they specifically recognize the allergen and initiate and orchestrate the asthmatic inflammatory response. In this article, we briefly review the role of allergen-specific CD4(+) T cells in the pathogenesis of human allergic airway inflammation in allergic individuals, discuss the use of allergen-major histocompatibility complex class II tetramers to characterize allergen-specific CD4(+) T cells, and highlight current gaps in knowledge and directions for future research pertaining to the role of allergen-specific CD4(+) T cells in human asthma. PMID:27027948

  13. Isolation and Characterization of Salmonid CD4+ T Cells.

    Science.gov (United States)

    Maisey, Kevin; Montero, Ruth; Corripio-Miyar, Yolanda; Toro-Ascuy, Daniela; Valenzuela, Beatriz; Reyes-Cerpa, Sebastián; Sandino, Ana María; Zou, Jun; Wang, Tiehui; Secombes, Christopher J; Imarai, Mónica

    2016-05-15

    This study reports the isolation and functional characterization of rainbow trout (Oncorhynchus mykiss) CD4-1(+) T cells and the establishment of an IL-15-dependent CD4-1(+) T cell line. By using Abs specific for CD4-1 and CD3ε it was possible to isolate the double-positive T cells in spleen and head kidney. The morphology and the presence of transcripts for T cell markers in the sorted CD4-1(+)CD3ε(+) cells were studied next. Cells were found to express TCRα, TCRβ, CD152 (CTLA-4), CD154 (CD40L), T-bet, GATA-3, and STAT-1. The sorted CD4-1(+) T cells also had a distinctive functional attribute of mammalian T lymphocytes, namely they could undergo Ag-specific proliferation, using OVA as a model Ag. The OVA-stimulated cells showed increased expression of several cytokines, including IFN-γ1, IL-4/13A, IL-15, IL-17D, IL-10, and TGF-β1, perhaps indicating that T cell proliferation led to differentiation into distinct effector phenotypes. Using IL-15 as a growth factor, we have selected a lymphoid cell line derived from rainbow trout head kidney cells. The morphology, cell surface expression of CD4-1, and the presence of transcripts of T cell cytokines and transcription factors indicated that this is a CD4-1(+) T cell line. To our knowledge, this is the first demonstration of the presence of CD4-1(+)CD3ε(+) T cells in salmonids. As in mammals, CD4-1(+) T cells may be the master regulators of immune responses in fish, and therefore these findings and the new model T cell line developed will contribute to a greater understanding of T cell function and immune responses in teleost fish. PMID:27053758

  14. Adoptive immunotherapy of cancer using CD4+ T cells

    OpenAIRE

    Muranski, Pawel; Restifo, Nicholas P

    2009-01-01

    CD4+ T cells are central to the function of the immune system but their role in tumor immunity remains underappreciated. It is becoming clear that there is an enormous diversity of CD4+ T cell polarization patterns including Th1, Th2, Th17, and regulatory T cells (Tregs). These functionally divergent T cell subsets can have opposing effects — they can trigger tumor rejection or inhibit treatment after adoptive cell transfer. Some polarized CD4+ cells have plasticity, and their phenotypes and ...

  15. Involvement of CD4+CD25+ regulatory T cells in the pathogenesis of polycythaemia vera

    Institute of Scientific and Technical Information of China (English)

    ZHAO Wen-bo; LI Ying; LIU Xin; ZHANG Ling-yan; WANG Xin

    2008-01-01

    Background Regulatory T cells (Treg) have been shown to play an important role in the regulation of hematopoietic activity. However, there is no information about the effect of Treg cells in the pathogenesis of polycythaemia vera (PV).Methods In this study, we investigated the percentage and function of Treg cells in the peripheral blood of 21 PV patients and 25 healthy donors. Treg cells were identified and characterized as CD4+CD25+FOXP3+ by flow cytometry.The suppressive activity of CD4+CD25+ Treg cells was assessed by the proliferation and cytokine secretion of the co-cultured CD4+CD25- fractions.Results The results showed that the percentage of Treg cells in the peripheral blood of PV patients significantly increased compared to healthy controls ((10.93±4.02)% vs (5.86±1.99)%, P <0.05). Moreover, the mRNA and protein expression of FOXP3 was higher in CD4+CD25+ Treg cells. Coordinately, when co-cultured with the activated CD4+CD25-cells, the CD4+CD25+ Treg cells showed enhanced suppressive function in PV. Yet, the underlying mechanism for the increased frequency and function of CD4+CD25+ Treg cells is still to be clarified.Conclusion Treg cells expansion might account for the abnormal T cell immunity in PV patients and thus contribute to the pathogenesis of PV.

  16. Tim-3 mRNA Expression in Peripheral Blood Mononuclear Cells and Its Relationship with CD4+CD25+ Regulatory T Cells from Asthmatic Children%哮喘儿童外周血单个核细胞Tim-3mRNA的表达及其与CD4+CD25+调节性T细胞的关系

    Institute of Scientific and Technical Information of China (English)

    陆小霞

    2011-01-01

    目的 观察哮喘患儿外周血单个核细胞(PBMC)中Tim-3 mRNA的表达及其与CD4+CD25+调节性T细胞(Treg)的关系,探讨Tim-3在哮喘发生发展中的作用.方法 收集哮喘门诊或住院患儿73例,其中哮喘缓解期38例(缓解组),轻至中度急性发作期35例(发作组).利用RT-PCR检测哮喘患儿PBMC中Tim-3 mRNA的表达并做半定量分析,流式细胞术检测PBMC中的CD4+CD25+ Treg的水平(CD4+CD25+ Treg占CD4+T细胞的百分比).利用酶联免疫吸附试验(ELISA)检测血浆中白细胞介素6(IL-6)、转化生长因子β(TGF-β)的水平,并分析Tim-3 mRNA与CD4+CD25+ Treg、IL-6水平的相关性.结果 哮喘发作组PBMC中Tim-3 mRNA吸光度值为(0.86±0.17),与缓解组(0.39±0.11)和正常对照组(0.06±0.03)比较,差异具有统计学意义(均P<0.05),并且缓解组与正常对照组比较差异亦具有统计学意义(P<0.05).哮喘发作组外周血CD4+CD25+ Treg百分率为(8.35±1.67)%,与缓解组[(10.21±2.04)%]和正常对照组[(12.43±2.58)%]比较,差异均具有统计学意义(P<0.05),并且缓解组与正常对照组比较差异亦具有统计学意义(P<0.05);哮喘发作组血浆中IL-6水平为(78.35±14.59)pg/mL,与缓解组[(36.48±9.18)pg/mL]和正常对照组[(10.24±3.57)pg/mL]比较,差异均具有统计学意义(P<0.05),缓解组与正常对照组比较差异亦有统计学意义(P<0.05).3组血浆中TGF-β水平没有明显差异;哮喘发作组和缓解组PBMC中Tim-3 mRNA的表达水平与CD4+CD25+ Treg百分率均呈负相关(r=-0.81,-0.79,均P<0.05),与IL-6的水平呈正相关(r=0.87,0.83,均P<0.01).结论 哮喘患儿PBMC中Tim-3 mRNA表达增高参与哮喘的发生与发展,其机制可能与升高血浆IL-6,抑制CD4+CD25+ Treg的生成有关.%Objective To detect the expression of T cell immunoglobulin mucin 3 ( Tim-3)mRNA in pcripheral blood mono nuclear cells(PBMC)isolated from asthmatic children and analyze its rclationship with CD4+ CD25+ rcgulatory T cells

  17. 脐血CD4+CD25+CD127low调节T细胞及淋巴细胞亚群分析%Study on CD4+CD25+CD127low Regulatory T Cells and Lymphocytes Subsets in Umbilical Cord Blood

    Institute of Scientific and Technical Information of China (English)

    张劼; 陈军浩

    2012-01-01

    目的 检测新生儿脐带血淋巴细胞亚群和调节性T细胞比率,了解脐带血免疫学的特征.方法 使用Sysmex XE2100血细胞分析仪分别计数脐带血、新生儿母亲及对照组外周血淋巴细胞;采用流式细胞术分别检测其CD3+T细胞、CD19+B细胞、CD3- CD16+56+ NK细胞、CD3+ CD4+细胞、CD3+ CD8+细胞占淋巴细胞百分比,以及CD4+ CD25+CD127low调节性T细胞占CD4+细胞的百分比.结果 脐带血、新生儿母亲及对照组淋巴细胞计数分别为(3.68±1.07)×109/L,(1.42±0.44)×109/L和(2.06±0.88)×109/L;B淋巴细胞为:15.71%±3.89%,11.13%±3.79%和9.69%±2.22%;CD4+T细胞为:50.27%±9.08%,37.25%±7.13%和34.65%±7.17%;调节性T细胞为:6.94%±1.09%,5.09%±0.95%和4.8%1±0.99%.上述检测结果脐带血均显著高于母亲及对照组,P<0.01,母亲与对照组差异无统计学显著性意义P>0.05.三组间CD3+T细胞(69.64%±9.97%,74.83%±5.91%和69.41%±5.42%)和NK(11.36%±7.93%,10.48%±6.78%和16.31%±4.69%)细胞无显著性差异,P>0.05.脐带血中CD8+T细胞低于母亲及对照组(19.38%±6.62%,32.39%±2.08%和31.16%±1.87%),P<0.01.结论 脐血中高水平的CD4+ CD25+ CD127low调节性T细胞和低水平的CD8+T细胞有助于保持脐带血的低免疫状态.%Objective The proportions of lymphocytes subsets and regulatory T cells in umbilical cord blood were analyzed to explore the characteristic of umbilical cord blood in immunology. Methods To count lymphocytes by Sysmex XE2100 hema-tocyte cytometer. The percentages of CD3 + T cells,CD19+ B cells,CD3- CD16 + 56+ NK cells,CD3+ CD4+ cells,CD3+ CD8+ cells,and CD4+CD25+CD127low regulatory T cells among the umbilical cord bloods and the peripheral bloods from their mothers or control group were determined by flow cytometry. Results The quantity of lymphocytes in cord blood was significantly higher compared with mothers or with control group (3. 68

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    lymphoid tissues of numerous species, as well as in numerous disease settings, including cancer. The expression of CD4 and CD8 is regulated by a very strict transcriptional program involving the transcription factors Runx3 and ThPOK. Initially thought to be mutually exclusive within CD4(+) and CD8(+) T...... 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....

  19. Adoptive immunotherapy via CD4+ versus CD8+ T cells

    Directory of Open Access Journals (Sweden)

    Vy Phan-Lai

    2016-04-01

    Full Text Available The goal of cancer immunotherapy is to induce specific and durable antitumor immunity. Adoptive T cell therapy (ACT has garnered wide interest, particularly in regard to strategies to improve T cell efficacy in trials. There are many types of T cells (and subsets which can be selected for use in ACT. CD4+ T cells are critical for the regulation, activation and aid of host defense mechanisms and, importantly, for enhancing the function of tumor-specific CD8+ T cells. To date, much research in cancer immunotherapy has focused on CD8+ T cells, in melanoma and other cancers. Both CD4+ T cells and CD8+ T cells have been evaluated as ACT in mice and humans, and both are effective at eliciting antitumor responses. IL-17 producing CD4+ T cells are a new subset of CD4+ T cells to be evaluated in ACT models. This review discusses the benefits of adoptive immunotherapy mediated by CD8+ and CD4+ cells. It also discusses the various type of T cells, source of T cells, and ex vivo cytokine growth factors for augmenting clinical efficacy of ACT. [Biomed Res Ther 2016; 3(4.000: 588-595

  20. Human CD141+ DCs induce CD4+ T cells to produce type 2 cytokines1

    Science.gov (United States)

    Yu, Chun I; Becker, Christian; Metang, Patrick; Marches, Florentina; Wang, Yuanyuan; Toshiyuki, Hori; Banchereau, Jacques; Merad, Miriam; Palucka, Karolina

    2014-01-01

    Dendritic cells (DCs) play the central role in the priming of naïve T cells and the differentiation of unique effector T cells. Here, using lung tissues and blood from both humans and humanized mice, we analyzed the response of human CD1c+ and CD141+ DC subsets to live-attenuated influenza virus (LAIV). Specifically, we analyzed the type of CD4+ T cell immunity elicited by LAIV-exposed DCs. Both DC subsets induce proliferation of allogeneic naïve CD4+ T cells with capacity to secrete IFN-γ. However, CD141+ DCs are uniquely able to induce the differentiation of IL-4 and IL-13 producing CD4+ T cells. CD141+ DCs induce IL-4 and IL-13 secreting CD4+ T cells through OX40L. Thus, CD141+ DCs demonstrate remarkable plasticity in guiding adaptive immune responses. PMID:25246496

  1. Self-reactive CD4+ T cells and B cells in the blood in health and autoimmune disease: increased frequency of thyroglobulin-reactive cells in Graves' disease

    DEFF Research Database (Denmark)

    Nielsen, Claus H; Moeller, Ane Christine; Hegedüs, Laszlo; Bendtzen, Klaus; Leslie, R Graham Q

    2006-01-01

    (+) T cells and B cells were found in patients with Graves' disease. Notably, both patient groups and healthy controls exhibited higher proliferative responses to thyroglobulin than to a foreign recall antigen, tetanus toxoid. Our results suggest that self-tolerance can be broken by exposure of...

  2. Changes in CD4+, CD8+, CD4+ CD8+, and Immunoglobulin M-Positive Peripheral Blood Mononuclear Cells of Postweaning Multisystemic Wasting Syndrome-Affected Pigs and Age-Matched Uninfected Wasted and Healthy Pigs Correlate with Lesions and Porcine Circovirus Type 2 Load in Lymphoid Tissues

    Science.gov (United States)

    Darwich, Laila; Segalés, Joaquim; Domingo, Mariano; Mateu, Enric

    2002-01-01

    Forty-one 8- to 12-week-old wasted pigs were selected from several conventional farms with histories of postweaning multisystemic wasting syndrome (PMWS) and classified into two groups according to their porcine circovirus type 2 (PCV2) infection status, as determined by in situ hybridization (ISH). Twenty-four pigs tested positive for PCV2 (PCV2-positive group), while 17 pigs tested negative for PCV2 (PCV2-negative group). In addition, eight uninfected healthy pigs from an experimental farm were used as controls. Heparinized blood samples were taken to obtain peripheral blood mononuclear cells. The CD4+, CD8+, CD4+ CD8+ (double-positive [DP]), and immunoglobulin M-positive (IgM+) cell subsets were analyzed by flow cytometry with appropriate monoclonal antibodies. Histopathological studies were done to evaluate the apparent degrees of lymphocyte depletion in different lymphoid organs (superficial inguinal and mesenteric lymph nodes, Peyer's patches, tonsils, and spleen) and to determine the viral load of the PCV2 genome by using an ISH technique. Animals of the PCV2-positive group showed a significant downshift of the CD8+ and DP cell subsets compared to the other groups (P < 0.05). Moreover, in PCV2-positive pigs, the amount of PCV2 genome in lymphoid tissues was related to the degree of cell depletion in those tissues (P < 0.05) as well as to the relative decrease in IgM+ and CD8+ cells in peripheral blood. These data support the notion that PCV2-positive pigs might have an impaired immune response. PMID:11874858

  3. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

    Directory of Open Access Journals (Sweden)

    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.

  4. CD4+ T cell responses in hepatitis C virus infection

    Institute of Scientific and Technical Information of China (English)

    Nasser Semmo; Paul Klenerman

    2007-01-01

    Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are relatively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type Ⅰ profile, which promotes cellular effector mechanisms are thought to be more likely to experience viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells,especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in determining the outcome of acute and chronic HCV infection will be discussed in this review.

  5. CD4 T-cell enumeration in a field setting: evaluation of CyFlow counter using the CD4 easy count kit-dry and Pima CD4 systems.

    Directory of Open Access Journals (Sweden)

    Djibril Wade

    Full Text Available BACKGROUND: Flow Cytometry (FCM is still considered to be the method of choice for accurate CD4 enumeration. However, the use of FCM in developing countries is problematic due to their cost and complexity. Lower-cost technologies have been introduced. We evaluated CyFlow Counter together with its lyophilized reagents, and Pima CD4 in high-temperature area, using FACSCount as reference. MATERIALS AND METHODS: Whole blood samples were consecutively collected by venipuncture from 111 HIV+ patients and 17 HIV-negative donors. CD4 T-cell enumeration was performed on CyFlow Counter, Pima CD4 and FACSCount. RESULTS: CyFlow Counter and Pima CD4 systems showed good correlation with FACSCount (slope of 0.82 and 0.90, and concordance ρc of 0.94 and 0.98, respectively. CyFlow Counter showed absolute or relative biases (LOA of -63 cells/mm(3 (-245 to 120 or -9.8% (-38.1 to 18.4 respectively, and Pima CD4 showed biases (LOA of -30 cells/mm(3 (-160 to 101 or -3.5% (-41.0 to 33.9%. CyFlow Counter and Pima CD4 showed respectively 106.7% and 105.9% of similarity with FACSCount. According to WHO-2010 ART initiation threshold of 350 cells/mm(3, CyFlow Counter and Pima CD4 showed respectively sensibility of 100% and 97%, and specificity of 91% and 93%. CyFlow Counter and Pima CD4 were strongly correlated (slope of 1.09 and ρc of 0.95. These alternative systems showed good agreement with bias of 33 cells/mm(3 (-132 to 203 or 6.3% (-31.2 to 43.8, and similarity of 104.3%. CONCLUSION: CyFlow Counter using CD4 easy count kit-dry and Pima CD4 systems can accurately provide CD4 T-cell counts with acceptable agreement to those of FACSCount.

  6. Differentiation of Effector CD4 T Cell Populations*

    OpenAIRE

    Zhu, Jinfang; Yamane, Hidehiro; Paul, William E.

    2010-01-01

    CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and r...

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

    Directory of Open Access Journals (Sweden)

    Michaela Lucas

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  8. Cellular plasticity of CD4+ T cells in the intestine

    Directory of Open Access Journals (Sweden)

    Verena eBrucklacher-Waldert

    2014-10-01

    Full Text Available Barrier sites such as the gastrointestinal tract are in constant contact with the environment which contains both beneficial and harmful components. The immune system at the epithelia must make the distinction between these components to balance tolerance, protection and immunopathology. This is achieved via multifaceted immune recognition, highly organised lymphoid structures and the interaction of many types of immune cells. The adaptive immune response in the gut is orchestrated by CD4+ helper T (Th cells which are integral to gut immunity. In recent years it has become apparent that the functional identity of these Th cells is not as fixed as initially thought. Plasticity in differentiated T cell subsets has now been firmly established, in both health and disease. The gut, in particular, utilises CD4+ T cell plasticity to mould CD4+ T cell phenotypes to maintain its finely poised balance of tolerance and inflammation and to encourage biodiversity within the enteric microbiome. In this review we will discuss intestinal helper T cell plasticity and our current understanding of its mechanisms, including our growing knowledge of an evolutionarily ancient symbiosis between microbiota and malleable CD4+ T cell effectors.

  9. Distribution of CD4 lymphocyte cells among apparently healthy HIV seropositive and seronegative populations

    Directory of Open Access Journals (Sweden)

    Abdulazeez A Abubakar

    2012-01-01

    Full Text Available Background: CD4 lymphocyte cells are often used as prognostic markers for monitoring the progression of immunosupression such as HIV infection. Aim: This study was conducted to assess the distribution of CD4 lymphocytes among apparently healthy human immunodeficiency virus (HIV seronegative and seropositive populations in a Nigerian state. Materials and Methods: A total of 1520 apparently healthy subjects aged 18-64 years, composed of 800 males and 720 females attending some selected health institutions in the state, participated in the study. Ten milliliters of blood was collected from each subject; 5 ml of this was used for HIV antibodies sero-typing while the remaining 5 ml was anticoagulated and used for CD4 lymphocytes level determination. Only samples tested positive both with Capillus and Determine HIV test kits were further differentiated into sero-types with a standard diagnostic HIV test kit. The CD4 lymphocyte levels of all the sample were determined; mean CD4 levels of 205.1±0.09 and 287.4±0.3 cells/μl were recorded among females seropositives and seronagatives respectively. Statistical analysis by the Student t-test showed a significant difference in the mean CD4 lymphocyte count by gender. Results: Findings showed a mean CD4 level of 311.7±1.2 cells/μl among seropositive males while 399.3±0.6 cells/μl was recorded among seronegatives (t=5.86. The study also recorded a CD4 lymphocyte range of 232-464 cells/μl among apparently healthy seronegative population in this locality. Conclusion: The findings showed a significantly higher mean CD4 lymphocyte count among adult male HIV seronegatives (χ2= 9.22 and seropositives (χ2=15.07 than their female counterparts. Further research work using the automation technique is suggested to confirm this new range for monitoring HIV subjects on antiretroviral therapy.

  10. Biomarkers of CD4+ CTL cell Mediated Immunity to Tuberculosis

    Science.gov (United States)

    The immune responses mediated by interactions between T-lymphocyte subsets and mycobacteria-infected macrophages are critical for control of tuberculosis. In these studies, the bovine model was used to characterize the cytolytic and mycobactericidal CD4+ T cell response induced by BCG vaccination. ...

  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

    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...

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  1. File list: NoD.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

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  1. IL-21-producer CD4+ T cell kinetics during primary simian immunodeficiency virus infection.

    Science.gov (United States)

    Shi, Shoi; Seki, Sayuri; Matano, Tetsuro; Yamamoto, Hiroyuki

    2013-01-01

    IL-21 signaling is important for T cell and B cell-mediated clearance of chronic viral infections. While non-cognate follicular helper CD4+ T cells (TFH) are indicated to be pivotal in providing IL-21-mediated help to activated B cells within germinal centers, how this signaling may be disrupted in early AIDS virus infection is not clear. In this study, we assessed the lineage and kinetics of peripheral blood IL-21-producing CD4+ T cells in primary simian immunodeficiency virus (SIV) infection of rhesus macaques. After SIV challenge, antigen-nonspecific IL-21 production was observed in Th1, Th2 and Th17 cells with Th1 dominance. While IL-21+ Th2 and IL-21+ Th17 showed variable kinetics, an increase in total IL-21+ CD4+ T cells and IL-21+ Th1 from week 3 to week 8 was observed, preceding plasma SIV-specific IgG development from week 5 to week 12. SIV Gag-specific IL-21+ CD4+ T cells detectable at week 2 were decreased in frequencies at week 5. Results imply that kinetics of IL-21+ CD4+ T cells comprised of multiple lineages, potentially targeted by SIV with a bias of existing frequencies during their precursor stage, associate with availability of cooperative B-cell help provided through a proportionate precursor pool developing into TFH and subsequent anti-SIV antibody responses. PMID:23791954

  2. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help.

    Science.gov (United States)

    Iijima, Norifumi; Iwasaki, Akiko

    2016-05-26

    Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood-brain barrier and blood-nerve barrier, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-γ and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread. PMID:27225131

  3. IFN-γ and TNF-α producing CD4+ T-cells in the blood after Mycoplasma hyosynoviae challenge of vaccinated pigs

    DEFF Research Database (Denmark)

    Riber, Ulla; Hansen, Mette Sif; Lauritsen, Klara Tølbøll;

    placebo pigs the cytokine production before (day -1), and after (day 15) challenge inoculation was therefore further characterized by flow cytometry. Briefly, PBMC cultures were incubated with Ag, PBS or staphylococcus enterotoxin B (SEB) in the presence of recombinant porcine IL-18 (50 ng/ml). Cultured....... hyosynoviae challenge inoculation three weeks later. Vaccination induced both antibodies and a cell-mediated immune response (CMI) in vaccinated pigs compared to placebo pigs as shown by M. hyosynoviae antigen (Ag) specific IFN-γ response in an IL-18 potentiated whole-blood IFN-γ stimulation assay (mean IFN...

  4. Apoptosis induced by low-dose aminophylline in asthmatic peripheral blood CD4+CD25+T regulatory cells%小剂量氨茶碱对支气管哮喘患者外周血CD4+CD25+调节性T细胞凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    梁瑞韵; 伍卫; 黄瑾; 江山平; 张蔚

    2009-01-01

    目的 观察小剂量氨茶碱对分离培养的健康人和支气管哮喘(简称哮喘)患者外周血CD4+CD25+调节性T细胞(T regulatory cells,Treg)凋亡的影响.方法 经密度梯度离心法、尼龙棉柱法、磁珠分离法分离出健康人和哮喘患者外周血CD4+CD25+Treg,分小剂量氨茶碱(1.13 mg/L)、及空白组培养72 h后,用流式细胞仪检测凋亡率变化.结果 ①健康人外周血CD4+CD25+Treg的纯度为77.4%~92.3%,哮喘患者CD4+CD25+Treg的纯度为75.2%~93.8%.②CD4+CD25+Treg占外周血CD4+T细胞的比例在健康组为4.12%~7.98%,在哮喘组为4.51%~8.68%.两者差异无统计学意义.③小剂量氨茶碱均可以诱导健康组及哮喘组外周血CD4+CD25+Treg凋亡率增加(P<0.05).结论 小剂量氨茶碱(1.13 mg/L)可能通过促进CD4+CD25+Treg凋亡来发挥免疫调节作用.

  5. 激素抵抗性哮喘患者外周血CD4+CD25+Foxp3+调节性T细胞及IL-10、TGF-β1的变化及意义%Changes and clinical significance of CD4+ CD25+Foxp3+ regulatory T cell and IL-10,TGF-β1 in steroid-resistant asthma patients of peripheral blood

    Institute of Scientific and Technical Information of China (English)

    钱一龙; 赵振中; 朱建俊; 谢中华; 王珠美

    2013-01-01

    目的 观察激素抵抗性哮喘(SRA)患者外周血CD4+ CD25+ Foxp3+调节性T细胞(Treg)及白介素10(IL-10)、转化生长因子β1(TGF-β1)的变化,分析其在SRA发病机制中的作用.方法 采用流式细胞术检测40例SRA患者(激素抵抗组)外周血单个核细胞CD4+ CD25+ Foxp3+ Treg数目,并计算CD4+ CD25+ Foxp3+ Treg占CD4+T淋巴细胞的百分比;酶联免疫吸附试验(ELISA)法检测其血清IL-10、TGF-β1水平,并与激素敏感性患者(激素敏感组,46例)及正常体检者(正常组,30例)进行对比.结果 激素抵抗组患者外周血CD4+ CD25+ Foxp3+ Treg占CD4+T淋巴细胞的百分比、CD4+ CD25+Foxp3+ Treg绝对值及血清IL-10、TGF-β1水平均明显低于激素敏感组与正常组(P<0.01,P<0.05);激素敏感组患者外周血CD4+ CD25+ Foxp3+ Treg占CD4+T淋巴细胞的百分比、CD4+ CD25+ Foxp3+Treg绝对值及血清TGF-β1水平明显低于正常组(P<0.01,P<0.05),血清IL-10无明显差异(P>0.05);CD4+ CD25+ Foxp3+ Treg/CD4+T及CD4+ CD25+ Foxp3+ Treg绝对数均与血清IL-10、TGF-β1水平呈明显正相关(P<0.01).结论 SRA患者外周血CD4+ CD25+ Foxp3+ Treg数目减少及IL-10、TGF-β1含量减低可能与SRA的发生、发展有关.%Objective To investigate the changes of CD4+ CD25+ Foxp3+ regulatory T cell and IL-10,TGF-β1 in steroid-resistant asthma patients of peripheral blood,to study their significance.Methods The CD4+ CD25+ Foxp3+ regulatory T cell in 40 cases steroid-resistant asthma patients were detected by flow cytometry.The levels of serum IL-10 and TGF-β1 were detected by ELISA.The control groups were 30 individuals having general physical examination and 46 patients with steroid-sensitive patients.Results The proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell and the levels of serum IL-10,TGF-β1 in steroid-resistant asthma group of Peripheral Blood were decreased significantly than steroid-sensitive group and healthy control group (P <0.01,P <0

  6. CD4+CD25+Treg细胞与支气管哮喘%CD4+ CD25+ Treg cells and bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    鞠云飞; 孙立锋; 胡华

    2011-01-01

    The main function of CD4+ CD25+ Treg cells are immunological anergy and inhibition,which is essential to the maintenance of immunological tolerance in the host.CD4+ CD25+ Treg cells produce inhibitory cytokines (TGF-β and IL-10),express membrane molecules (CTLA-4,GITR,etc) and Foxp3.There are abnormal in function and quantity of CD4+ CD25+ Treg cells of peripheral blood from asthmatic patients,which maybe one of the pathogenesis of asthma.Glucocorticoids can inhibit the airway inflamation of asthma by impacting CD4+ CD25+ Treg cells.%CD4+ CD25+ Treg细胞的主要作用表现为免疫无能性和免疫抑制性,是外周免疫耐受形成机制的主要组成部分.其主要作用机制为分泌抑制性细胞因子(IL-10和TGF-β)、表达细胞表面分子(CTLA-4、GITR等)及Foxp3等.支气管哮喘患者外周血CD4+ CD25+ Treg功能及数量存在异常,这可能是支气管哮喘发病机制之一.糖皮质激素可以通过影响CD4+ CD25+ Treg的状态起到抑制支气管哮喘气道炎症的作用.

  7. In ovo injection of anti-chicken CD25 monoclonal antibodies depletes CD4+CD25+ T cells in chickens.

    Science.gov (United States)

    Shanmugasundaram, Revathi; Selvaraj, Ramesh K

    2013-01-01

    The CD4(+)CD25(+) cells have T regulatory cell properties in chickens. This study investigated the effect of in ovo injection of anti-chicken CD25 monoclonal antibodies (0.5 mg/egg) on CD4(+)CD25(+) cell depletion and on amounts of interleukin-2 mRNA and interferon-γ mRNA in CD4(+)CD25(-) cells posthatch. Anti-chicken CD25 or PBS (control) was injected into 16-d-old embryos. Chicks hatched from eggs injected with anti-chicken CD25 antibodies had a lower CD4(+)CD25(+) cell percentage in the blood until 25 d posthatch. The anti-chicken CD25 antibody injection nearly depleted CD4(+)CD25(+) cells in the blood until 16 d posthatch. At 30 d posthatch, the CD4(+)CD25(+) cell percentage in the anti-CD25-antibody-injected group was comparable with the percentage in the control group. At 16 d posthatch, the anti-chicken CD25 antibody injection decreased CD4(+)CD25(+) cell percentages in the thymus, spleen, and cecal tonsils. Chickens hatched from anti-CD25-antibody-injected eggs had approximately 25% of CD4(+)CD25(+) cells in the cecal tonsils and thymus compared with those in the cecal tonsils and thymus of the control group. The CD4(+)CD25(-) cells from the spleen and cecal tonsils of chicks hatched from anti-chicken-CD25-injected eggs had higher amounts of interferon-γ and interleukin-2 mRNA than CD4(+)CD25(-) cells from the control group. It could be concluded that injecting anti-chicken CD25 antibodies in ovo at 16 d of incubation nearly depleted the CD4(+)CD25(+) cells until 25 d posthatch. PMID:23243240

  8. File list: InP.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: InP.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: ALL.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  12. File list: ALL.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. File list: ALL.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

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  14. File list: InP.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

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  15. File list: ALL.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

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  1. File list: ALL.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. Characterisation of CD4 T cells in healthy and diseased koalas (Phascolarctos cinereus) using cell-type-specific monoclonal antibodies.

    Science.gov (United States)

    Mangar, Chandan; Armitage, Charles W; Timms, Peter; Corcoran, Lynn M; Beagley, Kenneth W

    2016-07-01

    The koala (Phascolarctos cinereus) is an arboreal herbivorous marsupial that is an Australian icon. Koalas in many parts of Australia are under multiple threats including habitat destruction, dog attacks, vehicular accidents, and infectious diseases such as Chlamydia spp. and the koala retrovirus (KoRV), which may contribute to the incidence of lymphoma and leukaemia in this species. Due to a lack of koala-specific immune reagents and assays there is currently no way to adequately analyse the immune response in healthy, diseased or vaccinated animals. This paper reports the production and characterisation of the first anti-koala CD4 monoclonal antibody (mAb). The koala CD4 gene was identified and used to develop recombinant proteins for mAb production. Fluorochrome-conjugated anti-CD4 mAb was used to measure the levels of CD4(+) lymphocytes collected from koala spleens (41.1%, range 20-45.1%) lymph nodes (36.3%, range 19-55.9%) and peripheral blood (23.8%, range 17.3-35%) by flow cytometry. Biotin-conjugated anti-CD4 mAb was used for western blot to determine an approximate size of 52 kDa for the koala CD4 molecule and used in immunohistochemistry to identify CD4(+) cells in the paracortical region and germinal centres of spleen and lymph nodes. Using the anti-CD4 mab we showed that CD4 cells from vaccinated, but not control, koalas proliferated following in vitro stimulation with UV-inactivated Chlamydia pecorum and recombinant chlamydial antigens. Since CD4(+) T cells have been shown to play a pivotal role in clearing chlamydial infection in both human and mouse infections, using this novel antibody will help determine the role CD4(+) T cells play in protection against chlamydial infection in koalas and also enhance our knowledge of how KoRV affects the koala immune system. PMID:26905635

  5. Human CD4+ T Cell Response to Human Herpesvirus 6

    OpenAIRE

    Nastke, Maria-D.; Becerra, Aniuska; Yin, Liusong; Dominguez-Amorocho, Omar; Gibson, Laura; Stern, Lawrence J.; Calvo-Calle, J. Mauricio

    2012-01-01

    Following primary infection, human herpesvirus 6 (HHV-6) establishes a persistent infection for life. HHV-6 reactivation has been associated with transplant rejection, delayed engraftment, encephalitis, muscular dystrophy, and drug-induced hypersensitivity syndrome. The poor understanding of the targets and outcome of the cellular immune response to HHV-6 makes it difficult to outline the role of HHV-6 in human disease. To fill in this gap, we characterized CD4 T cell responses to HHV-6 using...

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

    Directory of Open Access Journals (Sweden)

    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.

  7. The effect of vitamin A on CD4+ and CD8+ cells irradiated by 60Co γ-ray

    International Nuclear Information System (INIS)

    The monocyte-depleted peripheral blood mononuclear cells were separated into CD4+ and CD8+ subpopulations by panning technique with McAb CD4 and CD8. The purity of CD4+ and CD8+ cells was 89.2% and 85.8% respectively, which was estimated by an indirect immunofluorescence technique. The radiosensitivities of CD4+ and CD8+ cells and the effect of DNA synthesis in both cells' subpopulations influenced by Vit A were assessed by 3H-TdR incorporation. The experimental result showed that after γ-radiation in different doses on CD4+ and CD8+ cells, the 3H-TdR incorporation was significantly decreased. The 3H-TdR incorporation rate in CD8+ cells irradiated with addition of 5 μg/ml Vit A increased significantly (p<0.05)

  8. Specific interaction of aurintricarboxylic acid with the human immunodeficiency virus/CD4 cell receptor

    International Nuclear Information System (INIS)

    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

  9. CD4+ T Lymphocytes count in sickle cell anaemia patients attending a tertiary hospital

    Directory of Open Access Journals (Sweden)

    Omotola Toyin Ojo

    2014-01-01

    Full Text Available Background: Sickle cell haemoglobin (HbS is the commonest abnormal haemoglobin and it has a worldwide distribution. Reports have shown that patients with sickle cell anaemia (HbSS have an increased susceptibility to infection leading to increased morbidity and mortality. Impaired leucocyte function and loss of both humoral and cell-mediated immunity are some of the mechanisms that have been reported to account for the immunocompromised state in patients with sickle cell disease. This study was carried out to determine the CD4+ T lymphocytes count in patients with sickle cell anaemia. Materials and Methods: A comparative cross-sectional study of 40 sickle cell anaemia patients in steady state (asymptomatic for at least 4 weeks attending haematology clinic and 40 age and sex-matched healthy HbA control were recruited into the study. Both HbS patients and the controls were HIV negative. The blood samples obtained were analyzed for CD4+ T cell by Flow cytometry. Results: The study found that there was no significant difference in the number of CD4+ T lymphocyte count between individuals with sickle cell anaemia and HbA (1016 ± 513 cells/μL vs 920 ± 364cells/μL. Conclusion: It is recommended that the functionality of CD4+ T lymphocyte should be considered rather than the number in further attempt to elucidate the cellular immune dysfunction in patients with sickle cell anaemia.

  10. Role of regulatory CD4+CD25+ Foxp3 T cells in bronchial asthma in Egyptian children.

    Science.gov (United States)

    Bakr, Salwa I; Mahran, Manal Z; Soliman, Dina A

    2013-01-01

    CD4+CD25+high Foxp3 regulatory T (Treg) cells are known to play a key role in balancing immune response to maintain peripheral tolerance against harmless antigens or allergens. Defective immunological suppression by CD4+CD25+high Foxp3 Treg cells can be a cause of the inflammation that leads to an allergic condition such as asthma. The aims of the study are to (1) determine CD4+CD25+high Foxp3 Treg cells frequency in the peripheral blood of children with and without asthma; and (2) investigate the association between CD4+CD25+high Foxp3 Treg cells frequency with disease severity and corticosteroid therapy. Sixty asthmatic children with varying disease severity (20 mild, 20 moderate and 20 severe) were enrolled in the study. Severe asthmatic children were further subdivided into two groups, one on corticosteroid therapy and the other was not on corticosteroid. Twenty age and sex matched healthy children were enrolled as controls. Number of circulating CD4+CD25+high Foxp3 Tregs were measured using flow cytometry. Our finding demonstrates that children with asthma had a significant decrease of CD4+CD25high Foxp3 Treg cells and Tregs/T effectors ratio in peripheral blood compared to children without asthma. Patients with moderate asthma demonstrated lower frequency of CD4+CD25+high Foxp3 Treg cells compared to mild and severe asthmatic patients. Those on corticosteroid therapy revealed significant increase in CD4+CD25+high Foxp3 Treg cells and decrease in T effectors. It is concluded that asthmatic children have decreased number of CD4+CD25+high Foxp3 Treg cells leading to increase in effectors cells which mediate inflammation in the airways. Corticosteroid therapy plays a role in elevating number of CD4+CD25+high Foxp3 Treg cells and maintaining its suppressor function. PMID:24617045

  11. Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4+ T-Cell Clones

    OpenAIRE

    Norris, Philip J.; Sumaroka, Marina; Brander, Christian; Moffett, Howell F.; Boswell, Steven L.; Nguyen, Tam; Sykulev, Yuri; Walker, Bruce D; Rosenberg, Eric S.

    2001-01-01

    Mounting evidence suggests that human immunodeficiency virus type 1 (HIV-1) Gag-specific T helper cells contribute to effective antiviral control, but their functional characteristics and the precise epitopes targeted by this response remain to be defined. In this study, we generated CD4+ T-cell clones specific for Gag from HIV-1-infected persons with vigorous Gag-specific responses detectable in peripheral blood mononuclear cells. Multiple peptides containing T helper epitopes were identifie...

  12. Gut Mucosal FOXP3+ Regulatory CD4+ T Cells and Nonregulatory CD4+ T Cells Are Differentially Affected by Simian Immunodeficiency Virus Infection in Rhesus Macaques▿

    OpenAIRE

    Allers, Kristina; Loddenkemper, Christoph; Hofmann, Jörg; Unbehaun, Anett; Kunkel, Désirée; Moos, Verena; Kaup, Franz-Josef; Stahl-Hennig, Christiane; Sauermann, Ulrike; Epple, Hans-Jörg; Schneider, Thomas

    2010-01-01

    The gastrointestinal tract represents a major site for human and simian immunodeficiency virus (HIV and SIV) replication and CD4+ T-cell depletion. Despite severe depletion of mucosal CD4+ T cells, FOXP3+ regulatory CD4+ T cells (Treg) are highly increased in the gut mucosa of chronically HIV-infected individuals and may contribute to HIV pathogenesis, either by their immunosuppressive function or as a significant target cell population for virus production. Little is known about the suscepti...

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

    OpenAIRE

    Lybeck, Kari; Sjurseth, Siri K.; Al-Touama, Zainab; Melvang, Heidi Mikkelsen; Aagaard, Claus; Lundegaard, Claus; Jungersen, Gregers; Andersen, Peter; Olsen, Ingrid; Tollefsen, Stig

    2015-01-01

    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 cel...

  14. Decreased expression of miR-21, miR-26a, miR-29a, and miR-142-3p in CD4⁺ T cells and peripheral blood from tuberculosis patients.

    Directory of Open Access Journals (Sweden)

    Katja Kleinsteuber

    Full Text Available The vast majority of Mycobacterium tuberculosis (M. tuberculosis infected individuals are protected from developing tuberculosis and T cells are centrally involved in this process. MicroRNAs (miRNA regulate T-cell functions and are biomarker candidates of disease susceptibility and treatment efficacy in M. tuberculosis infection. We determined the expression profile of 29 selected miRNAs in CD4(+ T cells from tuberculosis patients and contacts with latent M. tuberculosis infection (LTBI. These analyses showed lower expression of miR-21, miR-26a, miR-29a, and miR-142-3p in CD4(+ T cells from tuberculosis patients. Whole blood miRNA candidate analyses verified decreased expression of miR-26a, miR-29a, and miR-142-3p in children with tuberculosis as compared to healthy children with LTBI. Despite marked variances between individual donor samples, trends of increased miRNA candidate expression during treatment and recovery were observed. Functional in vitro analysis identified increased miR-21 and decreased miR-26a expression after re-stimulation of T cells. In vitro polarized Interleukin-17 positive T-cell clones showed activation-dependent miR-29a up-regulation. In order to characterize the role of miR-29a (a described suppressor of Interferon-γ in tuberculosis, we analyzed M. tuberculosis specific Interferon-γ expressing T cells in children with tuberculosis and healthy contacts but detected no correlation between miR-29a and Interferon-γ expression. Suppression of miR-29a in primary human T cells by antagomirs indicated no effect on Interferon-γ expression after in vitro activation. Finally, classification of miRNA targets revealed only a moderate overlap between the candidates. This may reflect differential roles of miR-21, miR-26a, miR-29a, and miR-142-3p in T-cell immunity against M. tuberculosis infection and disease.

  15. 自身免疫性血小板减少性紫癜患者外周血中CD4+CD25+调节性T细胞、sFas和sFasL的表达及临床意义%Expression and Clinical Significance of CD4 + CD25 + Treg Cells, sFas and sFasL in Peripheral Blood of Patients with Autoimmune Thrombocytopenic Purpura

    Institute of Scientific and Technical Information of China (English)

    贾瑞萍; 赵雪芸

    2011-01-01

    本研究通过检测成人自身免疫性血小板减少性紫癜(AITP)外周血中CI4+CD25+调节性T细胞(Treg)、sFas和sFasL的表达,探讨它们在AITP发病机制中的作用及临床意义,为寻求AITP治疗的有效方法提供理论依据.采用流式细胞术分别检测30例AITP患者和18例正常对照者外周血CD4+T、Treg、CD4+ CD25-T细胞表达率及Treg/CD4+T比值;用酶联免疫吸附法(ELISA)检测AITP患者治疗前后及对照组外周血sFas、sFasL表达水平.结果表明,AITP组外周血中CD4+T细胞表达率低于对照组(p<0.05),Treg细胞表达率及Treg/CD4+T比值明显低于正常对照组(p<0.0l).AITP组患者治疗前外周血中sFas和sFasL水平明显高于治疗后和正常对照组(p<0.01),AITP组治疗后与正常对照组外周血sFas、sFasL水平差异无统计学意义(p>0.05).AITP患者治疗前Treg细胞表达率、Treg/CD4+T细胞比值与血小板计数呈正相关;AITP患者外周血中sFas和sFasL水平呈正相关;CD4+T细胞、CD4+CD25 -T细胞表达率,sFas、sFasL浓度与血小板计数无明显相关;Treg细胞表达率和sFas、sFasL浓度间没有明显相关性.结论:Treg在AITP的发病机制中发挥一定作用;Treg细胞水平与AITP病情的严重程度有关;sFas和sFasL水平异常参与了AITP的免疫病理过程.%This study was aimed to detect the expression of CD4 * CD25 * regulatory T cells (Treg) , sFas and sFasL in patients with autoimmune thrombocytopenic purpura ( AITP) , and to explore their roles in the pathogenesis of AITP and clinical significance, so as to provie a theoretical basis for effective treatment for AITP. The expressions of CD4 * T, Treg, CD4 * CD25" T, Treg /CD4 * T in peripheral blood of 30 the patients with AITP and 18 controls were detected by flow cytometry, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of sFas and sFasL in peripheral blood of controls and the patients with AITP before and after treatment. The

  16. Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells MDSC and CD4+ T cells

    OpenAIRE

    Nagaraj, Srinivas; Gabrilovich, Dmitry I.

    2012-01-01

    Myeloid derived Suppressor Cells play a critical role in T cell suppression in cancer. Here, we discuss the mechanisms of how MDSC suppress CD4+ or CD8+ T cells in an antigen dependent or non-dependent manner.

  17. 前列腺癌患者手术前后外周血调节性T细胞和FOXP3mRNA的表达及临床意义%Levels of CD4+CD25+Regulatory T Cells & Expression of FOXP3 mRNA after Operation in Peripheral Blood from Patients with Prostate Cancer and its Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    章更生

    2011-01-01

    目的 探讨前列腺癌(Pca)患者手术前后外周血CD4+CD25+调节性T细胞(Tregs)及其特异标志物FOXP3mRNA的表达比例的变化及临床意义.方法 应用流式细胞术检测50例前列腺癌及50例正常对照组外周血单个核细胞(PBMC)中Tregs占CD4+T细胞的比例,应用RT-PCR技术检测人外周血PBMC FOXP3 mRNA的表达.结果 随着Gleason分级升高,CD4+CD25+Tregs/CD4+T比值和FOXP3 mRNA表达量均有升高趋势;Pca患者术前CD4+CD25+ Treg细胞占CD4+T细胞的比例和FOXP3 mRNA表达水平高于正常对照组(均P<0.05),术后水平与正常对照组差异无统计学意义;Pca组Tregs表达率与FOXP3 mRNA呈正相关(r=0.623,P<0.01).结论 Tregs及其特异标志物FOXP3具有维持自身免疫稳定和抑制肿瘤免疫作用,可能参与前列腺癌的发生.%Objective To explore the rate change of CD4+ CD25+ regulatory T cells and expression of F0XP3 mRNA after operation in peripheral blood from patients with prostate cancer and its clinical significance. Methods Flow cytometry was used to analyze the proportion of CD4+CD25+ regulatory T cells/CD4T cells in peripheral blood mononuclear cells (PBMC) among 50 patients with prostate cancer and 50 healthy controls. The expression of FOXP3 mRNA in PBMC was detected by RT-PCR. Results The value of CD4+CU25+Tregs/CD4+ T cells and expression of FOXP3 mRNA were increased with Gleason pathological parameters increased. And the value of CD4+CD25+ regulatory T cells/CD4+T cells and expression of FOXP3 mRNA in PBMC from patients with prostate cancer before operation were significantly higher than that of the healthy controls. But there were no statistical significance between patients with prostate cancer after operation and healthy controls. Correlative analysis showed that there was a positive correlation between the CD4+CD25+ regulatory T cells and the expression of F0XP3 mRNA in PBMC of the patients with prostate cancer (r=0.623,p<0.01). Conclusion CD4+CD25

  18. 佛波醇酯加离子霉素诱导脐血和成人外周血CD4+CD25+T细胞分泌IL-2的相关机制研究%Mechanisms underlying the induction of IL- 2 secretion by PDB plus ionomycin in CD4 + CD25 + T cells from cord blood and adult peripheral blood

    Institute of Scientific and Technical Information of China (English)

    肇静娴; 曾耀英; 李海仙; 曾祥凤; 季煜华; 何贤辉

    2006-01-01

    目的:以佛波醇酯加离子霉素作为刺激剂,验证CD4+CD25+调节性T细胞本身并不存在分泌IL-2障碍;同时通过对脐血和成人外周血的比较性研究,了解脐血CD4+CD25+T细胞的成熟度.方法:以autoMACS从足月婴儿脐血(CB)和成人外周血(PB)分选CD4+CD25+和CD4+CD25-T细胞,以PDB+ionomycin作为刺激剂,培养45h后流式细胞术检测各组细胞表达CD69和CD25水平,并以Luminex多重细胞因子检测技术检测培养上清中7种细胞因子的浓度.结果:经PDB+ionomycin刺激后,CB、PB的CD4+CD25+和CD4+CD25-T细胞均发生增殖,但在培养45h后CD4+CD25+T细胞均出现细胞状态变差或死亡倾向.CB、PB的CD4+CD25+T细胞活化后CD25分子表达进一步上调,高于CD25-细胞活化后的CD25分子密度.经PDB+ionomycin刺激后,PB CD4+CD25+和CD4+CD25-T细胞均分泌高水平的IFN-γ、IL-2和TNF-α,但CD25+细胞分泌IL-5、IL-4和IL-10水平远远高于CD25-细胞;CBCD4+CD25+和CD4+CD25-T细胞亦分泌高水平的IL-2和TNF-α,但IFN-γ水平远远低于PB,基本不分泌IL-5、IL-4和IL-10.结论:CD4+CD25+T细胞本身并不存在合成和分泌IL-2障碍,其可能具有与传统T细胞不同的T细胞受体信息转导模式;脐血CD4+CD25+T细胞功能尚未完全成熟.

  19. The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions.

    Science.gov (United States)

    Dimeloe, Sarah; Mehling, Matthias; Frick, Corina; Loeliger, Jordan; Bantug, Glenn R; Sauder, Ursula; Fischer, Marco; Belle, Réka; Develioglu, Leyla; Tay, Savaş; Langenkamp, Anja; Hess, Christoph

    2016-01-01

    Effector memory (EM) CD4(+) T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4(+) T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4(+) T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4(+) T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4(+) T cells in normoxic and hypoxic conditions. PMID:26621861

  20. Expression of PD-1 by CD4+CD25+CD127low Treg cells in the peripheral blood of lung cancer patients

    Directory of Open Access Journals (Sweden)

    Zhong AY

    2015-07-01

    Full Text Available AnYuan Zhong, Xue Pan, MinHua Shi Department of Respiratory Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of ChinaLung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide,1 with the majority of patients presenting with advanced disease.2 Treg cells diminish the activation and function of lymphocytes via cell-cell contact and secretion of soluble mediators.3 PD-1 is expressed on the surface of activated T and B cells and regulates their activation and proliferation.4 PD-L1 binds to the PD-1 receptor, leading to, among other responses, negative regulation of immune activity. Both Tregs and the PD-1/PD-L1 pathway play important roles in lung cancer pathogenesis;5,6 however, the association between these two factors remains poorly understood. Here, we examined PD-1 expression on Tregs, and compared these results with established clinical indicators of lung cancer. These analyses revealed significant expression of PD-1 on Tregs in lung cancer, which may be used to inform clinical diagnoses.

  1. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells.

    Science.gov (United States)

    Makita, Shin; Kanai, Takanori; Oshima, Shigeru; Uraushihara, Koji; Totsuka, Teruji; Sawada, Taisuke; Nakamura, Tetsuya; Koganei, Kazutaka; Fukushima, Tsuneo; Watanabe, Mamoru

    2004-09-01

    It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4(+)CD25(bright) T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4(+) T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4(+)CD25(-) T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4(+)CD25(+) T cells, however, cells expressing CD25 at high levels (CD4(+)CD25(bright)) suppressed the proliferation and various cytokine productions of CD4(+)CD25(-) T cells. LP CD4(+)CD25(bright) T cells by themselves produced fewer amounts of IL-2, IFN-gamma, and IL-10. Interestingly, LP CD4(+)CD25(bright) T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4(+)CD25(bright) T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis. PMID:15322172

  2. Prevention of Immunodeficiency Virus induced CD4+ T-Cell depletion by prior infection with a non-pathogenic virus

    OpenAIRE

    Terwee, Julie A.; Carlson, Jennifer K.; Sprague, Wendy S.; Sondgeroth, Kerry S.; Shropshire, Sarah B.; Troyer, Jennifer L.; VandeWoude, Sue

    2008-01-01

    Immune dysregulation initiated by a profound loss of CD4+ T-cells is fundamental to HIV-induced pathogenesis. Infection of domestic cats with a non-pathogenic lentivirus prevalent in the puma (puma lentivirus, PLV or FIVPCO) prevented peripheral blood CD4+ T-cell depletion caused by subsequent virulent FIV infection. Maintenance of this critical population was not associated with a significant decrease in FIV viremia, lending support to the hypothesis that direct viral cytopathic effect is no...

  3. A microfluidic device for practical label-free CD4+ T cell counting of HIV-infected subjects

    OpenAIRE

    Cheng, Xuanhong; Irimia, Daniel; Dixon, Meredith; Sekine, Kazuhiko; Demirci, Utkan; Zamir, Lee; Tompkins, Ronald G.; Rodriguez, William; Toner, Mehmet

    2006-01-01

    Practical HIV diagnostics are urgently needed in resource-limited settings. While HIV infection can be diagnosed using simple, rapid, lateral flow immunoassays, HIV disease staging and treatment monitoring require accurate counting of a particular white blood cell subset, the CD4+ T lymphocyte. To address the limitations of current expensive, technically demanding and/or time-consuming approaches, we have developed a simple CD4 counting microfluidic device. This device uses cell affinity chro...

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

    Science.gov (United States)

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

    2016-01-01

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

  5. Notch signalling inhibits CD4 expression during initiation and differentiation of human T cell lineage.

    Directory of Open Access Journals (Sweden)

    Stephen M Carlin

    Full Text Available The Delta/Notch signal transduction pathway is central to T cell differentiation from haemopoietic stem cells (HSCs. Although T cell development is well characterized using expression of cell surface markers, the detailed mechanisms driving differentiation have not been established. This issue becomes central with observations that adult HSCs exhibit poor differentiation towards the T cell lineage relative to neonatal or embryonic precursors. This study investigates the contribution of Notch signalling and stromal support cells to differentiation of adult and Cord Blood (CB human HSCs, using the Notch signalling OP9Delta co-culture system. Co-cultured cells were assayed at weekly intervals during development for phenotype markers using flow cytometry. Cells were also assayed for mRNA expression at critical developmental stages. Expression of the central thymocyte marker CD4 was initiated independently of Notch signalling, while cells grown with Notch signalling had reduced expression of CD4 mRNA and protein. Interruption of Notch signalling in partially differentiated cells increased CD4 mRNA and protein expression, and promoted differentiation to CD4(+ CD8(+ T cells. We identified a set of genes related to T cell development that were initiated by Notch signalling, and also a set of genes subsequently altered by Notch signal interruption. These results demonstrate that while Notch signalling is essential for establishment of the T cell lineage, at later stages of differentiation, its removal late in differentiation promotes more efficient DP cell generation. Notch signalling adds to signals provided by stromal cells to allow HSCs to differentiate to T cells via initiation of transcription factors such as HES1, GATA3 and TCF7. We also identify gene expression profile differences that may account for low generation of T cells from adult HSCs.

  6. Perforin Expression by CD4+ Regulatory T Cells Increases at Multiple Sclerosis Relapse: Sex Differences

    Directory of Open Access Journals (Sweden)

    Silvia Sánchez-Ramón

    2012-06-01

    Full Text Available Multiple sclerosis (MS represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ TReg in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (TReg within the cerebrospinal fluid (CSF takes place during MS relapse. Not previously described, the presence of CD4+ TReg in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2 and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ TReg playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ TReg in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ TReg in MS, and contributes to the understanding of MS pathophysiology.

  7. Decreased Expression of miR-21, miR-26a, miR-29a, and miR-142-3p in CD4+ T Cells and Peripheral Blood from Tuberculosis Patients

    OpenAIRE

    Kleinsteuber, Katja; Heesch, Kerrin; Schattling, Stefanie; Kohns, Malte; Sander-Jülch, Claudia; Walzl, Gerhard; Hesseling, Anneke; MAYATEPEK, Ertan; Fleischer, Bernhard; Marx, Florian M.; Jacobsen, Marc

    2013-01-01

    The vast majority of Mycobacterium tuberculosis (M. tuberculosis) infected individuals are protected from developing tuberculosis and T cells are centrally involved in this process. MicroRNAs (miRNA) regulate T-cell functions and are biomarker candidates of disease susceptibility and treatment efficacy in M. tuberculosis infection. We determined the expression profile of 29 selected miRNAs in CD4+ T cells from tuberculosis patients and contacts with latent M. tuberculosis infection (LTBI). Th...

  8. 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

    donors with high background levels of spontaneous IFN-gamma production, indicating an inhibitory effect of the lysate. CONCLUSIONS: This method for detection of a peripheral T-cell immune response in melanoma patients has several advantages for clinical use. The tumor lysate preparations may contain......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...... 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 to...

  9. 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.

  10. Role of Circulating CD4+ CD25high Foxp3+ Regulatory T-Cells in Paediatric Asthma

    Directory of Open Access Journals (Sweden)

    Ensaf Khalil Mohammed*, Zeinab Farag Asheiba

    2011-04-01

    Full Text Available Background: The role of T-Helper 2 (Th2 cells in the pathogenesis of allergy and asthma has been well described. However, the immunologic mechanisms that down modulate and protect against the development of these disorders are poorly characterized. A spectrum of CD4+ T cells, including, FOXP3-positive CD4+CD25+ T regulatory cells (Tregs might play a critical role in regulating these diseases. Objective: To investigate the role of CD4+CD25high FoxP3 Tregs in the pathogenesis of pediatric asthma. Methods: The study included 24 asthmatic children, 12 had mild intermittent asthma and 12 were of severe persistent asthma . In addition, 12 healthy subjects were used as controls. All patients were subjected to clinical examination and laboratory investigations including complete blood count with differential leucocytic and absolute eosinophilic count, serum total IgE level by ELIZA and flow cytometry was used to study the frequency of Tregs in peripheral blood lymphocytes of all studied groups using specific markers: cell-surface CD25 and CD4 expression and cytoplasmic FoxP3 expression. Results: It was noticed a significant decrease in CD4+CD25+ % and CD4+CD25 high % in both mild intermittent cases and severe persistent asthmatic patients when compared to healthy controls. FoxP3 expression in Tregs was significantly lower in CD4+CD25high T-cells of mild asthmatic patients when compared to control group. While the FoxP3 expression in Tregs was non- significantly lower in CD4+CD25high T-cells of severe asthmatic patients .Tregs cells % was correlated significantly with mild asthma .While it did not show correlation with severe asthma . An inverse correlation between FoxP3 protein expression was revealed within CD4+CD25high T-cells and total serum IgE when analyzed for all subjects. However, when correlation analysis was performed in each studied group separately, no significant correlation was found between FoxP3 expression and total serum IgE levels and

  11. The induced IL-21 levels in CD+ T cells of peripheral blood from the different clinical types of patients infected with hepatitis B virus%IL-21在不同乙型肝炎病毒感染者外周血CD4+T细胞中表达的初步研究

    Institute of Scientific and Technical Information of China (English)

    丁艳荣; 张野; 连建奇; 李新红; 王临旭; 黄长形

    2011-01-01

    目的:探讨乙肝病毒感染不同临床表现患者外周血CD4+T细胞中IL-21表达的差异及其在发病机制中的作用.方法:分离乙肝病毒感染不同临床表现患者及健康人外周血单个核细胞(PBMC),使用PMA+ionomycin进行刺激,同时每份标本未加PMA+ionomyein刺激做阴性对照,流式细胞术(FCM)检测IL-21的表达情况及其与Th17细胞亚群的关系.结果:PMA+ionomyein刺激能够诱导IL-21的产生,产生IL21的主要为CD4+T细胞,IL-17A+IL-21+CD4+T细胞几乎检测不到,IL-2I+CD4+T细胞比例在急性乙型肝炎组、乙肝病毒携带组中较正常对照组和慢重肝组有所升高,Th17细胞亚群比例在各组中没有统计学差异;除急性乙型肝炎组外,其余各组中IL-21+CD4+T细胞比例与Th17细胞亚群比例均有较好的相关性.结论:IL-21在HBV感染不同临床表现患者外周血CD4+T的表达有一定差异,并且其与Th17细胞亚群有相关性,提示IL-21在HBV感染的发病机制可能发挥一定作用.%AIM: To investigate the levels of interleukin (IL) -21 in CD4 + T cells of peripheral blood from the different types of patients infected with hepatitis B virus (HBV) and elucidate its role in the hepatitis B pathogenesis. METHODS: Peripheral blood mononuclear cells (PBMCs) from the patients infected with HBV and healthy individuals were stimulated with or without PMA coupled with ionomycin. The levels of IL-21 in CD4 + T cells and Th17 cells were analyzed by flow cytometry. RESULTS: PMA and ionomycin induced the expression of IL-21, and IL-21 was mainly produced by CD4 + T cells, but IL-17A+ IL-21 + CD4 + T cells were not detected. The frequencies of IL-21+ CD4 + T cells in the patients of acute hepatitis B and chronic asymptomatic HBV carriers were higher than in healthy controls and severe chronic hepatitis B patients; there were no remarkable differences in the proportion of Th17 cells among the different groups of patients. Furthermore, the proportion of IL-21

  12. Depletion of the surface CD4 molecule by the envelope protein of human immunodeficiency virus expressed in a human CD4+ monocytoid cell line

    International Nuclear Information System (INIS)

    A CD4+ human monocytoid cell line, U937, was transfected with a constructed plasmid which has the envelope gene of human immunodeficiency virus under the transcriptional control of the human metallothionein IIA promoter and was cloned thereafter. These cloned cell lines (EH and EL cells) expressed the viral gp160 in the cytoplasm. The expression of surface CD4 antigen examined by Leu3a and OKT4 monoclonal antibodies, however, disappeared completely in EH cells, which produce a larger amount of gp160, while diminishing only partly in EL cells, which produce a smaller amount of gp160. These results indicate that the level of expression of surface CD4 antigen correlates inversely with the amount of intracellular gp160. Moreover, immunoprecipitation studies using lysate from EH cells showed that OKT4 monoclonal antibody precipitated a significant number of CD4 molecules even after surface CD4 disappeared. However, Leu3a monoclonal antibody, which recognizes the binding site for envelope protein, could not precipitate any CD4 molecules in the same cell lysate. Taken together, these results suggested that CD4 molecules are still synthesized normally after the augmented production of gp160 in the cells but form a complex with the envelope protein in the cytoplasm and become unable to be transported to the cell surface, resulting in the observed depletion of surface CD4 antigen. This mechanism may explain the decrease or absence of surface CD4 antigens in human lymphocytes infected with human immunodeficiency virus

  13. Expression and clinical significance of IL-17-producing CD4+ T and IL-17-producing CD8+ T cells in the peripheral blood of lung cancer patients%肺癌患者外周血白细胞介素-17+CD4+T细胞和白细胞介素-17+CD8+T细胞表达的意义

    Institute of Scientific and Technical Information of China (English)

    黄建红; 王艳峰; 翟晋芳; 石理; 苏文; 韩福才

    2013-01-01

    Objective To investigate the expression and clinical significance of Th17 and Tc17 cells in peripheral blood of lung cancer patients.Methods The percentages of Th17 cells and Tc17 cells in 60 lung cancer patients and 40 healthy controls were evaluated by flow cytometry analysis (FCM).Results The percentages of Th17 cells [(1.795±0.623) %] and Te17 cells [(0.865±0.357) %] in lung cancer group were significandy higher than those in controls [(1.405±0.256) %,(0.640 ±0.204) %],(t =28.944,P < 0.001,t =14.051,P < 0.001).Furthermore,there was a positive correlation between Th17 cells and Tc17 cells in the two groups (lung cancer group r =0.770,P < 0.05,control group r =0.532,P < 0.05).The percentages of Th17 cells and Tc17 cells were closely associated with clinical stage (F =4.882,P =0.011,F =3.633,P =0.033),but not connected with pathological types (P > 0.05,P > 0.05).Conclusion The overexpression of Th17 and Tc17 may be involved in the occurrence and development of lung cancer,which can be used as new indicators for immunologic function of lung cancer patients,and provide a reference in monitoring the disease.%目的 检测白细胞介素(IL)-17+CD4+T(Th17)细胞和IL-17+CD8+ T(Tc17)细胞在肺癌患者外周血中的表达水平,探讨二者在肺癌免疫中的作用及临床意义.方法 采用流式细胞术(FCM)检测60例肺癌患者及40例健康对照者外周血中Th17和Tc17细胞占CD;T细胞的比例.结果 肺癌组外周血中Th17细胞[(1.795±0.623)%]和Tc17细胞[(0.865±0.357)%]比例分别高于对照组[(1.405±0.256)%、(0.640±0.204)%],(t=28.944,P< 0.001;t=14.051,P< 0.001).两组内Th17细胞与Tc17细胞的表达水平均呈正相关(肺癌组r=0.770,P<0.05;对照组r=0.532,P<0.05).Th7细胞和Tc17细胞表达均与临床分期有关(F值分别为4.882、3.633,均P<0.05),但与病理类型无关(均P>0.05).结论 肺癌患者体内Th17细胞和Tc17细胞表达升高,二者可能参与了

  14. Decreased Expression of T-Cell Costimulatory Molecule CD28 on CD4 and CD8 T Cells of Mexican Patients with Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    German Bernal-Fernandez

    2010-01-01

    Full Text Available Patients with tuberculosis frequently develop anergy, a state of T-cell hyporesponsiveness in which defective T-cell costimulation could be a factor. To know if the expression of T-cell costimulatory molecules was altered in tuberculosis, we analyzed the peripheral blood T-cell phenotype of 23 Mexican patients with pulmonary tuberculosis. There was severe CD4 (P<.001 and CD8 (P<.01 lymphopenia and upregulation of costimulatory molecule CD30 on CD4 and CD8 T cells (P<.05; this increase was higher in relapsing tuberculosis. The main finding was severe downregulation of the major costimulatory molecule CD28 on both CD8 and CD4 T cells (P<.001. Depletion of the CD4/CD28 subset, a hitherto undescribed finding, is relevant because CD4 T cells constitute the main arm of the cell-mediated antimycobacterial immune response.

  15. Decrease of FOXP3 mRNA in CD4~+ T cells in latent autoimmune diabetes in adult

    Institute of Scientific and Technical Information of China (English)

    杨治芳

    2006-01-01

    Objective To study the percentage of peripheral blood CD4+ CD25+ T cells and the expression of F0XP3 mRNA in patients with latent autoimmune diabetes in adult (LADA). Methods Fresh peripheral blood samples were obtained from 60 patients with LADA,30 patients with type 2 diabetes and 30 age- and sex-matched

  16. CTLA-4 is Required by CD4+CD25+ Treg to Control CD4+ T Cell Lymphopenia-Induced Proliferation

    OpenAIRE

    Sojka, Dorothy K.; Hughson, Angela; Fowell, Deborah J.

    2009-01-01

    CTLA-4 is constitutively expressed by CD4+CD25+Foxp3+ regulatory T cells (Treg) but its precise role in Treg function is not clear. Although blockade of CTLA-4 interferes with Treg function, studies using CTLA-4 deficient Treg have failed to reveal an essential requirement for CTLA-4 in Treg suppression in vivo. Conditional deletion of CTLA-4 in Foxp3+ T cells disrupts immune homeostasis in vivo but the immune processes disrupted by CTLA-4 deletion have not been determined. We demonstrate tha...

  17. Expression of regulatory CD4+CD25+ Treg,CD4+CD25higTreg cells and Foxp3 mRNA in wheezing infants and its clinical significance%CD4+CD25+、CD4+CD25hig调节性T细胞和Foxp3mRNA在婴幼儿喘息中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    彭力; 钟礼立; 黄寒; 厉娟; 梁沫; 李云

    2012-01-01

    Objective To evaluate the changes of CD4+ CD25+ Treg,CD4 +CD25hig Treg and Foxp3 mRNA in peripheral blood from wheezing infantsMethods Fifty-one wheezing infants and twenty healthy volunteers were included in this study. The proportion of CD4 + CD25 + Treg and CD4 + CD25hig Treg population in total T cells was evaluated by flow cytometric analysis. The expression of Foxp3 mRNA was tested by flow cytometry. Total serum IgE of wheezy infants was detected by enzyme immunoassay. Results Compared with those of healthy control, the frequency of CD4 + CD25 + Treg and CD4 + CD25hig Treg in the peripheral blood from wheezing infants showed a significant increase (6. 31 + 2. 96) % / (3.52 + 1.46) % ,P<0. 01 ,P<0. 01, respectively).The expression of CD4 + CD25+ Treg,CD4 + CD25hig Treg and Foxp3 mRNA in peripheral blood from wheezing infants with atopy burden was lower than those from non-wheezing infants(P<0. 05). The correlation analysis showed that CD4 + CD25hig Treg (r= -0. 75 , P<0.01) and Foxp3 mRNA(r= -0. 61,P<0. 01) had significantly positive relation with total serum IgE,while CD4+CD25 + Treg had significantly negative relation with total serum IgE(r=0. 36,P<0. 05). Conclusion CD4+CD25+ Treg, CD4+CD25hig Treg and Foxp3 mRNA play an important role in activation of wheezing infants.%目的 探讨婴幼儿喘息CD4+CD25+、CD4+CD25hig调节性T细胞(Treg)和叉头/翼状螺旋转录因子(Foxp3)mRNA的表达及意义.方法 采用流式细胞术检测51例首次喘息婴幼儿外周血CD4+CD25+Treg和CD4+CD25higTreg的比例,RT-PCR检测Foxp3 mRNA的表达量,酶联免疫吸附法(ELASA)检测总IgE水平,并与正常婴幼儿对照.结果 喘息婴幼儿外周血CD4+CD25+Treg、CD4+CD25higTreg占CD4+T细胞的百分比分别为(6.31+2.96)%和(3.52+1.46)%,均明显低于健康对照组(P<0.01);特应征喘息组CD4+CD25+Treg、CD4+CD25higTreg及Foxp3 mRNA表达均低于非特应征喘息组(P<0.05).喘息患儿CD4+CD25higTreg百分率及Foxp3 mRNA表达与

  18. File list: Oth.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: His.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: His.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: His.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  2. File list: Oth.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  3. File list: Oth.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: Oth.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  5. File list: Oth.Bld.10.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: Oth.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: InP.Bld.50.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: Oth.Bld.50.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  9. File list: InP.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  10. File list: InP.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: InP.Bld.10.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: Oth.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study.

    Directory of Open Access Journals (Sweden)

    Zheng-Feng Zhu

    Full Text Available OBJECTIVE: CD4(+ latency-associated peptide (LAP(+ regulatory T cells (Tregs are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS has not been explored. We designed to investigate whether circulating frequency and function of CD4(+LAP(+ Tregs are defective in ACS. METHODS: One hundred eleven ACS patients (acute myocardial infarction and unstable angina and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA and chest pain syndrome (CPS. The frequencies of circulating CD4(+LAP(+ Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP on CD4(+ T cells were determined by flow cytometry. The function of CD4(+LAP(+ Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10 and transforming growth factor-β protein (TGF-β levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs was measured by real time-polymerase chain reaction. RESULTS: We found ACS patients had a significantly lower frequency of circulating CD4(+LAP(+ Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+ T cells and the serum levels of TGF-β in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. CONCLUSIONS: A novel regulatory T cell subset, defined as CD4(+LAP(+ T cells is defective in ACS patients.

  14. Increased cytotoxicity of CD4+ invariant NKT cells against CD4+CD25hiCD127lo/− regulatory T cells in allergic asthma

    OpenAIRE

    Nguyen, Khoa D.; Vanichsarn, Chris; Nadeau, Kari C.

    2008-01-01

    CD4+CD25hiCD127lo/− regulatory T cells (Treg) have been implicated in the resolution of asthma-associated inflammation while the opposite role of CD4+ invariant NKT (iNKT) cells has been the subject of recent investigations. Studies here focused on mechanisms of interaction between CD4+ iNKT cells and Treg to further explore their roles in allergic asthma (AA). Flow cytometry analysis revealed a significant increase in the expression of the natural cytotoxicity receptors NKp30 and NKp46 by CD...

  15. 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. PMID:26553320

  16. Effects of Delays in Peripheral Blood Processing, Including Cryopreservation, on Detection of CD31 Expression on Naïve CD4 T Cells▿

    OpenAIRE

    Higgins, Jeanette; Metcalf, Julia A.; Stevens, Randy A.; Baseler, Michael; Proschan, Michael; Lane, H. Clifford; Sereti, Irini

    2008-01-01

    Delayed processing of peripheral blood or peripheral blood mononuclear cell isolation and cryopreservation can lead to the detection of somewhat higher levels of CD31 expression on naïve CD4 T cells by flow cytometry. These observations should be considered in the planning of multicenter clinical trials and in the interpretation of the results of functional studies.

  17. Production of Primary Human CD4+ T Cell Lines and Clones

    OpenAIRE

    Matthis, Jessica; Reijonen, Helena

    2013-01-01

    Tetramer staining of CD4+ T cells is a valuable technique in immunology for detecting rare auto-reactive T cells. Generating clones or cell lines from auto-antigen tetramer positive CD4+ T cells allows further characterization and phenotyping of auto-reactive cells.

  18. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells

    OpenAIRE

    Liu, Weihong; Putnam, Amy L.; Xu-yu, Zhou; Szot, Gregory L; Lee, Michael R.; Zhu, Shirley; Gottlieb, Peter A.; Kapranov, Philipp; Gingeras, Thomas R.; de St. Groth, Barbara Fazekas; Clayberger, Carol; Soper, David M.; Ziegler, Steven F.; Bluestone, Jeffrey A.

    2006-01-01

    Regulatory T (T reg) cells are critical regulators of immune tolerance. Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4+ T cells in peripheral blood. We demonstrate that the majority of these cells are FoxP3+, including those that express low levels or no C...

  19. 妊娠期糖尿病母亲新生儿T细胞亚群及NK细胞活性的变化及其与血糖相关的研究%Changes of CD3+ , CD4+ and CD8+ T cells and natural killer cells in neonates born to gestational diabetes mellitus mothers and their relationship with blood glucose

    Institute of Scientific and Technical Information of China (English)

    王合丽; 孙学梅; 孙正芸; 王娜; 林霞

    2011-01-01

    目的 探讨妊娠期糖尿病母亲新生儿T细胞亚群及NK细胞活性的变化及其与患儿出生后24 h内微量血糖的关系.方法 选择妊娠期糖尿病母亲足月新生儿33例(观察组)及健康足月新生儿30例(对照组),应用流式细胞术检测出生后24h内静脉血CD3+、CD4+、CD8+T细胞及CD16+CD56+NK细胞;采用血糖检测仪检测新生儿生后24 h内的微量血糖,并研究观察组血糖与CD3+、CD4+、CD8+5T细胞、CD4+/CD8+、CD16+CD56+NK细胞有无相关性.结果 观察组新生儿的CD3+,CD4+T细胞计数,CD4+/CD8+比值、CD16+CD56+NK细胞活性均低于对照组新生儿(P<0.01),微量血糖亦低于对照组(P<0.05),观察组低血糖发生率21.21%,对照组无低血糖发生,两组低血糖发生率差异有统计学意义(P=0.023).CD3+、CD4+T细胞计数,CD16+CD56+NK细胞活性与微量血糖呈正相关性(P均<0.05).结论 妊娠期糖尿病可导致新生儿CD3+、CD4+T细胞计数,CD4+/CD8+比值,CD16+CD56+NK细胞活性下降,导致其免疫功能下降,应加强其围产期护理,预防新生儿期感染的发生.%Objective To investigate changes of CD3 +, CD4+ and CD8 + T cells and natural killer(NK) cells in neonates bom to gestational diabetes mellitus(GDM) mothers and their relationship with blood glucose. Methods 33 fullterm neonates bom to GDM mothers were enrolled as the experimental group and 30 healthy full-term neonates were enrolled as the control group. Numbers of CD3 +, CD4 + and CD8 + T cells and activity of NK cells were measured by flow cytometry within 24 h after birth. Blood glucose was detected by a trace glucose meter. Results Compared with the control group, numbers of CD3 + and CD4 + T cells, activity of NK cells and the ratio of CD4+/CD8+ were lower in the experimental group ( P <0.01 ). The level of blood glucose in the experimental group was lower ( P < 0.05 ).The incidence of hypoglycemia in the experimental group was 21.21%, which was higher than that in the

  20. Aire-Overexpressing Dendritic Cells Induce Peripheral CD4+ T Cell Tolerance

    Science.gov (United States)

    Li, Dongbei; Li, Haijun; Fu, Haiying; Niu, Kunwei; Guo, Yantong; Guo, Chuan; Sun, Jitong; Li, Yi; Yang, Wei

    2015-01-01

    Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study’s aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4+ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4+ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4+ IFN-γ+ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca2+ and p-ERK) in CD4+ T cells. We observed that Aire cells-induced CD4+ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4+IFN-γ+ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire. PMID:26729097

  1. 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.

  2. Ex vivo restimulation of human PBMC expands a CD3+CD4-CD8- γδ+ T cell population that can confound the evaluation of CD4 and CD8 T cell responses to vaccination.

    Science.gov (United States)

    Sedgmen, B J; Papalia, L; Wang, L; Dyson, A R; McCallum, H A; Simson, C M; Pearse, M J; Maraskovsky, E; Hung, D; Eomois, P P; Hartel, G; Barnden, M J; Rockman, S P

    2013-01-01

    The measurement of vaccine-induced humoral and CD4(+) and CD8(+) cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3(+)CD4(-)CD8(-) γδ (+) T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3(+)CD4(-)CD8(-) γδ (+) T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4(+) and CD8(+) immune responses following vaccination, the CD3(+)CD4(-)CD8(-) γδ (+) T cells are either excluded or separately enumerated from the overall frequency determination. PMID:24066003

  3. Ex Vivo Restimulation of Human PBMC Expands a CD3+CD4−CD8−γδ+ T Cell Population That Can Confound the Evaluation of CD4 and CD8 T Cell Responses to Vaccination

    Science.gov (United States)

    Sedgmen, B. J.; Papalia, L.; Wang, L.; Dyson, A. R.; McCallum, H. A.; Simson, C. M.; Pearse, M. J.; Maraskovsky, E.; Hung, D.; Eomois, P. P.; Hartel, G.; Barnden, M. J.; Rockman, S. P.

    2013-01-01

    The measurement of vaccine-induced humoral and CD4+ and CD8+ cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3+CD4−CD8−γδ+ T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3+CD4−CD8−γδ+ T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4+ and CD8+ immune responses following vaccination, the CD3+CD4−CD8−γδ+ T cells are either excluded or separately enumerated from the overall frequency determination. PMID:24066003

  4. Ex Vivo Restimulation of Human PBMC Expands a CD3+CD4-CD8-γδ+ T Cell Population That Can Confound the Evaluation of CD4 and CD8 T Cell Responses to Vaccination

    Directory of Open Access Journals (Sweden)

    B. J. Sedgmen

    2013-01-01

    Full Text Available The measurement of vaccine-induced humoral and CD4+ and CD8+ cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3+CD4-CD8-γδ+ T cell population in the peripheral blood of 90/610 (15% healthy subjects. The appearance of CD3+CD4-CD8-γδ+ T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4+ and CD8+ immune responses following vaccination, the CD3+CD4-CD8-γδ+ T cells are either excluded or separately enumerated from the overall frequency determination.

  5. Effects of BCG-polysaccharide nucleic acid on CD4+IL-17+ T cells and CD4+Foxp3+ Treg in asthmatic rats%卡介苗多糖核酸对哮喘大鼠CD4+IL-17+T细胞与CD4+Foxp3+调节性T细胞的影响

    Institute of Scientific and Technical Information of China (English)

    涂玲; 梁颖红; 魏明; 刘佳; 龚艳杰; 张俊华; 张宜花

    2015-01-01

    lavage fluid (BALF),peripheral blood and lymph fluids from asthmatic rats and the possible mechanism.Methods Sixty SD rats were randomly divided into control group (n=15),asthma group (n=15),BCG-PSN control group (n=15) and BCG-PSN asthma group (n=15),respectively.The rats in the asthma group and the BCG-PSN asthma group were modeled to be of asthma by challenging with ovalbumin (OVA),while those in control group and BCG-PSN control group were sham-challenged with equal volume of normal saline.The BCG-PSN asthma group and the BCG-PSN control group were treated with BCG-PSN as an intervention.The rat BALF,peripheral blood and lymph fluids were collected from each group.Flow cytometry (FCM) was used to determine the percentage of CD4+IL-17+ T cells and CD4+Foxp3+ Treg.Enzyme-linked immunosorbent assay (ELISA) was used to determine the IL-10 and IL-17 levels.Results All groups showed significantly higher CD4+Foxp3+ Treg percentage and IL-10 level,lower CD4+ IL-17+ T cells percentage and IL-17 level in lymph fluid than those in blood and BALF (all P<0.01).In asthma group,the percentage of CD4+Foxp3+ Treg,IL-10 were significantly lower,and CD4+IL-17+ T cells percentage and IL-17 level were higher compared with those in BALF,lymph fluid and peripheral blood in the other 3 groups (all P<0.01).In BCG-PSN asthma group,there were higher CD4+Foxp3+ Treg percentage and IL-10 level,lower CD4+IL-17+ T cells percentage and IL-17 level in BALF,lymph fluid and peripheral blood compared with the asthma group (all P<0.01),but these values were statistically comparable to those in the control group and BCG-PSN control group (all P>0.05).Conclusion BCG-PSN may improve host immune response and thereby ameliorate the inflammation in asthma through regulating the percentage of CD4+Foxp3+ Treg and CD4+IL-17+ T cells,and the level of certain cytokines in lymph and peripheral blood of asthma rats.

  6. 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....

  7. Spontaneous loss and alteration of antigen receptor expression in mature CD4+ T cells

    International Nuclear Information System (INIS)

    The T-cell receptor CD3 (TCR/CD3) complex plays a central role in antigen recognition and activation of mature T cells, and therefore abnormalities in the expression of the complex should induce unresponsiveness of T cells to antigen stimulus. Using flow cytometry, we detected and enumerated variant cells with loss or alteration of surface TCR/CD3 expression among human mature CD4+ T cells. The presence of variant CD4+ T cells was demonstrated by isolating and cloning them from peripheral blood, and their abnormalities can be accounted for by alterations in TCR expression such as defects of protein expression and partial protein deletion. The variant frequency in peripheral blood increased with aging in normal donors and was highly elevated in patients with ataxia telangiectasia, an autosomal recessive inherited disease with defective DNA repair and variable T-cell immunodeficiency. These findings suggest that such alterations in TCR expression are induced by somatic mutagenesis of TCR genes and can be important factors related to age-dependent and genetic disease-associated T-cell dysfunction. (author)

  8. Hemeoxygenase-1 expression effect on the up-regulation of peripheral blood CD4+CD25+CD127low/- regulatory T cells mediated by mesenchymal stem cells in asthma patients%血红素加氧酶1在间充质干细胞上调哮喘患者外周血调节性T细胞中的作用

    Institute of Scientific and Technical Information of China (English)

    温冰; 颛孙永勋; 颜富德; 陈瑞; 张蔚; 冯素玲; 李建国

    2011-01-01

    BACKGROUND: Up-regulating CD4+CD25+CD127low/- regulatory T cells is a new target in the treatment of asthma. Human bone marrow mesenchymal stem cells (MSCs) can up-regulate CD4+CD25+CD127low/- regulatory T cells in vitro, while the mechanism is not clear.OBJECTIVE: To study the effect of hemeoxygenase -1 (HO-1) expression in the up-regulation of peripheral blood CD4+CD25+CD127low/- regulatory T cells mediated by MSCs in asthma patients.METHODS: Real-time PCR was used to examine the expression of HO-1 mRNA in MSCs pretreated with 0, 15, 30, 45,60 μmol/L Hemin (the revulsive of HO-1) and 0, 5, 10, 15, 20 μmol/L ZnPP (the inhibitor of HO-1) respectively. Peripheral blood mononuclear cells (PBMCs), which were isolated from 10 cases of asthma patients with acute episode and 10 cases of healthy controls using Ficoll density gradient centrifugation, were incubated with MSCs pretreated with Hemin, ZnPP and mock respectively.RESULTS AND CONCLUSION: The expression of HO-1 in MSCs can be induced and inhibited in vitro. The higher concentration of Hemin added to MSCs, the higher expression of HO-1 mRNA was tested (P < 0.05). With the increasing concentration of ZnPP added to MSCs, the expression of HO-1 mRNA was becoming lower (P < 0.05). The proportion of CD4 +CD25+CD127low/-regulatory T cells in CD4+ T cells could be up-regulated by MSCs (P < 0.01) and also by MSCs with induction of HO-1 expression (P < 0.01). While MSCs with inhibition of HO-1 expression could down-regulate the proportion of CD4 +CD25+CD127low/-regulatory T cells in CD4 + T cells (P < 0.01). The expression of HO-1 partially contributed to the up-regulation of CD4+CD25+CD127low/- regulatory T cells mediated by MSCs in asthma patients.%背景:上调CD4+CD25+CD127low/-调节性T 细胞是目前治疗哮喘的新靶点.骨髓间充质干细胞在体外可上调正常人外周血的调节性T 细胞,但机制尚未明确.目的:观察血红素加氧酶1 对间充质干细胞上调哮喘患者外周血CD

  9. CD4+ T cell effects on CD8+ T cell location defined using bioluminescence.

    Directory of Open Access Journals (Sweden)

    Mitra Azadniv

    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.

  10. Multifunctional CD4 T Cell Responses in Patients with Active Tuberculosis

    OpenAIRE

    Qiu, Zhengang; Zhang, Mingxia; Zhu, Yuzhen; Zheng, Feiqun; Lu, Puxuan; Liu, Haiying; Michael W Graner; Zhou, Boping; Chen, Xinchun

    2012-01-01

    The roles of multifunctional CD4 T cells in human tuberculosis are not well defined. In this study, we found that patients with tuberculosis had decreased PMA/ionomycin stimulated multifunctional CD4 T cells, and increased Mycobacterium tuberculosis antigen-specific multifunctional CD4 T cells, when compared to individuals with latent tuberculosis infection and healthy controls. PMA/ionomycin stimulated IFN-γ+IL-2+TNF-α+ CD4 T cell responses were decreased in patients with smear-positive tube...

  11. The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4(+) T cells

    DEFF Research Database (Denmark)

    Munir, Shamaila; Andersen, Gitte Holmen; Svane, Inge Marie; Andersen, Mads Hald

    2013-01-01

    Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8(+) T cells. In the present study, we develop these findings and report that CD4(+) helper T cells...... spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A*0201-restricted PD-L1-epitope for the presence of possible CD4(+) T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4(+) T cells among the peripheral blood lymphocytes of cancer patients and - to...... lesser extents - healthy donors, by means of ELISPOT assays. PD-L1-specific CD4(+) T cells appeared to be TH17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4(+) T cells released interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-17 (IL-17) in response to...

  12. Spleen-resident CD4+ and CD4- CD8α- dendritic cell subsets differ in their ability to prime invariant natural killer T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Emilie Bialecki

    Full Text Available One important function of conventional dendritic cells (cDC is their high capacity to capture, process and present Ag to T lymphocytes. Mouse splenic cDC subtypes, including CD8α(+ and CD8α(- cDC, are not identical in their Ag presenting and T cell priming functions. Surprisingly, few studies have reported functional differences between CD4(- and CD4(+ CD8α(- cDC subsets. We show that, when loaded in vitro with OVA peptide or whole protein, and in steady-state conditions, splenic CD4(- and CD4(+ cDC are equivalent in their capacity to prime and direct CD4(+ and CD8(+ T cell differentiation. In contrast, in response to α-galactosylceramide (α-GalCer, CD4(- and CD4(+ cDC differentially activate invariant Natural Killer T (iNKT cells, a population of lipid-reactive non-conventional T lymphocytes. Both cDC subsets equally take up α-GalCer in vitro and in vivo to stimulate the iNKT hybridoma DN32.D3, the activation of which depends solely on TCR triggering. On the other hand, and relative to their CD4(+ counterparts, CD4(- cDC more efficiently stimulate primary iNKT cells, a phenomenon likely due to differential production of co-factors (including IL-12 by cDC. Our data reveal a novel functional difference between splenic CD4(+ and CD4(- cDC subsets that may be important in immune responses.

  13. IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells

    DEFF Research Database (Denmark)

    Skov, S; Bonyhadi, M; Odum, Niels; Ledbetter, J A

    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 cel...

  14. 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 these ...

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

    International Nuclear Information System (INIS)

    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 (TR). 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- TR 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- TR expanded in response to IL-2, but not to CMV antigenic restimulation. The anti-proliferative effect of CMV-CD4+CD27-CD28- TR significantly decreased after granzyme B or TGFβ inhibition. The CMV-CD4+CD27-CD28- TR 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- TR. The CMV-CD4+CD27-CD28- TR may contribute to the downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.

  16. 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.

  17. 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

    -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......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...... xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4(+), but not...

  18. Diminished frequency and function of CD4(+) CD25(high) regulatory T cells associated with active uveitis in Vogt-Koyanagi-Harada syndrome

    NARCIS (Netherlands)

    Chen, L.; Yang, P.Z.; Zhou, H.Y.; He, H.; Ren, X.R.; Chi, W.; Wang, L.; Kijlstra, A.

    2008-01-01

    PURPOSE. CD4(+)CD25(high) regulatory T (Treg) cells have been shown to be involved in the pathogenesis of autoimmune diseases. Vogt-Koyanagi-Harada (VKH) syndrome is an organ-specific autoimmune disease. This study was designed to phenotypically and functionally characterize peripheral blood CD4(+)C

  19. When aging reaches CD4+ T-cells: phenotypic and functional changes

    Directory of Open Access Journals (Sweden)

    Marco Antonio Moro-García

    2013-05-01

    Full Text Available Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28null T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8+T-cell compartment, these mechanisms ultimately fail with age.

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

    Directory of Open Access Journals (Sweden)

    Megan KL Macleod

    2015-09-01

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

  1. Differences in expression of gut-homing receptors on CD4+ T cells in black and white HIV-negative men who have sex with men.

    Science.gov (United States)

    Kelley, Colleen F; Lai, Lilin; Ibegbu, Chris; Rosenberg, Eli S; Kaur, Surinder; Patel, Kalpana; Mulligan, Mark J; Marconi, Vincent C; Sullivan, Patrick S; Amara, Rama R

    2016-05-15

    HIV incidence rates are higher among black men who have sex with men (BMSM) as compared with MSM of other race/ethnicities in the USA. We found that blood memory CD4 cells from BMSM express higher levels of α4β7, the gut-homing integrin, compared with white MSM. Higher expression of α4β7 on blood CD4 cells correlated with higher percentage of proliferating CD4α4β7 cells in rectal tissue suggesting increased trafficking of potential HIV target cells to rectal mucosa could increase HIV susceptibility among BMSM. PMID:26891038

  2. Decreased percentage of CD4+Foxp3+TGF-β+ and increased percentage of CD4+IL-17+ cells in bronchoalveolar lavage of asthmatics

    OpenAIRE

    Barczyk, Adam; Pierzchala, Wladyslaw; Caramori, Gaetano; Wiaderkiewicz, Ryszard; Kaminski, Marcin; Barnes, Peter J; Adcock, Ian M.

    2014-01-01

    Background Asthma is a chronic inflammatory disorder of the airways with the proven role of Th2 cells in its pathogenesis. The role and characteristic of different subsets of CD4+ cells is much less known. Aim The aim of the study was to analyze the incidence of different subsets of CD4+ T cells, in particular different subsets of CD4+ cells with the co-expression of different cytokines. Methods Twenty five stable asthmatic and twelve age-matched control subjects were recruited to the study. ...

  3. HIV-specific CD4(+) T cells and viremia: who's in control?

    NARCIS (Netherlands)

    C.A. Jansen; D. van Baarle; F. Miedema

    2006-01-01

    It has been proposed that HIV-specific CD4(+) T cells with a central memory phenotype might be involved in controlling HIV replication. Based on recent data (lack of protective effects of HIV-specific CD4+ T-cell responses in acutely infected patients undergoing treatment interruptions; loss of init

  4. A false expression of CD8 antigens on CD4+ T cells in a routine flow cytometry analysis.

    Directory of Open Access Journals (Sweden)

    Danuta Kowalczyk

    2006-09-01

    Full Text Available The two-colour flow cytometry method applied in a routine enumeration of peripheral blood T lymphocyte subsets reveals that in some patients the entire population of CD4+ lymphocytes seems to express CD8 determinants as well. However, expression of the CD8 antigens on the cell surface is much lower in comparison with typical CD8+ cells. Moreover, in one-colour staining with an anti-CD8 antibody, cells with weak CD8 expression are not observed and only one typical population of CD8+ lymphocytes is seen. Investigating this phenomenon, we showed that after washing patient cells in RPMI before CD4/CD8 staining, the CD4+ T cell population did not show CD8 "co-expression". These results suggest that CD4+ lymphocytes, which seem to co-express CD8 antigen, in fact do not have this antigen on their surface. Moreover, after the addition of patient plasma to healthy donor cells prior to CD4/CD8 staining, a weak CD8 expression on normal CD4+ cells was noticed. Therefore we can assume that the agent(s causing this phenomenon is/are present in the plasma of some patients. Altogether, these observations suggest that this phenomenon is nonspecific and probably results from cross-linking of anti-CD8 mAbs with anti-CD4 mAbs caused by factor(s present in plasma of some patient. However, identification of that/these factor(s requires further research.

  5. Flow-cytometric measurement of CD4-8- T cells bearing T-cell receptor αβ chains, 1

    International Nuclear Information System (INIS)

    In this study we detected rare, possibly abnormal, T cells bearing CD3 surface antigen and T-cell receptor (TCR) αβ chains but lacking both CD4 and CD8 antigens (viz., TCRαβ+CD4-8- cells, as determined by flow cytometry). The TCRαβ+CD4-8-T cells were detected at a mean frequency of 0.63 ± 0.35 % (mean ± standard deviation) in peripheral blood TCRαβ+ cells of 119 normal persons. Two unusual cases besides the 119 normal persons showed extremely elevated frequencies of TCRαβ+CD4-8-T cells, viz., approximately 5 % to 10 % and 14 % to 19 % in whole TCRαβ+ cells. Both individuals were males who were otherwise physiologically quite normal with no history of severe illness, and these high frequencies were also observed in blood samples collected 2 or 8 years prior to the current measurements. The TCRαβ+CD4-8-T cells of the two individuals were found to express mature T-cell markers such as CD2,3, and 5 antigens, as well as natural killer (NK) cell markers, viz., CD11b, 16, 56, and 57 antigens, when peripheral blood lymphocytes were subjected to three-color flow cytometry. Lectin-dependent or redirected antibody-dependent cell-mediated cytotoxicities were observed for both freshly sorted TCRαβ+CD4-8- cells and in vitro established clones. Nevertheless, NK-like activity was not detected. Further, Southern blot analysis of TCRβ and γ genes revealed identical rearrangement patterns for all the TCRαβ+CD4-8- clones established in vitro. These results suggest that the TCRαβ+CD4-8-T cells from these two mean exhibit unique characteristics and proliferate clonally in vivo. (author)

  6. Dysregulation of complement system and CD4+ T cell activation pathways implicated in allergic response.

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    Alexessander Couto Alves

    Full Text Available Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13 and of the Th2 master regulator (GATA3, suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1 are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

  7. 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. PMID:16360834

  8. Human mesenchymal stem cells elevate CD4+CD25+CD127low/- regulatory T cells of asthmatic patients via heme oxygenase-1.

    Science.gov (United States)

    Li, Jian-guo; Zhuan-sun, Yong-xun; Wen, Bing; Wu, Hao; Huang, Feng-ting; Ghimire, Hridaya bibhu; Ran, Pi-xin

    2013-09-01

    Up-regulation of CD4+CD25+CD127low/- regulatory T cells (Tregs) is a new target in the treatment of asthma. Human bone marrow mesenchymal stem cells can up-regulate CD4+CD25+CD127low/- regulatory T cells in vitro, meanwhile, heme oxygenase-1 (HO-1) plays an important role in the development and maintenance of CD4+CD25+ regulatory T cells. However the mechanism has not yet been adequately understood. Hence, we wondered what effect of Heme Oxygenase-1 made on regulation of CD4+CD25+CD127low/- regulatory T cells mediated by mesenchymal stem cells. Peripheral blood mononuclear cells isolated from asthmatic patients and healthy controls were co-cultured with human bone marrow mesenchymal stem cells which were pretreated with Hemin (the revulsive of Heme Oxygenase-1), Protoporphyrin Ⅸ zinc (the inhibitor of Heme Oxygenase-1) and saline. The expression of Heme Oxygenase-1 in MSCs was enhanced by Hemin and inhibited by Protoporphyrin  zinc in vitro. Overexpression of Heme Oxygenase-1 elevated the proportion of CD4+CD25+CD127low/- regulatory T cells in CD4+ T cells, meanwhile, inhibition of Heme Oxygenase-1 decreased the proportion of CD4+CD25+CD127low/- regulatory T cells in CD4+ T cells as compared with mesenchymal stem cells alone. Taken together, these data demonstrated that Heme Oxygenase-1 contributed to the up-regulation of CD4+CD25+CD127low/- regulatory T cells mediated by mesenchymal stem cells in asthma.  PMID:23893806

  9. Schistosoma haematobium infection and CD4+ T-cell levels: a cross-sectional study of young South African women.

    Directory of Open Access Journals (Sweden)

    Elisabeth Kleppa

    Full Text Available Schistosoma (S. haematobium causes urogenital schistosomiasis and has been hypothesized to adversely impact HIV transmission and progression. On the other hand it has been hypothesized that HIV could influence the manifestations of schistosomiasis. In this cross-sectional study, we explored the association between urogenital S. haematobium infection and CD4 cell counts in 792 female high-school students from randomly selected schools in rural KwaZulu-Natal, South Africa. We also investigated the association between low CD4 cell counts in HIV positive women and the number of excreted schistosome eggs in urine. Sixteen percent were HIV positive and 31% had signs of urogenital schistosomiasis (as determined by genital sandy patches and / or abnormal blood vessels on ectocervix / vagina by colposcopy or presence of eggs in urine. After stratifying for HIV status, participants with and without urogenital schistosomiasis had similar CD4 cell counts. Furthermore, there was no significant difference in prevalence of urogenital schistosomiasis in HIV positive women with low and high CD4 cell counts. There was no significant difference in the number of eggs excreted in urine when comparing HIV positive and HIV negative women. Our findings indicate that urogenital schistosomiasis do not influence the number of circulating CD4 cells.

  10. Interleukin-2 Enhances the Regulatory Functions of CD4(+)T Cell-Derived CD4(-)CD8(-) Double Negative T Cells.

    Science.gov (United States)

    Cong, Min; Liu, Tianhui; Tian, Dan; Guo, Hongbo; Wang, Ping; Liu, Kai; Lin, Jun; Tian, Yue; Shi, Wen; You, Hong; Jia, Jidong; Zhang, Dong

    2016-08-01

    CD4(+) T cells can be converted to CD4(-)CD8(-) double negative T cells (DN T cells) under appropriate conditions, and IL-2 enhanced the conversion. Here, we investigated the effect of IL-2 on the proliferation and function of converted DN T cells in vitro and in vivo. DN T cells were hyporesponsive when restimulated by mature dendritic cells (mDCs), IL-2 completely restored their responsiveness in vitro. In addition, IL-2 increased the resistance of DN T cells to apoptosis in vivo. DN T cells profoundly inhibited the proliferation of CD4(+)CD25(-) T effector cells triggered by mDCs in vitro, and this suppression was further enhanced by IL-2. Adoptively transferring of DN T cells, in combination with IL-2, inhibited the proliferation and enhanced apoptosis of alloreactive CD4(+) T cells, which resulted in significant prolongation of skin allograft survival time. Perforin plays a key role in the enhancement of DN T cells immune regulation by IL-2. In conclusion, we elucidated that IL-2 promoted DN T cell proliferation and suppressive function. The combination of DN T cells and exogenous IL-2 may represent a novel therapy in the clinical setting to prevent allograft rejection and induce immune tolerance. PMID:27135902

  11. Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL.

    Science.gov (United States)

    Sande, Obondo J; Karim, Ahmad F; Li, Qing; Ding, Xuedong; Harding, Clifford V; Rojas, Roxana E; Boom, W Henry

    2016-01-15

    Mycobacterium tuberculosis cell wall glycolipid, lipoarabinomannan, can inhibit CD4(+) T cell activation by downregulating the phosphorylation of key proximal TCR signaling molecules: Lck, CD3ζ, ZAP70, and LAT. Inhibition of proximal TCR signaling can result in T cell anergy, in which T cells are inactivated following an Ag encounter, yet remain viable and hyporesponsive. We tested whether mannose-capped lipoarabinomannan (LAM)-induced inhibition of CD4(+) T cell activation resulted in CD4(+) T cell anergy. The presence of LAM during primary stimulation of P25 TCR-transgenic murine CD4(+) T cells with M. tuberculosis Ag85B peptide resulted in decreased proliferation and IL-2 production. P25 TCR-transgenic CD4(+) T cells primed in the presence of LAM also exhibited decreased response upon restimulation with Ag85B. The T cell anergic state persisted after the removal of LAM. Hyporesponsiveness to restimulation was not due to apoptosis, generation of Foxp3-positive regulatory T cells, or inhibitory cytokines. Acquisition of the anergic phenotype correlated with upregulation of gene related to anergy in lymphocytes (GRAIL) protein in CD4(+) T cells. Inhibition of human CD4(+) T cell activation by LAM also was associated with increased GRAIL expression. Small interfering RNA-mediated knockdown of GRAIL before LAM treatment abrogated LAM-induced hyporesponsiveness. In addition, exogenous IL-2 reversed defective proliferation by downregulating GRAIL expression. These results demonstrate that LAM upregulates GRAIL to induce anergy in Ag-reactive CD4(+) T cells. Induction of CD4(+) T cell anergy by LAM may represent one mechanism by which M. tuberculosis evades T cell recognition. PMID:26667170

  12. Transcriptional characteristics of CD4+ T cells in young asthmatic children: RORC and FOXP3 axis

    Directory of Open Access Journals (Sweden)

    Hamzaoui A

    2011-11-01

    Full Text Available Agnes Hamzaoui1,2,*, Haïfa Maalmi1,*, Anissa Berraïes1,2, Hanadi Abid1,2, Jamel Ammar1,2, Kamel Hamzaoui11Department of Pediatrics and Respiratory Disease, Homeostasis and Cell Dysfunction Unit Research, Abderrahman Mami Hospital, Ariana, Tunisia; 2Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia *These authors contributed to this work equallyBackground: Asthma is a chronic inflammatory disorder, hypothetically caused by autoreactive Th2 cells, whereas Th1 and regulatory T cells may confer protection. The development of Th subpopulations is dependent on the expression of lineage-specific transcription factors.Purpose: This study aimed to assess the balance of CD4+ T cell populations in asthmatic children.Methods: Peripheral blood mononuclear cells (PBMC mRNA expression was assessed in 30 asthmatic children (18 patients with mild asthma and 12 with moderate asthma. Real-time polymerase chain reaction (RT-PCR quantified TBX21, GATA-3, RORC, FOXP3, and EBI3 mRNA expression. Intracellular cytokine expression of IL-2, IL-4, IL-10, and IFN-γ in CD4+ T cells in asthmatic children was measured by flow cytometry. IL-6 and IL-17 cytokines were assessed in serum by enzyme-linked immunosorbent assay (ELISA.Results: A significant increase was found in the percentage of CD4+ and CD8+ T cell-producing IL-4, IL-6, and IL-17. A decreased percentage of CD4+ producing IFN-γ in asthmatic children was found. Expression of GATA-3 (Th2, retinoid-related orphan receptor C (RORC (Th17, and EBI3 were increased in asthmatic patients compared to healthy controls. Expression of FOXP3 (Treg and TBX21 (Th1 were decreased (P < 0.0001 and P < 0.0001 in asthmatic children. Analysis of transcription factor ratios revealed an increase in the RORC/FOXP3 (P = 0.0001, and a significant decrease of TBX21/GATA-3 (P = 0.0001 ratios in patients with asthma.Conclusion: Young asthmatics were characterized by increased IL-4 production and low IFN-γ synthesis. The

  13. 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.

  14. Development of Virus-Specific CD4+ and CD8+ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

    OpenAIRE

    Wang, Fang; Chi, Jing; Peng, Guangyong; Zhou, Feng; Wang, Jinfeng; Li, Lingyun; Feng, Dongju; Xie, Fangyi; Gu, Bin; Qin, Jian; CHEN, YUN; Yao, Kun

    2014-01-01

    Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus. The mechanisms by which HHV-6 establishes latency and immunosuppression in its host are not well understood. Here we characterized HHV-6-specific T cells in peripheral blood mononuclear cells (PBMCs) from HHV-6-infected donors. Our results showed that HHV-6 infection could induce both CD4+ and CD8+ HHV-6-specific regulatory T (Treg) cells. These HHV-6-specific Treg cells had potent suppressive activity a...

  15. Bioenergetics profile of CD4(+) T cells in relapsing remitting multiple sclerosis subjects.

    Science.gov (United States)

    De Riccardis, Lidia; Rizzello, Antonia; Ferramosca, Alessandra; Urso, Emanuela; De Robertis, Francesca; Danieli, Antonio; Giudetti, Anna Maria; Trianni, Giorgio; Zara, Vincenzo; Maffia, Michele

    2015-05-20

    Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. There are four clinical forms of MS, the most common of which is characterized by a relapsing remitting course (RRMS). The etiology of MS is unknown, but many studies suggested that genetic, environmental and infectious agents may contribute to the development of this disease. In experimental autoimmune encephalomyelitis (EAE), the animal model for MS, it has been shown that CD4(+) T cells play a key role in MS pathogenesis. In fact, these cells are able to cross the blood-brain barrier and cause axonal damage with neuronal death. T cell activation critically depends on mitochondrial ATP synthesis and reactive oxygen species (ROS) production. Interestingly, lots of studies linked the oxidative damage arising from mitochondrial changes to neurodegenerative disorders, such as MS. Based on these evidences, this work focused on the metabolic reprogramming of CD4(+) T cells in MS subjects, being this cell population directly implicated in pathogenesis of disease, paying attention to mitochondrial function and response to oxidative stress. Such aspects, once clarified, may open new opportunities for a therapeutic metabolic modulation of MS disorder. PMID:25701681

  16. Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia

    OpenAIRE

    Johnson, Susan; Eller, Michael; Teigler, Jeffrey E.; Maloveste, Sebastien M.; Schultz, Bruce T.; Soghoian, Damien Z.; Lu, Richard; Oster, Alexander F.; Chenine, Agnès-Laurence; Alter, Galit; Dittmer, Ulf; Marovich, Mary; Merlin L Robb; Michael, Nelson L.; Bolton, Diane

    2015-01-01

    CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcri...

  17. High proportions of CD4⁺ T cells among residual bone marrow T cells in childhood acute lymphoblastic leukemia are associated with favorable early responses.

    Science.gov (United States)

    Lustfeld, Imke; Altvater, Bianca; Ahlmann, Martina; Ligges, Sandra; Brinkrolf, Peter; Rosemann, Annegret; Moericke, Anja; Rossig, Claudia

    2014-01-01

    Residual nonmalignant T cells in the bone marrow of patients with acute leukemias may be involved in active immune responses to leukemic cells. Here, we investigated the phenotypic signature of T cells present at diagnosis in 39 pediatric patients with acute lymphoblastic leukemia (ALL) treated within standardized ALL-BFM study protocols. Previously described age associations of lymphocyte subpopulations in the peripheral blood of healthy children were reproduced in leukemic bone marrow. Analysis of individual lymphocyte parameters and risk-associated variables using univariate linear regression models revealed a correlation of higher CD4/CD8 ratios at diagnosis with a favorable bone marrow response on day 15. Separate analysis of CD4cells with the CD4⁺CD25(hi)FoxP3⁺ T(reg) cell phenotype showed that the association was caused by non-T(reg) CD4cells. The association of higher CD4/CD8 ratios with a favorable bone marrow response on day 15 of treatment persisted in a cohort extended to 69 patients. We conclude that CD4⁺ non-T(reg) cells in leukemic bone marrow at diagnosis may have a role in early response to treatment. Prospective analysis of the CD4/CD8 ratio in a large cohort of pediatric patients is now needed. Moreover, future experiments will establish the functional role of the individual T cell subsets in immune control in pediatric ALL. PMID:24021585

  18. 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.

  19. Regulatory T cells diminish transmission of HIV from Dendritic cells to conventional CD4+ T cells

    OpenAIRE

    Maria Eugenia Moreno-Fernandez; Joedicke, Jara J; Claire Anne Chougnet

    2014-01-01

    Formation of immunological synapses between dendritic cells (DC) and conventional CD4+ T cells (Tcon) is critical for productive immune responses. However, when DCs are HIV-infected such synapses are critical to establish HIV infection. As regulatory T cells (Treg) control DC-Tcon interactions, we inquired whether Treg might interfere with DC to Tcon HIV transmission. We developed a model, using monocyte-derived DC infected with R5-HIV, and cultured with Tcon in the presence or absence of a...

  20. Specific CD4+ T-Cell Reactivity and Cytokine Release in Different Clinical Presentations of Leptospirosis.

    Science.gov (United States)

    Volz, Magdalena Sarah; Moos, Verena; Allers, Kristina; Luge, Enno; Mayer-Scholl, Anne; Nöckler, Karsten; Loddenkemper, Christoph; Jansen, Andreas; Schneider, Thomas

    2015-12-01

    Clinical manifestations of leptospirosis are highly variable: from asymptomatic to severe and potentially fatal. The outcome of the disease is usually determined in the immunological phase, beginning in the second week of symptoms. The underlying mechanisms, predictive factors, and individual immune responses that contribute to clinical variations are not well understood. The aim of this study was to determine the specifics of CD4(+) T-cell reactivity and cytokine release after stimulation with leptospiral antigens in patients with leptospirosis of different disease severities (patients with mild and severe symptoms) and in control subjects (with and without proven exposure to Leptospira). Whole-blood specimens were stimulated with Leptospira antigens in vitro. Subsequently, intracellular staining of cytokines was performed, and flow cytometry was used to assess the expression of CD40 ligand (CD40L) and the production of gamma interferon (IFN-γ), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-α) by CD4(+) T cells. The production of inflammatory cytokines such as TNF-α by CD4(+) T cells after stimulation with leptospiral antigens was highest in patients with severe disease. In contrast, the ratio of IL-10 production to TNF-α production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-α may be useful markers of the severity of the immunological phase of leptospirosis. IL-10 production by T cells after antigen-specific stimulation may indicate a more successful downregulation of the inflammatory response and may contribute to an asymptomatic course of the disease. PMID:26491036

  1. CD4+ lymphoid tissue inducer cells promote innate immunity in the gut

    OpenAIRE

    Sonnenberg, Gregory F.; Monticelli, Laurel A.; Elloso, M. Merle; Fouser, Lynette A.; Artis, David

    2010-01-01

    Fetal CD4+ lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid-tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that following infection with Citrobacter rodentium, CD4+ LTi cells were a dominant source of interleukin-...

  2. Modeling the Slow CD4+ T Cell Decline in HIV-Infected Individuals.

    Science.gov (United States)

    Wang, Sunpeng; Hottz, Patricia; Schechter, Mauro; Rong, Libin

    2015-12-01

    The progressive loss of CD4+ T cell population is the hallmark of HIV-1 infection but the mechanism underlying the slow T cell decline remains unclear. Some recent studies suggested that pyroptosis, a form of programmed cell death triggered during abortive HIV infection, is associated with the release of inflammatory cytokines, which can attract more CD4+ T cells to be infected. In this paper, we developed mathematical models to study whether this mechanism can explain the time scale of CD4+ T cell decline during HIV infection. Simulations of the models showed that cytokine induced T cell movement can explain the very slow decline of CD4+ T cells within untreated patients. The long-term CD4+ T cell dynamics predicted by the models were shown to be consistent with available data from patients in Rio de Janeiro, Brazil. Highly active antiretroviral therapy has the potential to restore the CD4+ T cell population but CD4+ response depends on the effectiveness of the therapy, when the therapy is initiated, and whether there are drug sanctuary sites. The model also showed that chronic inflammation induced by pyroptosis may facilitate persistence of the HIV latent reservoir by promoting homeostatic proliferation of memory CD4+ cells. These results improve our understanding of the long-term T cell dynamics in HIV-1 infection, and support that new treatment strategies, such as the use of caspase-1 inhibitors that inhibit pyroptosis, may maintain the CD4+ T cell population and reduce the latent reservoir size. PMID:26709961

  3. CCL2 Increases X4-tropic HIV-1 Entry into Resting CD4+ T Cells*

    OpenAIRE

    Campbell, Grant R.; Spector, Stephen A.

    2008-01-01

    During human immunodeficiency virus type 1 (HIV-1) infection, there is a strong positive correlation between CCL2 levels and HIV viral load. To determine whether CCL2 alters HIV-1 infection of resting CD4+ T cells, we infected purified resting CD4+ T cells after incubation with CCL2. We show that CCL2 up-regulates CXCR4 on resting CD4+ T cells in a CCR2-dependent mechanism, and that this augmentation of CXCR4 expression by CCL2 increases the ability of these cells to b...

  4. CD4(+) T cells producing interleukin (IL)-17, IL-22 and interferon-? are major effector T cells in nickel allergy

    DEFF Research Database (Denmark)

    Dyring Andersen, Beatrice; Skov, Lone; Løvendorf, Marianne B; Bzorek, Michael; Søndergaard, Knud; Lauritsen, Jens-Peter H; Dabelsteen, Sally Anne Malene; Geisler, Carsten; Bonefeld, Charlotte Menné

    2013-01-01

    Background It has been suggested that interleukin (IL)-17 and IL-22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL-17 and IL-22 in human allergic contact dermatitis are unknown. Objectives To determine the...... frequencies of CD4(+) , CD8(+) and γδ T cells producing IL-17, IL-22 and interferon (IFN)-γ in the blood and skin from nickel-allergic patients. Patients/materials/methods Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6......-allergic patients, there was massive cellular infiltration dominated by CD4(+) T cells producing IL-17, IL-22 and IFN-γ in nickel-challenged skin but not in vehicle-challenged skin. Conclusion CD4(+) T cells producing IL-17, IL-22 and IFN-γ are important effector cells in the eczematous reactions of nickel...

  5. 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...... antigens. T-cell lines were now generated by cultivating CD4+ cells with peptides instead of PPDj. Initially, both healthy and MAP-infected goats were vaccinated with 119 peptides defined by in silico analysis. Cellular responses to the peptides were not detected using standard IFN- γ plasma ELISA. However...

  6. Antigen-Specific CD4+ T Cells Recognize Epitopes of Protective Antigen following Vaccination with an Anthrax Vaccine

    OpenAIRE

    Laughlin, Elsa M.; Miller, Joseph D.; James, Eddie; Fillos, Dimitri; Ibegbu, Chris C.; Mittler, Robert S.; Akondy, Rama; Kwok, William; Ahmed, Rafi; Nepom, Gerald,

    2007-01-01

    Detection of antigen-specific CD4+ T cells is facilitated by the use of fluorescently labeled soluble peptide-major histocompatibility complex (MHC) multimers which mirror the antigen specificity of T-cell receptor recognition. We have used soluble peptide-MHC class II tetramers containing peptides from the protective antigen (PA) of Bacillus anthracis to detect circulating T cells in peripheral blood of subjects vaccinated with an anthrax vaccine. PA-specific HLA class II-restricted T lympho...

  7. Cocaine Enhances HIV-1 Replication in CD4+ T Cells by Down-Regulating MiR-125b

    OpenAIRE

    Mantri, Chinmay K.; Jui Pandhare Dash; Jyoti Velamarti Mantri; Dash, Chandravanu C. V.

    2012-01-01

    The main objective of this study was to examine effects of cocaine on HIV-1 replication in primary CD4+ T cells. Cocaine a commonly used drug among HIV-1 positive individuals serves as a cofactor for HIV-1 infection and progression to acquired immunodeficiency syndrome (AIDS). Accumulating evidence suggest that cocaine increases HIV-1 replication in cell cultures, peripheral blood mononuclear cells (PBMCs) and animal models. Intriguingly, there are no studies on cocaine-induced alterations in...

  8. TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis.

    Science.gov (United States)

    Lu, Ning; Wang, Yi-Hong; Wang, Yui-Hsi; Arima, Kazuhiko; Hanabuchi, Shino; Liu, Yong-Jun

    2009-09-28

    Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4(+) T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4(+) T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4(+) T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4(+) T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4(+) T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4(+) T cell homeostasis. PMID:19770269

  9. 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

  10. Cocaine enhances HIV-1 replication in CD4+ T cells by down-regulating MiR-125b.

    Directory of Open Access Journals (Sweden)

    Chinmay K Mantri

    Full Text Available The main objective of this study was to examine effects of cocaine on HIV-1 replication in primary CD4+ T cells. Cocaine a commonly used drug among HIV-1 positive individuals serves as a cofactor for HIV-1 infection and progression to acquired immunodeficiency syndrome (AIDS. Accumulating evidence suggest that cocaine increases HIV-1 replication in cell cultures, peripheral blood mononuclear cells (PBMCs and animal models. Intriguingly, there are no studies on cocaine-induced alterations in HIV-1 replication in primary CD4+ T cells that serve as the main targets for HIV-1 replication in vivo. In this report, we demonstrate cocaine-induced enhancement of HIV-1 replication in primary CD4+ T cells isolated from human PBMCs. To decipher a potential mechanism, we examined whether cocaine targets the innate antiviral immunity of CD4+ T cells mediated by cellular microRNAs (miRNAs. This is because recently a network of anti-HIV miRNAs in CD4+ T cells is highlighted to suppress viral replication. Our genome wide miRNA expression analysis indicated downregulation of several anti-HIV miRNAs (miR-28, miR-125b, miR-150, miR-223, and miR-382 in cocaine treated CD4+ T cells. However, our real-time quantitative PCR analysis revealed significant downregulation of miR-125b only. Our results illustrated that miR-125b knockdown enhances HIV-1 replication, whereas overexpression of miR-125b decreases HIV-1 replication in these cells. Therefore, we believe miR-125b is a key player for the cocaine induced enhancement of HIV-1 replication in CD4+ T cells. Since, miR-125b targets the 3' UTR regions of HIV-1 transcripts and inhibits viral protein translation, our data suggest modulation of post entry steps of HIV-1 by cocaine. Given that a plethora of studies suggest that cocaine regulates HIV entry, our results implicate a potentially novel mechanism by which cocaine can increase viral replication in CD4+ T cells.

  11. Natural CD4+ T-cell responses against indoleamine 2,3-dioxygenase.

    Directory of Open Access Journals (Sweden)

    Shamaila Munir

    Full Text Available BACKGROUND: The enzyme indoleamine 2,3-dioxygenase (IDO contributes to immune tolerance in a variety of settings. In cancer IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it endorses the establishment of peripheral immune tolerance to tumor antigens. Recently, we described cytotoxic CD8(+ T-cell reactivity towards IDO-derived peptides. METHODS AND FINDINGS: In the present study, we show that CD4(+ helper T cells additionally spontaneously recognize IDO. Hence, we scrutinized the vicinity of the previously described HLA-A*0201-restricted IDO-epitope for CD4(+ T-cell epitopes. We demonstrated the presence of naturally occurring IDO-specific CD4(+ T cells in cancer patients and to a lesser extent in healthy donors by cytokine release ELISPOT. IDO-reactive CD4(+ T cells released IFN-γ, TNF-α, as well as IL-17. We confirm HLA class II-restriction by the addition of HLA class II specific blocking antibodies. In addition, we detected a trend between class I- and class II-restricted IDO responses and detected an association between IDO-specific CD4(+ T cells and CD8(+ CMV-responses. Finally, we could detect IL-10 releasing IDO-reactive CD4(+ T cells. CONCLUSION: IDO is spontaneously recognized by HLA class II-restricted, CD4(+ T cells in cancer patients and in healthy individuals. IDO-specific T cells may participate in immune-regulatory networks where the activation of pro-inflammatory IDO-specific CD4(+ responses may well overcome or delay the immune suppressive actions of the IDO-protein, which are otherwise a consequence of the early expression of IDO in maturing antigen presenting cells. In contrast, IDO-specific regulatory T cells may enhance IDO-mediated immune suppression.

  12. Role of Gag and lipids during HIV-1 assembly in CD4 T cells and Macrophages

    OpenAIRE

    DelphineMMuriaux; PhilippeBenaroch

    2014-01-01

    HIV-1 is an RNA enveloped virus that preferentially infects CD4+ T lymphocytes and also macrophages. In CD4+ T cells, HIV-1 mainly buds from the host cell plasma membrane. The viral Gag polyprotein targets the plasma membrane and is the orchestrator of the HIV assembly as its expression is sufficient to promote the formation of virus-like particles particles carrying a lipidic envelope deriving from the host cell membrane. Certain lipids are enriched in the viral...

  13. The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

    OpenAIRE

    Haxhinasto, Sokol; Mathis, Diane; Benoist, Christophe

    2008-01-01

    CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially dimi...

  14. 支气管哮喘患者外周血CD4+ CD25+调节性T细胞水平及Foxp3 mRNA表达的分析%CD4+ CD25+ regulatory T cells and expressions of forkhead/winged helix transcription factor ( Foxp 3 ) mRNA in peripheral blood of patients with asthma

    Institute of Scientific and Technical Information of China (English)

    薛克营; 周咏明; 熊盛道; 熊维宁

    2006-01-01

    目的 观察支气管哮喘(哮喘)患者外周血单个核细胞(PBMCs)中CD4+ CD25+调节性T细胞(Treg)水平及叉状头/翅膀状螺旋转录因子(Foxp3)mRNA表达的变化,探讨CD4+ CD25+ Treg在哮喘发病中的作用.方法采用流式细胞仪检测78例哮喘患者(急性发作期组30例,慢性持续期组25例,缓解期组23例)和29例健康志愿者(正常对照组)PBMCs中CD4+ CD25+ Treg的比例;反转录-聚合酶链反应(RT-PCR)检测PBMCs中Foxp3 mRNA的表达.结果 急性发作期组和慢性持续期组PBMCs中CD4+ CD25+ Treg的比例及Foxp3 mRNA的表达明显低于缓解期组和正常对照组(P<0.05);缓解期组CD4+ CD25+ Treg的比例及Foxp3 mRNA的表达虽亦低于正常对照组,但差异无统计学意义(P>0.05);急性发作期组CD4+ CD25+ Treg的比例及Foxp3 mRNA的表达低于慢性持续期组(P<0.05).结论 哮喘患者外周血中具有免疫抑制活性的CD4+ CD25+ Treg数量减少,功能下降,可能参与哮喘的发生和发展.

  15. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development.

    Directory of Open Access Journals (Sweden)

    Seung-Joo Lee

    2012-01-01

    Full Text Available Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo.

  16. Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy

    Directory of Open Access Journals (Sweden)

    Campbell James J

    2006-07-01

    Full Text Available Abstract Background Circulating memory T cells can be divided into tissue-specific subsets, which traffic through distinct tissue compartments during physiologic immune surveillance, based on their expression of adhesion molecules and chemokine receptors. We reasoned that a bias (either enrichment or depletion of CSF T cell expression of known organ-specific trafficking determinants might suggest that homing of T cells to the subarachnoid space could be governed by a CNS-specific adhesion molecule or chemokine receptor. Results The expression of cutaneous leukocyte antigen (CLA and CC-chemokine receptor 4 (CCR4; associated with skin-homing as well as the expression of integrin α4β7 and CCR9 (associated with gut-homing was analyzed on CD4+ memory T cells in CSF from individuals with non-inflammatory neurological diseases using flow cytometry. CSF contained similar proportions of CD4+ memory T cells expressing CLA, CCR4, integrin α4β7 and CCR9 as paired blood samples. Conclusion The results extend our previous findings that antigen-experienced CD4+ memory T cells traffic through the CSF in proportion to their abundance in the peripheral circulation. Furthermore, the ready access of skin- and gut-homing CD4+ memory T cells to the CNS compartment via CSF has implications for the mechanisms of action of immunotherapeutic strategies, such as oral tolerance or therapeutic immunization, where immunogens are administered using an oral or subcutaneous route.

  17. Human Immunodeficiency Virus Type 1 DNA Sequences Genetically Damaged by Hypermutation Are Often Abundant in Patient Peripheral Blood Mononuclear Cells and May Be Generated during Near-Simultaneous Infection and Activation of CD4+ T Cells

    OpenAIRE

    Janini, Mario; Rogers, Melissa; Birx, Deborah R.; McCutchan, Francine E.

    2001-01-01

    G-to-A hypermutation has been sporadically observed in human immunodeficiency virus type 1 (HIV-1) proviral sequences from patient peripheral blood mononuclear cells (PBMC) and virus cultures but has not been systematically evaluated. PCR primers matched to normal and hypermutated sequences were used in conjunction with an agarose gel electrophoresis system incorporating an AT-binding dye to visualize, separate, clone, and sequence hypermutated and normal sequences in the 297-bp HIV-1 proteas...

  18. 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.

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

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    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.

  20. B Cells Regulate CD4+ T cell Responses to Papain Following BCR-Independent Papain Uptake

    OpenAIRE

    Dwyer, Daniel F.; Woodruff, Matthew C.; Carroll, Michael C.; Austen, K. Frank; Gurish, Michael F.

    2014-01-01

    Papain, a cysteine protease allergen with inherent adjuvant activity, induces potent IL4 expression by T cells in the popliteal lymph nodes (PLN) of mice following footpad immunization. Here we identify a novel, non-BCR mediated capacity for B cells to rapidly bind and internalize papain. B cells subsequently regulate the adaptive immune response by enhancing Inducible T cell Costimulator (ICOS) expression on CD4+ T cells and amplifying Th2 and T follicular helper induction. Antibody blockade...

  1. Circulating HIV-Specific Interleukin-21(+)CD4(+) T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions.

    Science.gov (United States)

    Schultz, Bruce T; Teigler, Jeffrey E; Pissani, Franco; Oster, Alexander F; Kranias, Gregory; Alter, Galit; Marovich, Mary; Eller, Michael A; Dittmer, Ulf; Robb, Merlin L; Kim, Jerome H; Michael, Nelson L; Bolton, Diane; Streeck, Hendrik

    2016-01-19

    A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21(+)CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21(+)CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses. PMID:26795249

  2. 支气管哮喘患者外周血Th17、CD4+CD25+Treg细胞表达特征%The prevalence of blood Th17 and CD4+CD25+Treg cells in patients with bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    施宇衡; 时国朝; 万欢英; 蒋黎华; 艾香艳; 朱海星; 汤葳

    2010-01-01

    目的:探讨外周血Th17和CD4+CD25+调节性T细胞(Treg)在支气管哮喘患者中的表达特征.方法:41例慢性持续期哮喘患者,分为间歇-轻度组(n=23)和中重度组(n=18),行肺功能检查和哮喘控制问卷(ACQ)调查,20例正常人作为对照.通过流式细胞术检测外周血Th17和CD4+CD25+Treg细胞的比例.ELISA检测血浆以及植物血凝素刺激24小时后外周血单个核细胞(PBMC)上清液中的IL-17、IL-10、TGF-β水平.结果:中重度哮喘组外周血Th17细胞比例及血浆IL-17水平高于间歇-轻度哮喘和正常人组,而外周血CD4+CD25+Foxp3+Treg细胞比例及血浆IL-10、TGF-β水平则降低.中重度哮喘组PBMC上清液中IL-17水平增高.哮喘患者FEV1(%预计值)与Th17细胞及血浆IL-17表达成负相关,与CD4+CD25+Treg表达成正相关.ACQ平均得分与Th17细胞和血浆IL-17表达成正相关,与外周血CD4+CD25+Treg表达成负相关.结论:中重度哮喘中外周血Th17细胞应答增强,而CD4+CD25+ Treg细胞缺乏,哮喘的严重程度及症状控制与外周血Th17/Treg免疫应答失衡密切相关.

  3. Methodologies for the analysis of HCV-specific CD4+ T cells

    Directory of Open Access Journals (Sweden)

    Megha eLokhande

    2015-02-01

    Full Text Available Virus-specific CD4+ T cells play a major role in viral infections, such as hepatitis C virus (HCV. Viral clearance is associated with vigorous and multispecific CD4+ T cell responses, while chronic infection has been shown to be associated with weak or absent T cell responses. Most of these studies have used functional assays to analyse virus-specific CD4+ T cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4+ T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analysed in detail. A novel assay, in which virus-specific CD4+ T cell frequencies can be determined by de novo CD154 (CD40 ligand expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4+ T cells will be discussed in this review.

  4. HBV宫内感染新生儿外周血调节性T细胞表达%Detection and analysis of CD4 + CD25+ regulatory T cell in peripheral blood from newborns with HBV intrauterine infection

    Institute of Scientific and Technical Information of China (English)

    高怡; 郭健; 付振东; 郝海燕; 刘明慧; 汪波; 丰淑英; 王素萍

    2013-01-01

    目的 探讨CD4+ CD25+调节性T细胞(Treg)在乙肝病毒(HBV)宫内感染新生儿外周血中的表达和意义.方法 选择乙肝表面抗原(HBsAg)阳性孕妇及其分娩新生儿79例,用酶联免疫吸附试验检测孕妇和新生儿外周血HBV标志物,实时荧光定量PCR检测母亲和新生儿外周血HBV DNA含量,用流式细胞仪检测新生儿外周血CD4+ CD25+ Treg和CD4+ CD25+ Foxp3+ Treg水平.结果 宫内感染HBV新生儿外周血CD4+ CD25+Treg和CD4+ CD25+ Foxp3+ Treg占CD4+T细胞比例分别为(10.57±2.25)%和(1.67±0.37)%,均高于未感染新生儿,差异有统计学意义(P<0.05),随产妇HBV DNA载量增加,新生儿外周血CD4+ CD25+ Treg和CD4+CD25+ Foxp3+ Treg增加,CD4+ CD25+ Treg比例高于阴性组(P <0.05);CD4+CD25+ Treg和CD4+ CD25+Foxp3+ Treg均与产妇HBV DNA载量呈正相关(r=0.430、0.409,P<0.05).结论 Treg可能通过抑制机体细胞免疫反应影响乙肝病毒清除,新生儿HBV宫内感染可能与Treg表达上调有关.

  5. CELLULAR AND POPULATION PLASTICITY OF HELPER CD4 T CELL RESPONSES

    Directory of Open Access Journals (Sweden)

    Gesham eMagombedze

    2013-08-01

    Full Text Available Vertebrates are constantly exposed to pathogens, and the adaptive immunity has most likely evolved to control and clear such infectious agents. CD4 T cells are the major players in the adaptive immune response to pathogens. Following recognition of pathogen-derived antigens naïve CD4 T cells differentiate into effectors which then control pathogen replication either directly by killing pathogen-infected cells or by assisting with generation of cytotoxic T lymphocytes or pathogen-specific antibodies. Pathogen-specific effector CD4 T cells are highly heterogeneous in terms of cytokines they produce. Three major subtypes of effector CD4 T cells have been identified: T-helper 1 (Th1 cells producing IFN-g and TNF-α, Th2 cells producing IL-4 and IL-10, and Th17 cells producing IL-17. How this heterogeneity is maintained and what regulates changes in effector T cell composition during chronic infections remains poorly understood. In this review we discuss recent advances in our understanding of CD4 T cell differentiation in response to microbial infections. We propose that a change in the phenotype of pathogen-specific effector CD4 T cells during chronic infections, for example, from Th1 to Th2 response as observed in Mycobacteriumavium ssp. paratuberculosis (MAP infection of ruminants, can be achieved by conversion of T cells from one effector subset to another (cellular plasticity or due to differences in kinetics (differentiation, proliferation, death of different effector T cell subsets (population plasticity. We also shortly review mathematical models aimed at describing CD4 T cell differentiation and outline areas for future experimental and theoretical research.

  6. A dominant EV71-specific CD4+ T cell epitope is highly conserved among human enteroviruses.

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    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.

  7. CD161+CD4+ T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and Interferon-gamma

    Directory of Open Access Journals (Sweden)

    Yu-Hoi eKang

    2012-11-01

    Full Text Available Hepatitis C virus infection is a major cause of chronic liver disease. CD4+ T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4+ T cells are not well defined. We have previously shown that CD8+ T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22 and IFNγ. We therefore analysed expression of CD161 on CD4+ T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichment of CD161+CD4+ T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4+ T cells. IL-22 and IL-17 secreting CD4+ cells were readily found in the livers of HCV+ and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-γ dual secretors (p=0.02 compared to blood, a result reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161+ expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFNγ and IL-22 in the liver may be particularly significant.

  8. Technical performance evaluation of the MyT4 point of care technology for CD4+ T cell enumeration.

    Directory of Open Access Journals (Sweden)

    Matilu Mwau

    Full Text Available Though absolute CD4+ T cell enumeration is the primary gateway to antiretroviral therapy initiation for HIV-positive patients in all developing countries, patient access to this critical diagnostic test is relatively poor. We technically evaluated the performance of a newly developed point-of-care CD4+ T cell technology, the MyT4, compared with conventional CD4+ T cell testing technologies.Over 250 HIV-positive patients were consecutively enrolled and their blood tested on the MyT4, BD FACSCalibur, and BD FACSCount.Compared with the BD FACSCount, the MyT4 had an r2 of 0.7269 and a mean bias of -23.37 cells/µl. Compared with the BD FACSCalibur, the MyT4 had an r2 of 0.5825 and a mean bias of -46.58 cells/µl. Kenya currently uses a CD4+ T cell test threshold of 350 cells/µl to determine patient eligibility for antiretroviral therapy. At this threshold, the MyT4 had a sensitivity of 95.3% (95% CI: 88.4-98.7% and a specificity of 87.9% (95% CI: 82.3-92.3% compared with the BD FACSCount and sensitivity and specificity of 88.2% (95% CI: 79.4-94.2% and 84.2% (95% CI: 78.2-89.2%, respectively, compared with the BD FACSCalibur. Finally, the MyT4 had a coefficient of variation of 12.80% compared with 14.03% for the BD FACSCalibur.We conclude that the MyT4 performed well at the current 350 cells/µl ART initiation eligibility threshold when used by lower cadres of health care facility staff in rural clinics compared to conventional CD4+ T cell technologies.

  9. Increased Expression of Ganglioside GM1 in Peripheral CD4+ T Cells Correlates Soluble Form of CD30 in Systemic Lupus Erythematosus Patients

    Directory of Open Access Journals (Sweden)

    Lingli Dong

    2010-01-01

    Full Text Available Gangliosides GM1 is a good marker of membrane microdomains (lipid rafts with important function in cellular activation processes. In this study we found that GM1 expression on CD4+ T cells and memory T cells (CD45RO/CD4 were dramatic increased after stimulation with phytohaemagglutinin in vitro. Next, we examined the GM1 expression on peripheral blood CD4+ T cells and CD8+ T cells from 44 patients with SLE and 28 healthy controls by flow cytometry. GM1 expression was further analyzed with serum soluble CD30 (sCD30, IL-10, TNF-alpha and clinical parameters. The mean fluorescence intensity of GM1 on CD4+ T cells from patients with SLE was significantly higher than those from healthy controls, but not on CD8+ T cells. Increased expression of GM1 was more marked on CD4+/CD45RO+ memory T cells from active SLE patients. Patients with SLE showed significantly elevated serum sCD30 and IL-10, but not TNF-alpha levels. In addition, we found that enhanced GM1 expression on CD4+ T cells from patients with SLE positively correlated with high serum levels of sCD30 and IgG as well as disease activity (SLEDAI scores. Our data suggested the potential role of aberrant lipid raft/GM1 on CD4+ T cells and sCD30 in the pathogenesis of SLE.

  10. In Vivo Identification and Characterization of CD4+ Cytotoxic T Cells Induced by Virulent Brucella abortus Infection

    OpenAIRE

    Martirosyan, Anna; von Bargen, Kristine; Arce Gorvel, Vilma; Zhao, Weidong; Hanniffy, Sean; Bonnardel, Johnny; Méresse, Stéphane; Gorvel, Jean-Pierre

    2013-01-01

    CD4+ T cells display a variety of helper functions necessary for an efficient adaptive immune response against bacterial invaders. This work reports the in vivo identification and characterization of murine cytotoxic CD4+ T cells (CD4+ CTL) during Brucella abortus infection. These CD4+ CTLs express granzyme B and exhibit immunophenotypic features consistent with fully differentiated T cells. They express CD25, CD44, CD62L ,CD43 molecules at their surface and produce IFN-γ. Moreover, these cel...

  11. 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; Madsen, Hans Ole; Ødum, Niels; Bliddal, Henning; Danneskiold-Samsøe, Bente; Ribel-Madsen, Søren; Ryder, Lars P.

    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 sa...

  12. 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.

  13. Detection of CD4+/CD8+T Lymphocyte Ratio and CD4+CD25+ Treg in Peripheral Blood of Patients with Sporadic Vitiligo%散发型白癜风患者外周血CD4+/CD8+T细胞比值及CD4+CD25+T细胞的检测

    Institute of Scientific and Technical Information of China (English)

    叶蓉; 马刚; 胡小平; 彭曦

    2012-01-01

    目的 检测散发型白癜风患者外周血CD4+/CD8+T细胞比值及CD4+CD25+调节性T细胞水平,探讨其与散发型白癜风发病的关系.方法 散发型白癜风患者29例,男13例,女16例.通过流式细胞仪对散发型白癜风患者外周血CD4+/CD8+T细胞比值及CD4+CD25+调节性T细胞水平进行检测,并与20例健康人相比较.结果 与健康对照组相比,散发型白癜风患者外周血中CD4+/CD8+T细胞比值的差异无统计学意义(P>0.05),而CD4+CD25+调节性T细胞水平明显减少,差异有统计学意义(P<0.05),但在不同病程的患者中CD4+CD25+调节性T细胞数量的差异无统计学意义(P>0.05).结论 散发型白癜风患者外周血中存在CD4+CD25+调节性T细胞水平下降,可能与散发型白癜风的发生发展有一定关系.%Objective To detect the CD4+/CD8+ T lymphocyte ratio and the CD4+CD25+ Treg level in peripheral blood of patients with sporadic vitiligo, and to investigate its role in the pathogenesis of sporadic vitiligo. Methods Peripheral blood samples were taken from 29 outpatients with sporadic vitiligo, including 13 males and 16 females. The CD4+/CD8+ T lymphocyte ratio and the CD4+CD25+ Treg level was detected in peripheral blood of patients with sporadic vitiligo by flow cytometry, as well as controlled samples from 20 healthy human. Results There was no difference on the ratio of CD4+/CD8+ T lymphocyte between the patients with sporadic vitiligo and healthy people (P>0.05). Compared to the controlled group, the proportion of CD4+CD25+ Treg was significantly lower in sporadic vitiligo patients(P0.05). Conclusion The level of CD4+CD25+ Treg is lower in peripheral blood of sporadic vitiligo patients, which might play a role in the pathogenesis and development of sporadic vitiligo.

  14. Follicular Helper CD4+ T Cells in Human Neuroautoimmune Diseases and Their Animal Models

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    Xueli Fan

    2015-01-01

    Full Text Available Follicular helper CD4+ T (TFH cells play a fundamental role in humoral immunity deriving from their ability to provide help for germinal center (GC formation, B cell differentiation into plasma cells and memory cells, and antibody production in secondary lymphoid tissues. TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21. It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells. A balance of TFH cell generation and function is critical for protective antibody response, whereas overactivation of TFH cells or overexpression of TFH-associated molecules may result in autoimmune diseases. Emerging data have shown that TFH cells and TFH-associated molecules may be involved in the pathogenesis of neuroautoimmune diseases including multiple sclerosis (MS, neuromyelitis optica (NMO/neuromyelitis optica spectrum disorders (NMOSD, and myasthenia gravis (MG. This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

  15. Blockade of Human Immunodeficiency Virus Type 1 Production in CD4^+ T Cells by an Intracellular CD4 Expressed Under Control of the Viral Long Terminal Repeat

    Science.gov (United States)

    Buonocore, Linda; Rose, John K.

    1993-04-01

    A retroviral vector was constructed in which a gene encoding a mutated soluble CD4 protein that is retained in the endoplasmic reticulum (sCD4-KDEL) is expressed under control of human immunodeficiency virus type 1 (HIV-1) regulatory elements. HIV-1 infection of a human T-cell line transduced with this vector led to induction of sCD4-KDEL synthesis and a block in transport of the HIV envelope protein to the cell surface. There was a complete block to maturation of infectious HIV-1 in the transduced cells, no viral spread, and little or no syncytium formation. Infected cells gradually disappeared from the culture over a period of 2 months. This intracellular trap for HIV has potential application in gene therapy for AIDS.

  16. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria.

    Science.gov (United States)

    Hepworth, Matthew R; Monticelli, Laurel A; Fung, Thomas C; Ziegler, Carly G K; Grunberg, Stephanie; Sinha, Rohini; Mantegazza, Adriana R; Ma, Hak-Ling; Crawford, Alison; Angelosanto, Jill M; Wherry, E John; Koni, Pandelakis A; Bushman, Frederic D; Elson, Charles O; Eberl, Gérard; Artis, David; Sonnenberg, Gregory F

    2013-06-01

    Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal

  17. CD4+ T cells mediate mucosal and systemic immune responses to experimental hookworm infection

    OpenAIRE

    DONDJI, B.; Sun, T.; BUNGIRO, R. D.; VERMEIRE, J. J.; HARRISON, L. M.; BIFULCO, C.; Cappello, M

    2010-01-01

    Hookworm infection is associated with anaemia and malnutrition in many resource-limited countries. Ancylostoma hookworms have previously been shown to modulate host cellular immune responses through multiple mechanisms, including reduced mitogen-mediated lymphocyte proliferation, impaired antigen presentation/processing, and relative reductions in CD4+ T cells in the spleen and mesenteric lymph nodes. Syrian hamsters were depleted of CD4+ for up to 9 days following intraperitoneal injection (...

  18. Progesterone Levels Associate with a Novel Population of CCR5+CD38+ CD4 T Cells Resident in the Genital Mucosa with Lymphoid Trafficking Potential.

    Science.gov (United States)

    Swaims-Kohlmeier, Alison; Haaland, Richard E; Haddad, Lisa B; Sheth, Anandi N; Evans-Strickfaden, Tammy; Lupo, L Davis; Cordes, Sarah; Aguirre, Alfredo J; Lupoli, Kathryn A; Chen, Cheng-Yen; Ofotukun, Igho; Hart, Clyde E; Kohlmeier, Jacob E

    2016-07-01

    The female genital tract (FGT) provides a means of entry to pathogens, including HIV, yet immune cell populations at this barrier between host and environment are not well defined. We initiated a study of healthy women to characterize resident T cell populations in the lower FGT from lavage and patient-matched peripheral blood to investigate potential mechanisms of HIV sexual transmission. Surprisingly, we observed FGT CD4 T cell populations were primarily CCR7(hi), consistent with a central memory or recirculating memory T cell phenotype. In addition, roughly half of these CCR7(hi) CD4 T cells expressed CD69, consistent with resident memory T cells, whereas the remaining CCR7(hi) CD4 T cells lacked CD69 expression, consistent with recirculating memory CD4 T cells that traffic between peripheral tissues and lymphoid sites. HIV susceptibility markers CCR5 and CD38 were increased on FGT CCR7(hi) CD4 T cells compared with blood, yet migration to the lymphoid homing chemokines CCL19 and CCL21 was maintained. Infection with GFP-HIV showed that FGT CCR7(hi) memory CD4 T cells are susceptible HIV targets, and productive infection of CCR7(hi) memory T cells did not alter chemotaxis to CCL19 and CCL21. Variations of resident CCR7(hi) FGT CD4 T cell populations were detected during the luteal phase of the menstrual cycle, and longitudinal analysis showed the frequency of this population positively correlated to progesterone levels. These data provide evidence women may acquire HIV through local infection of migratory CCR7(hi) CD4 T cells, and progesterone levels predict opportunities for HIV to access these novel target cells. PMID:27233960

  19. Laboratory and field evaluation of the Partec CyFlow miniPOC for absolute and relative CD4 T-cell enumeration.

    Directory of Open Access Journals (Sweden)

    Djibril Wade

    Full Text Available A new CD4 point-of-care instrument, the CyFlow miniPOC, which provides absolute and percentage CD4 T-cells, used for screening and monitoring of HIV-infected patients in resource-limited settings, was introduced recently. We assessed the performance of this novel instrument in a reference laboratory and in a field setting in Senegal.A total of 321 blood samples were obtained from 297 adults and 24 children, all HIV-patients attending university hospitals in Dakar, or health centers in Ziguinchor. Samples were analyzed in parallel on CyFlow miniPOC, FACSCount CD4 and FACSCalibur to assess CyFlow miniPOC precision and accuracy.At the reference lab, CyFlow miniPOC, compared to FACSCalibur, showed an absolute mean bias of -12.6 cells/mm3 and a corresponding relative mean bias of -2.3% for absolute CD4 counts. For CD4 percentages, the absolute mean bias was -0.1%. Compared to FACSCount CD4, the absolute and relative mean biases were -31.2 cells/mm3 and -4.7%, respectively, for CD4 counts, whereas the absolute mean bias for CD4 percentages was 1.3%. The CyFlow miniPOC was able to classify HIV-patients eligible for ART with a sensitivity of ≥ 95% at the different ART-initiation thresholds (200, 350 and 500 CD4 cells/mm3. In the field lab, the room temperature ranged from 30 to 35°C during the working hours. At those temperatures, the CyFlow miniPOC, compared to FACSCount CD4, had an absolute and relative mean bias of 7.6 cells/mm3 and 2.8%, respectively, for absolute CD4 counts, and an absolute mean bias of 0.4% for CD4 percentages. The CyFlow miniPOC showed sensitivity equal or greater than 94%.The CyFlow miniPOC showed high agreement with FACSCalibur and FACSCount CD4. The CyFlow miniPOC provides both reliable absolute CD4 counts and CD4 percentages even under the field conditions, and is suitable for monitoring HIV-infected patients in resource-limited settings.

  20. The potential role of cell surface complement regulators and circulating CD4+ CD25+ T-cells in the development of autoimmune myasthenia gravis

    OpenAIRE

    Hamdoon, Mohamed Nasreldin Thabit; Fattouh, Mona; El-din, Asmaa Nasr; Elnady, Hassan M.

    2016-01-01

    Introduction CD4+CD25+ regulatory T-lymphocytes (T-regs) and regulators of complement activity (RCA) involving CD55 and CD59 play an important role in the prevention of autoimmune diseases. However, their role in the pathogenesis of human autoimmune myasthenia gravis (MG) remains unclear. This study aimed to determine the frequency of peripheral blood T-regs and CD4+ T-helper (T-helper) cells and the red blood cells (RBCs) level of expression of CD55 and CD59 in MG patients. Methods Fourteen ...

  1. Comparison of the expression levels of IL-17+CD4+T (Th17) cells and IL-17+CD8+T (Tc17) cells in the peripheral blood of patients with lung cancer%IL-17+CD4+T(Th17)细胞和IL-17+CD8+T(Tc17)细胞在肺癌患者外周血中的表达水平比较

    Institute of Scientific and Technical Information of China (English)

    谢志翔

    2014-01-01

    Objective To study the expression levels of Interleukin IL-17+CD4+T (Th17) cells and IL-17+CD8+T (Tc17) cells in the peripheral blood of patients with lung cancer. Methods Seventy cases of lung cancer from March 2010 to March 2013 in our hospital were studied. And 40 healthy volunteers were selected as the con-trol group. Flow cytometry was used in both groups Th17 cells and Tc17 cell expression were detected and ana-lyzed. Results The difference of expression levels of Th17 and Tc17 cells were not found between adenocarcino-ma, squamous cell carcinoma and small cell carcinoma (F=1.762 1, P=0.179 8;F=0.161 3, P=0.853 0). This indi-cates that the expression levels of Th17 and Tc17 cells is independent of pathological types of lung cancer pa-tients. Statistical significance was found between the expression levels of Th17 and Tc17 cells in different TNM stages of lung cancer (F=5.783 1, P=0.004 8;F=3.751 4, P=0.028 7), and the expression of Th17 and Tc17 cells in patients with advanced disease (stageⅢ and Ⅳ) were significantly higher than in those with stage Ⅰ and Ⅱ (P<0.05). Conclusion We found that the expression levels of Th17 and Tc17 cells in the peripheral blood were differ-ent in different TNM stages of lung cancer, and Th17 cells and Tc17 cells in patients with lung cancer were in-crease significantly.%目的:对比白细胞介素(IL)-17+CD4+T (Th17)细胞和IL-17+CD8+T (Tc17)细胞在肺癌患者外周血中的表达水平。方法选择2010年3月至2013年3月我院接诊的70例肺癌患者进行研究(肺癌组),同时选择40例健康体检者作为对照组。采用流式细胞术对两组的Th17细胞和Tcl7细胞表达情况进行检测并分析。结果检测发现,腺癌、鳞癌、小细胞癌三种病理类型患者的Th17细胞和Tcl7细胞表达水平差异无统计学意义(F=1.7621, P=0.1798;F=0.1613,P=0.8530)。表明Th17细胞和Tc17细胞表达水平与肺癌患者的病理类型无关。不

  2. Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis.

    Science.gov (United States)

    Hwang, SuJin; Cobb, Dustin A; Bhadra, Rajarshi; Youngblood, Ben; Khan, Imtiaz A

    2016-08-22

    CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)-susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell-intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches. PMID:27481131

  3. Computational modeling of heterogeneity and function of CD4+ T cells

    Directory of Open Access Journals (Sweden)

    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.

  4. IL-33 enhances retinoic acid signaling on CD4+ T cells.

    Science.gov (United States)

    Gajardo, Tania; Pérez, Francisco; Terraza, Claudia; Campos-Mora, Mauricio; Noelle, Randolph J; Pino-Lagos, Karina

    2016-09-01

    Several molecules have been described as CD4+ T cells differentiation modulators and among them retinoic acid (RA) and more recently, IL-33, have been studied. Due to the similarities in T helper cell skewing properties between RA and IL-33, we asked whether IL-33 intersects, directly or indirectly, the RA signaling pathway. Total CD4+ T cells from DR5-luciferase mice were activated in the presence of RA with or without IL-33, and RA signaling was visualized using ex vivo imaging. Our results demonstrate that IL-33 itself is able to trigger RA signaling on CD4+ T cells, which is highly increased when IL-33 is added in conjunction with RA. This study presents IL-33 as a potential player that may synergize with RA in controlling T cell differentiation, and suggests that IL-33 may be an attractive target in controlling T cell differentiation in vivo. PMID:27322964

  5. 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

    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...... 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......-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...

  6. Dissecting How CD4 T Cells Are Lost During HIV Infection.

    Science.gov (United States)

    Doitsh, Gilad; Greene, Warner C

    2016-03-01

    Although the replicative life cycle of HIV within CD4cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4cell demise and the chronic inflammatory response generated during pyroptosis. PMID:26962940

  7. Expression of CD39 and CD73 by CD4+T cells in peripheral blood of patients with allergic asthma and its clinical significance%过敏性哮喘患者外周血CD4+T细胞表达CD39和CD73水平变化及其临床意义

    Institute of Scientific and Technical Information of China (English)

    王林林; 王玺; 时国朝; 万欢英; 周敏; 侯小霞; 潘丽娜; 陶连琴; 石宝玉

    2014-01-01

    目的:初步探讨CD4+T细胞表达的腺苷CD39和CD73在过敏性哮喘患者外周血中的水平变化及与叉头蛋白3 (FoxP3) 、GATA结合蛋白3(GATA3)和维A酸相关孤儿受体(ROR)-γt mRNA相关性.方法:选择54例对屋尘螨过敏的慢性持续期哮喘患者[间歇状态和轻度持续哮喘组(间歇-轻度组)29例,中重度组25例]和45名健康志愿者,通过荧光实时定量PCR方法检测并比较研究对象外周血CD4+T细胞中CD39 、CD73 、FoxP3 、GATA3和ROR-γtmRNA水平.结果:CD39 mRNA水平正常对照组明显高于间歇-轻度组(P=0.000),间歇-轻度组明显高于中重度组(P=0.001).CD73 mRNA水平正常对照组明显高于间歇-轻度组(P=0.001),哮喘亚组间差异无统计学意义(P=0.126).哮喘组CD4+T细胞表达的CD39 mRNA与FoxP3 mRNA水平呈显著正相关性(r=0.607,P=0.000),与GATA3 mRNA水平呈显著负相关性(r=-0.505,P=0.000),与ROR-γtmRNA无显著相关性(r=-0.287,P=0.054).哮喘组CD4+T细胞表达的CD73 mRNA与FoxP3和ROR-γtmRNA水平无显著相关性(r=0.110,P=0.450;r=-0.227,P=0.138),与GATA3mRNA水平呈显著负相关性(r=-0.286,P=0.040).结论:CD4+T细胞表达的CD39和CD73在过敏性哮喘免疫反应过程中起到重要作用.

  8. CD4(+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis.

    Directory of Open Access Journals (Sweden)

    Jamie C Zampell

    Full Text Available INTRODUCTION: Lymphedema is a chronic disorder that occurs commonly after lymph node removal for cancer treatment and is characterized by swelling, fibrosis, inflammation, and adipose deposition. Although previous histological studies have investigated inflammatory changes that occur in lymphedema, the precise cellular make up of the inflammatory infiltrate remains unknown. It is also unclear if this inflammatory response plays a causal role in the pathology of lymphedema. The purpose of this study was therefore to characterize the inflammatory response to lymphatic stasis and determine if these responses are necessary for the pathological changes that occur in lymphedema. METHODS: We used mouse-tail lymphedema and axillary lymph node dissection (ANLD models in order to study tissue inflammatory changes. Single cell suspensions were created and analyzed using multi-color flow cytometry to identify individual cell types. We utilized antibody depletion techniques to analyze the causal role of CD4+, CD8+, and CD25+ cells in the regulation of inflammation, fibrosis, adipose deposition, and lymphangiogenesis. RESULTS: Lymphedema in the mouse-tail resulted in a mixed inflammatory cell response with significant increases in T-helper, T-regulatory, neutrophils, macrophages, and dendritic cell populations. Interestingly, we found that ALND resulted in significant increases in T-helper cells suggesting that these adaptive immune responses precede changes in macrophage and dendritic cell infiltration. In support of this we found that depletion of CD4+, but not CD8 or CD25+ cells, significantly decreased tail lymphedema, inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells significantly increased lymphangiogenesis both in our tail model and also in an inflammatory lymphangiogenesis model. CONCLUSIONS: Lymphedema and lymphatic stasis result in CD4+ cell inflammation and infiltration of mature T-helper cells. Loss of CD4+ but

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

    Science.gov (United States)

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

    2016-02-01

    CD4(+) memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4(+) memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4(+) effector memory T cells in vitro and in vivo. Simultaneously, intravenous transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4(+) T cells, not central memory CD4(+) T cells, which play a major role in chronic inflammatory responses in mice with EAE. Intravenous transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4(+) effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo. PMID:26111522

  10. Green tea epigallocatechin-3-gallate modulates differentiation of naive CD4+ T cells into specific lineage effector cells

    Science.gov (United States)

    CD4+ T helper (Th) subsets Th1, Th9, and Th17 cells are implicated in inducing autoimmunity whereas regulatory T cells (Treg) have a protective effect. We previously showed that epigallocatechin-3-gallate (EGCG) attenuated experimental autoimmune encephalomyelitis (EAE) and altered CD4+ T cell subpo...

  11. 胃癌患者外周血及癌组织中CD4+CD25+调节性T细胞、转录因子Foxp3的表达及临床意义%Expression and clinical signification of CD4+CD25+ regulatory T cells,the transcription factor Foxp3 in peripheral blood and cancerous tissue of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    陆威; 李永翔; 张尚鑫; 闫强

    2013-01-01

    目的 探讨胃癌患者外周血及胃癌组织中CD4+CD25+调节性T细胞(Tregs)和转录因子Foxp3表达及临床意义.方法 收集38例胃癌患者术前血液样本和20例健康体检者血液样本进行流式细胞仪检测,同时胃癌组中留取胃癌组织和癌旁组织(距肿瘤边缘>5 cm)进行免疫组化染色,检测CD4+CD25+Foxp3+Tregs表达,并与胃癌的TNM分期、肿瘤分化程度、淋巴转移、肿瘤所在部位、肿瘤直径等相关参数进行分析.结果 胃癌组外周血中CD4+CD25+Foxp3+Tregs的表达水平与对照组相比差异有统计学意义(P<0.01),且在胃癌TNM分期、淋巴转移组内比较差异有统计学意义(P<0.01).胃癌组织中Foxp3+Tregs的表达水平与癌旁组织相比,差异有统计学意义(P<0.01),且在胃癌TNM分期、分化程度、淋巴转移组内比较差异有统计学意义(P<0.01,P<0.05).外周血中CD4+CD25+ Foxp3+Tregs与胃癌组织中Foxp3+Tregs的表达水平呈显著正相关(r=0.786,P 5 cm ) from gastric cancer were subjected to immunohis-tochemistry to detect CD4 + CD25 + Foxp3 + Tregs expression, and the correlation analysis with some clinical related parameters was made. Results The percentages of CD4 + CD25 + Foxp3 + Tregs in peripheral blood of gastric cancer group were significantly higher than those from healthy control group( P <0. 01 ),and were highly correlated to TNM stage, lymph node metastases( P <0. 01 ). The percentages of Foxp3 + Tregs in gastric cancer tissue were significantly higher than those from para-tumorous tissue( P <0. 01 ),and were highly correlated to TNM stage,tumor differentiation,lymph node metastases( P < 0. 01 , P < 0. 05 ). The percentages of CD4 + CD25 + Foxp3 + Tregs in peripheral blood was positively correlated to Foxp3 + Tregs in gastric cancer tissue( r - 0. 786, P < 0. 01 ). Conclusion The proportion of CD4 + CD25 + Foxp3 + Tregs in Peripheral blood and Foxp3 + Tregs in gastric cancer tissue is significantly elevated in

  12. IFNγ/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children.

    Directory of Open Access Journals (Sweden)

    Prasanna Jagannathan

    2014-01-01

    Full Text Available Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4(+ T cell responses were measurable in nearly all children, with the majority of children having CD4(+ T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4(+ T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001 and inversely correlated with duration since malaria (Rho = -0.39, P<0.001. Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003. While TNFα-producing CD4(+ T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4(+ T cells dominating this response among

  13. CD4+ T Cell Depletion in Human Immunodeficiency Virus (HIV Infection: Role of Apoptosis

    Directory of Open Access Journals (Sweden)

    Angelita Rebollo

    2011-05-01

    Full Text Available Human immunodeficiency virus (HIV infection is principally a mucosal disease and the gastrointestinal (GI tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis.

  14. CD4+ T Cell Depletion in Human Immunodeficiency Virus (HIV) Infection: Role of Apoptosis

    Science.gov (United States)

    Février, Michèle; Dorgham, Karim; Rebollo, Angelita

    2011-01-01

    Human immunodeficiency virus (HIV) infection is principally a mucosal disease and the gastrointestinal (GI) tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT) might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis. PMID:21994747

  15. Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity

    Directory of Open Access Journals (Sweden)

    Marie Wunsch

    2015-08-01

    Full Text Available Most humans become infected with human cytomegalovirus (HCMV. Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the TH1, TH2, and TH17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC. Using the enzyme-linked Immunospotr assay (ELISPOT that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN- and/or interleukin (IL-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of TH1, TH2, and TH17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN- and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the TH1, TH2, and TH17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails.

  16. Role of Gag and lipids during HIV-1 assembly in CD4+ T cells and macrophages

    OpenAIRE

    Mariani, Charlotte; Desdouits, Marion; Favard, Cyril; Benaroch, Philippe; Muriaux, Delphine M.

    2014-01-01

    HIV-1 is an RNA enveloped virus that preferentially infects CD4+ T lymphocytes and also macrophages. In CD4+ T cells, HIV-1 mainly buds from the host cell plasma membrane. The viral Gag polyprotein targets the plasma membrane and is the orchestrator of the HIV assembly as its expression is sufficient to promote the formation of virus-like particles carrying a lipidic envelope derived from the host cell membrane. Certain lipids are enriched in the viral membrane and are thought to play a key r...

  17. CD26 + CD4 + T cell counts and attack risk in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Ross, C; Koch-Henriksen, Nils;

    2005-01-01

    patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta....... CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in...

  18. Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro✩

    OpenAIRE

    Secor, Eric R.; Singh, Anurag; Guernsey, Linda A.; McNamara, Jeff T.; Zhan, Lijun; Maulik, Nilanjana; Thrall, Roger S.

    2009-01-01

    Bromelain (Br), an extract from pineapple stem with cysteine protease activity, exerts anti-inflammatory effects in a number of inflammatory models. We have previously shown that Br treatment decreased activated CD4+ T cells and has a therapeutic role in an ovalbumin-induced murine model of allergic airway disease. The current study was designed to determine the effect of Br on CD4+ T cell activation, specifically the expression of CD25 in vitro. CD25 is up regulated upon T cell activation, f...

  19. Low dose antigen promotes induction of FOXP3 in human CD4+ T cells

    OpenAIRE

    Long, S. Alice; Rieck, Mary; Tatum, Megan; Bollyky, Paul L.; Wu, Rebecca P.; Muller, Isabelle; Ho, Jhon-Chun; Shilling, Heather G.; Buckner, Jane H.

    2011-01-01

    Low antigen dose promotes induction and persistence of Treg in mice, yet few studies have addressed the role of antigen dose in the induction of adaptive CD4+FOXP3+ Treg in humans. To this end, we examined the level of FOXP3 expression in human CD4+CD25− T cells upon activation with autologous antigen presenting cells and varying doses of peptide. Antigen specific T cells expressing FOXP3 were identified by flow cytometry using MHC Class II tetramer (Tmr). We found an inverse relationship bet...

  20. Role of CD4+ and CD8+ T cells in murine resistance to street rabies virus.

    OpenAIRE

    Perry, L. L.; Lodmell, D L

    1991-01-01

    Mice of the SJL/J and BALB/cByJ inbred strains are naturally resistant to street rabies virus (SRV) injected via the intraperitoneal route. To determine the cellular mechanism of resistance, monoclonal antibodies specific for CD4+ or CD8+ subsets of T cells were used to deplete the respective cell population in SRV-infected animals. Elimination of CD4+ T-helper cells abrogated the production of immunoglobulin G (IgG) neutralizing antibodies in response to rabies virus infection and reversed t...

  1. Isolation of a new herpes virus from human CD4 sup + T cells

    Energy Technology Data Exchange (ETDEWEB)

    Frenkel, N.; Schirmer, E.C.; Wyatt, L.S.; Katsafanas, G.; Roffman, E.; Danovich, R.M. (National Institutes of Health, Rockville, MD (USA)); June, C.H. (Naval Medical Research Institute, Bethesda, MD (USA))

    1990-01-01

    A new human herpes virus has been isolated from CD4{sup +} T cells purified from peripheral blood mononuclear cells of a healthy individual (RK), following incubation of the cells under conditions promoting T-cell activation. The virus could not be recovered from nonactivated cells. Cultures of lymphocytes infected with the RK virus exhibited a cytopathic effect, and electron microscopic analyses revealed a characteristic herpes virus structure. RK virus DNA did not hybridize with large probes derived from herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, and human cytomegalovirus. The genetic relatedness of the RK virus to the recently identified T-lymphotropic human herpes virus 6 (HHV-6) was investigated by restriction enzyme analyses using 21 different enzymes and by blot hydridization analyses using 11 probes derived from two strains of HHV-6 (Z29 and U1102). Whereas the two HHV-6 strains exhibited only limited restriction enzyme polymorphism, cleavage of the RK virus DNA yielded distinct patterns. Of the 11 HHV-6 DNA probes tested, only 6 cross-hybridized with DNA fragments derived from the RK virus. Taken together, the maximal homology amounted to 31 kilobases of the 75 kilobases tested. The authors conclude that the RK virus is distinct from previously characterized human herpesviruses. The authors propose to designate it as the prototype of a new herpes virus, the seventh human herpes virus identified to date.

  2. Memory IL-22-producing CD4+ T cells specific for Candida albicans are present in humans.

    Science.gov (United States)

    Liu, Yun; Yang, Binyan; Zhou, Maohua; Li, Li; Zhou, Hui; Zhang, Jianping; Chen, Hui; Wu, Changyou

    2009-06-01

    Co-expression of IL-22 and IL-17 has been identified and demonstrated to be involved in the immunopathogenesis of some autoimmune diseases as well as the defense against pathogenic infections in animal studies. However, the properties of IL-22-producing cells in humans remain largely unclear. In the present study, we showed that IL-22 could be induced from human PBMC following various polyclonal stimulations. The majority of IL-22-producing cells in PBMC were CD4(+) T cells with a memory cell phenotype. In addition, we found that a subset of IL-22(+) T cells produced IL-22 alone, whereas other IL-22(+) T cells co-expressed cytokines typical of Th1, Th2 and Th17 cells. Importantly, stimulation of PBMC from healthy adults with heat-inactivated Candida albicans (C. albicans) yeast or hyphae resulted in IL-22 production by central and effector memory CD4(+) T cells. Moreover, CD4(+)CCR6(+) but not CD4(+)CCR6(-) T cells produced IL-22 when stimulated with either C. albicans or PMA and ionomycin. In addition, PBMC from the individuals infected with C. albicans produced a significantly higher amount of IL-22 compared with healthy controls following stimulation with C. albicans. These data demonstrate that IL-22-producing T cells in humans may play an important role in the defense against fungal infections such as C. albicans. PMID:19449309

  3. Downregulation of IL-12 and a novel negative feedback system mediated by CD25+CD4+ T cells

    International Nuclear Information System (INIS)

    CD25+CD4+ regulatory T cells suppress immune responses and are believed to play roles in preventing autoimmune diseases. However, the mechanism(s) underlying the suppression and the regulation of their homeostasis remain to be elucidated. Here we show that these regulatory T cells downregulated CD25-CD4+ T-cell-mediated production of IL-12 from antigen-presenting cells, which can act as a growth factor for CD25-CD4+ T cells. We further found that CD25+CD4+ T cells, despite their well-documented 'anergic' nature, proliferate significantly in vitro only when CD25-CD4+ T cells are present. Notably, this proliferation was strongly dependent on IL-2 and relatively independent of IL-12. Thus, CD25+CD4+ T cells suppress CD25-CD4+ T-cell responses, at least in part, by inhibiting IL-12 production while they themselves can undergo proliferation with the mediation of CD25-CD4+ T cells in vitro. These results offer a novel negative feedback system involving a tripartite interaction among CD25+CD4+ and CD25-CD4+ T cells, and APCs that may contribute to the termination of immune responses

  4. 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.

  5. HIV-1 gp120 induces NFAT nuclear translocation in resting CD4+ T-cells

    International Nuclear Information System (INIS)

    The replication of human immunodeficiency virus (HIV) in CD4+ T-cells is strongly dependent upon the state of activation of infected cells. Infection of sub-optimally activated cells is believed to play a critical role in both the transmission of virus and the persistence of CD4+ T-cell reservoirs. There is accumulating evidence that HIV can modulate signal-transduction pathways in a manner that may facilitate replication in such cells. We previously demonstrated that HIV gp120 induces virus replication in resting CD4+ T cells isolated from HIV-infected individuals. Here, we show that in resting CD4+ T-cells, gp120 activates NFATs and induces their translocation into the nucleus. The HIV LTR encodes NFAT recognition sites, and NFATs may play a critical role in promoting viral replication in sub-optimally activated cells. These observations provide insight into a potential mechanism by which HIV is able to establish infection in resting cells, which may have implications for both transmission of HIV and the persistence of viral reservoirs

  6. Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells

    Science.gov (United States)

    Church, Sarah E; Jensen, Shawn M; Antony, Paul A; Restifo, Nicholas P; Fox, Bernard A

    2014-01-01

    Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4+ T cells enhance CD8+ T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4+ transgenic T cells-CD4+ T cells and pmel-CD8+ T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8+ T cells with tumor-specific cytokine expression. When combined with CD4+ T cells, transfer of total (naïve and effector) or effector CD8+ T cells were highly effective, suggesting CD4+ T cells can help mediate therapeutic effects by maintaining function of activated CD8+ T cells. In addition, CD4+ T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8+ T cells recovered from mice treated with both CD8+ and CD4+ T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4+ T cells help reduce CD8+ T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4+ and CD8+ T cells for treatment of patients with cancer. PMID:24114780

  7. Effector CD4 and CD8 T Cells and Their Role in the Tumor Microenvironment

    DEFF Research Database (Denmark)

    Hadrup, Sine; Donia, Marco; thor Straten, Per

    2012-01-01

    with colo-rectal cancer (CRC), and also for others solid cancers. These data goes hand in hand with studies of clonality of TIL showing the T cells among TIL are expanded clonally, and also that tumor specific T cells of CD4 as well as CD8 type are enriched at the tumor site. The tumor microenvironment...

  8. Human CD4+ T cells require exogenous cystine for glutathione and DNA synthesis

    DEFF Research Database (Denmark)

    Levring, Trine B; Kongsbak-Wismann, Martin; Rode, Anna Kathrine Obelitz;

    2015-01-01

    aim of this study was to elucidate why activated human T cells require exogenous Cys2 in order to proliferate. We activated purified naïve human CD4+ T cells and found that glutathione (GSH) levels and DNA synthesis were dependent on Cys2 and increased in parallel with increasing concentrations of Cys...

  9. CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection.

    Science.gov (United States)

    Espinosa, J; Herr, F; Tharp, G; Bosinger, S; Song, M; Farris, A B; George, R; Cheeseman, J; Stempora, L; Townsend, R; Durrbach, A; Kirk, A D

    2016-04-01

    Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy. PMID:26603381

  10. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis

    OpenAIRE

    Huber, Magdalena; Lohoff, Michael

    2015-01-01

    Summary The activation of naive CD4+ and CD8+ T cells in response to antigen and their subsequent proliferation and differentiation into effectors are important features of a cell-mediated immune response. CD4+ T cells (also known as T helper cells, Th) differentiate into several subpopulations including Th1, Th2, Th9, Th17, Tfh and Treg cells, characterized by specific cytokine profiles and effector functions. However, recent evidence indicates that CD8+ T cells (termed cytotoxic T lymphocyt...

  11. Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Yiyuan; Wang, Xin Xiang; Mariuzza, Roy A [Maryland

    2012-07-11

    Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ~65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.

  12. Music exposure induced prolongation of cardiac allograft survival and generated regulatory CD4cells 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. PMID:22564629

  13. Identification of two regulatory elements controlling Fucosyltransferase 7 transcription in murine CD4+ T cells.

    Science.gov (United States)

    Pink, Matthias; Ratsch, Boris A; Mardahl, Maibritt; Schröter, Micha F; Engelbert, Dirk; Triebus, Julia; Hamann, Alf; Syrbe, Uta

    2014-11-01

    Fucosyltransferase VII encoded by the gene Fut7 is essential in CD4(+) T cells for the generation of E- and P-selectin ligands (E- and P-lig) which facilitate recruitment of lymphocytes into inflamed tissues and into the skin. This study aimed to identify regulatory elements controlling the inducible Fut7 expression in CD4(+) T cells that occurs upon activation and differentiation of naive T cells into effector cells. Comparative analysis of the histone modification pattern in non-hematopoetic cells and CD4(+) T cell subsets revealed a differential histone modification pattern within the Fut7 locus including a conserved non-coding sequence (CNS) identified by cross-species conservation comparison suggesting that regulatory elements are confined to this region. Cloning of the CNS located about 500 bp upstream of the Fut7 locus, into a luciferase reporter vector elicited reporter activity after transfection of the αβ-WT T cell line, but not after transfection of primary murine CD4(+) Th1 cells. As quantification of different Fut7 transcripts revealed a predominance of transcripts lacking the first exons in primary Th1 cells we searched for an alternative promoter. Cloning of an intragenic region spanning a 1kb region upstream of exon 4 into an enhancer-containing vector indeed elicited promoter activity. Interestingly, also the CNS enhanced activity of this intragenic minimal promoter in reporter assays in primary Th1 cells suggesting that both elements interact in primary CD4(+) T cells to induce Fut7 transcription. PMID:24915132

  14. In vivo ultraviolet-exposed human epidermal cells activate T suppressor cell pathways that involve CD4+CD45RA+ suppressor-inducer T cells

    International Nuclear Information System (INIS)

    In vivo UV exposure of human epidermis abrogates the function of CD1+DR+ Langerhans cells and induces the appearance of CD1-DR+ Ag-presenting macrophages. Epidermal cells from UV-exposed skin, in contrast to epidermal cells from normal skin, potently activate autologous CD4+ T cells, and, in particular, the CD45RA+ (2H4+) (suppressor-inducer) subset. We therefore determined whether UV-exposure in humans leads to a T cell response in which suppression dominates. Autologous blood T cells were incubated with epidermal cell suspensions from in vivo UV-irradiated skin. After activation, repurified T cells were transferred in graded numbers to autologous mononuclear cells (MNC) stimulated with PWM and the resultant IgG production analyzed by ELISA. Relative to T cells activated by unirradiated control epidermal cells, T cells activated by UV-exposed epidermal cells demonstrated enhanced capacity to suppress IgG production (n = 6; p less than or equal to 0.03). Within the T cell population, CD8+ cells stimulated by UV-exposed epidermal cells could be directly activated to suppress PWM-stimulated MNC Ig production if IL-2 was provided in the reaction mixture. The suppressive activity was also transferable with purified CD4+ T cells stimulated by UV-exposed epidermal cells (n = 10; p less than or equal to 0.01), and was radiosensitive. Suppression was decreased when PWM-stimulated MNC were depleted of CD8+ T cells before mixing with CD4+ T cells activated by UV-exposed epidermal cells, suggesting indirect induction of CD8+ Ts cells contained within the responding MNC populations. Indeed, physical depletion of CD45RA+ cells resulted in total abrogation of the suppressor function contained in the CD4+ T cells. Activation of suppressor function was critically dependent on DR+ APC contained in UV-exposed epidermis

  15. CD4+ natural regulatory T cells prevent experimental cerebral malaria via CTLA-4 when expanded in vivo.

    Directory of Open Access Journals (Sweden)

    Ashraful Haque

    Full Text Available Studies in malaria patients indicate that higher frequencies of peripheral blood CD4(+ Foxp3(+ CD25(+ regulatory T (Treg cells correlate with increased blood parasitemia. This observation implies that Treg cells impair pathogen clearance and thus may be detrimental to the host during infection. In C57BL/6 mice infected with Plasmodium berghei ANKA, depletion of Foxp3(+ cells did not improve parasite control or disease outcome. In contrast, elevating frequencies of natural Treg cells in vivo using IL-2/anti-IL-2 complexes resulted in complete protection against severe disease. This protection was entirely dependent upon Foxp3(+ cells and resulted in lower parasite biomass, impaired antigen-specific CD4(+ T and CD8(+ T cell responses that would normally promote parasite tissue sequestration in this model, and reduced recruitment of conventional T cells to the brain. Furthermore, Foxp3(+ cell-mediated protection was dependent upon CTLA-4 but not IL-10. These data show that T cell-mediated parasite tissue sequestration can be reduced by regulatory T cells in a mouse model of malaria, thereby limiting malaria-induced immune pathology.

  16. Calpain 4 is not necessary for LFA-1-mediated function in CD4+ T cells.

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    Sarah A Wernimont

    Full Text Available BACKGROUND: T cell activation and immune synapse formation require the appropriate activation and clustering of the integrin, LFA-1. Previous work has reported that the calpain family of calcium-dependent proteases are important regulators of integrin activation and modulate T cell adhesion and migration. However, these studies have been limited by the use of calpain inhibitors, which have known off-target effects. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used a LoxP/CRE system to specifically deplete calpain 4, a small regulatory calpain subunit required for expression and activity of ubiquitously expressed calpains 1 and 2, in CD4+ T cells. CD4+ and CD8+ T cells developed normally in Capn4(F/F:CD4-CRE mice and had severely diminished expression of Calpain 1 and 2, diminished talin proteolysis and impaired casein degradation. Calpain 4-deficient T cells showed no difference in adhesion or migration on the LFA-1 ligand ICAM-1 compared to control T cells. Moreover, there was no impairment in conjugation between Capn4(F/F:CD4-CRE T cells and antigen presenting cells, and the conjugates were still capable of polarizing LFA-1, PKC-theta and actin to the immune synapse. Furthermore, T cells from Capn4(F/F:CD4-CRE mice showed normal proliferation in response to either anti-CD3/CD28 coated beads or cognate antigen-loaded splenocytes. Finally, there were no differences in the rates of apoptosis following extrinsic and intrinsic apoptotic stimuli. CONCLUSION/SIGNIFICANCE: Our findings demonstrate that calpain 4 is not necessary for LFA-1-mediated adhesion, conjugation or migration. These results challenge previous reports that implicate a central role for calpains in the regulation of T cell LFA-1 function.

  17. TLR2-Modulating Lipoproteins of the Mycobacterium tuberculosis Complex Enhance the HIV Infectivity of CD4+ T Cells.

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    Ciaran Skerry

    Full Text Available Co-infection with Mycobacterium tuberculosis accelerates progression from HIV to AIDS. Our previous studies showed that M. tuberculosis complex, unlike M. smegmatis, enhances TLR2-dependent susceptibility of CD4+ T cells to HIV. The M. tuberculosis complex produces multiple TLR2-stimulating lipoproteins, which are absent in M. smegmatis. M. tuberculosis production of mature lipoproteins and TLR2 stimulation is dependent on cleavage by lipoprotein signal peptidase A (LspA. In order to determine the role of potential TLR2-stimulating lipoproteins on mycobacterial-mediated HIV infectivity of CD4+ T cells, we generated M. smegmatis recombinant strains overexpressing genes encoding various M. bovis BCG lipoproteins, as well as a Mycobacterium bovis BCG strain deficient in LspA (ΔlspA. Exposure of human peripheral blood mononuclear cells (PBMC to M. smegmatis strains overexpressing the BCG lipoproteins, LprF (p<0.01, LprH (p<0.05, LprI (p<0.05, LprP (p<0.001, LprQ (p<0.005, MPT83 (p<0.005, or PhoS1 (p<0.05, resulted in increased HIV infectivity of CD4+ T cells isolated from these PBMC. Conversely, infection of PBMC with ΔlspA reduced HIV infectivity of CD4+ T cells by 40% relative to BCG-infected cells (p<0.05. These results may have important implications for TB vaccination programs in areas with high mother-to-child HIV transmission.

  18. Frequently Increased but Functionally Impaired CD4+CD25+ Regulatory T Cells in Patients with Oral Lichen Planus.

    Science.gov (United States)

    Zhou, Leilei; Cao, Tianyi; Wang, Yufeng; Yao, Hui; Du, Guanhuan; Chen, Guangjie; Niu, Xiaoyin; Tang, Guoyao

    2016-06-01

    Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease, and CD4(+)CD25(+) regulatory T cells (Tregs) are considered involved in the pathogenesis of OLP. In this study, to investigate whether there are intrinsic factors that might cause functional changes in Tregs in this disease, we evaluated the frequency of Tregs in peripheral blood and oral lesions and the expression levels of function-related transcription factors, forkhead/winged-helix transcription factor box P3 (FOXP3), transforming growth factor β (TGF-β), interleukin 10 (IL-10), and TGF-β receptors (TβRI and TβRII) mRNAs in Tregs of patients with oral lichen planus (OLP). We also investigated the frequency of pro-inflammatory cytokines (IFN-γ and IL-17A) producing Foxp3(+) regulatory cells. Increased proportions of Tregs were found in OLP patients. The expression of FOXP3 on mRNA and protein level was elevated in the Tregs of OLP. The expression of TGF-β was lower both on the mRNA and serum level, whereas the expression of IL-10 showed no significant difference between the OLP patients and normal controls. The percentages of CD4(+)FOXP3(+)IL-17(+) T cells were significantly higher than that of normal controls, whereas the percentages of CD4(+)FOXP3(+)IFN-γ(+) T cells did not differ significantly. Furthermore, impaired suppressive function of CD4(+)CD25(+) T cells was demonstrated in OLP patients by in vitro proliferation assay. These data indicate that Tregs in OLP are frequently expanded but functionally deficient. This could explain, at least in part, why the increased Tregs in OLP fail to control the pathogenesis and development of this autoimmune disease. PMID:27106476

  19. IL-33 induces IL-9 production in human CD4+ T cells and basophils

    DEFF Research Database (Denmark)

    Blom, Lars; Poulsen, Britta Cathrina; Jensen, Bettina M.;

    2011-01-01

    IL-33, an IL-1 family member and ligand for the IL-1 receptor-related protein ST2, has been associated with induction of Th2 cytokines such as IL-4, IL-5, and IL-13. Here, we report that IL-33 can initiate IL-9 protein secretion in vitro in human CD4+ T cells and basophils isolated from peripheral...... important, although not an absolute requirement, for IL-9 production in CD4+ T cells. IL-9 production by purified (>95%) human basophils, cultured for 24 h with IL-3 or IL-33, was found, with a strong synergy between the two, likely to be explained by the IL-3 upregulated ST2 expression. Collectively, these...... blood. TGF-β has been described as a critical factor for IL-9 induction in Th2 cells; however, we found that TGF-β also induces co-production of IL-9 in purified, naïve (>99%) CD4(+)CD45RA(+)CD45RO(-)CD25(-) T cells differentiated towards a Th1 profile. Subsequently, it was demonstrated that TGF-β is...

  20. Prevention of immunodeficiency virus induced CD4+ T-cell depletion by prior infection with a non-pathogenic virus

    International Nuclear Information System (INIS)

    Immune dysregulation initiated by a profound loss of CD4+ T-cells is fundamental to HIV-induced pathogenesis. Infection of domestic cats with a non-pathogenic lentivirus prevalent in the puma (puma lentivirus, PLV or FIVPCO) prevented peripheral blood CD4+ T-cell depletion caused by subsequent virulent FIV infection. Maintenance of this critical population was not associated with a significant decrease in FIV viremia, lending support to the hypothesis that direct viral cytopathic effect is not the primary cause of immunodeficiency. Although this approach was analogous to immunization with a modified live vaccine, correlates of immunity such as a serum-neutralizing antibody or virus-specific T-cell proliferative response were not found in protected animals. Differences in cytokine transcription profile, most notably in interferon gamma, were observed between the protected and unprotected groups. These data provide support for the importance of non-adaptive enhancement of the immune response in the prevention of CD4+ T-cell loss

  1. Regulatory activity of azabisphosphonate-capped dendrimers on human CD4+ T cell proliferation enhances ex-vivo expansion of NK cells from PBMCs for immunotherapy

    Directory of Open Access Journals (Sweden)

    Caminade Anne-Marie

    2009-09-01

    Full Text Available Abstract Background Adoptive cell therapy with allogenic NK cells constitutes a promising approach for the treatment of certain malignancies. Such strategies are currently limited by the requirement of an efficient protocol for NK cell expansion. We have developed a method using synthetic nanosized phosphonate-capped dendrimers allowing such expansion. We are showing here that this is due to a specific inhibitory activity towards CD4+ T cell which could lead to further medical applications of this dendrimer. Methods Mononuclear cells from human peripheral blood were used to investigate the immunomodulatory effects of nanosized phosphonate-capped dendrimers on interleukin-2 driven CD4+T cell expansion. Proliferation status was investigated using flow cytometry analysis of CFSE dilution and PI incorporation experiments. Magnetic bead cell sorting was used to address activity towards individual or mixed cell sub-populations. We performed equilibrium binding assay to assess the interaction of fluorescent dendrimers with pure CD4+ T cells. Results Phosphonate-capped dendrimers are inhibiting the activation, and therefore the proliferation; of CD4+ T cells in IL-2 stimulated PBMCs, without affecting their viability. This allows a rapid enrichment of NK cells and further expansion. We found that dendrimer acts directly on T cells, as their regulatory property is maintained when stimulating purified CD4+ T cells with anti-CD3/CD28 microbeads. Performing equilibrium binding assays using a fluorescent analogue, we show that the phosphonate capped-dendrimers are specifically interacting with purified CD4+ T cells. Ultimately, we found that our protocol prevents the IL-2 related expansion of regulatory T cells that would be deleterious for the activity of infused NK cells. Conclusion High yield expansion of NK cells from human PBMCs by phosphonate-capped dendrimers and IL-2 occurs through the specific inhibition of the CD4+ lymphocyte compartment. Given the

  2. The ARTμS: a novel microfluidic CD4+ T-cell enumeration system for monitoring antiretroviral therapy in HIV patients.

    Science.gov (United States)

    Liu, Qian; Chernish, Alexis; DuVall, Jacquelyn A; Ouyang, Yiwen; Li, Jingyi; Qian, Qiang; Bazydlo, Lindsay A L; Haverstick, Doris M; Landers, James P

    2016-02-01

    We report on a novel and cost-effective microfluidic platform that integrates immunomagnetic separation and cell enumeration via DNA-induced bead aggregation. Using a two-stage immunocapture microdevice, 10 μL of whole blood was processed to isolate CD4+ T-cells. The first stage involved the immuno-subtraction of monocytes by anti-CD14 magnetic beads, followed by CD4+ T-cell capture with anti-CD4 magnetic beads. The super hydrophilic surface generated during polydimethylsiloxane (PDMS) plasma treatment allowed for accurate metering of the CD4+ T-cell lysate, which then interacted with silica-coated magnetic beads under chaotropic conditions to form aggregates. Images of the resulting aggregates were captured and processed to reveal the mass of DNA, which was used to back-calculate the CD4+ T-cell number. Studies with clinical samples revealed that the analysis of blood within 24 hours of phlebotomy yielded the best results. Under these conditions, an accurate cell count was achieved (R(2) = 0.98) when compared to cell enumeration via flow cytometry, and over a functional dynamic range from 106-2337 cells per μL. PMID:26687070

  3. Adoptive Cell Therapy for Lymphoma with CD4 T Cells Depleted of CD137 Expressing Regulatory T Cells

    OpenAIRE

    Goldstein, Matthew J; Kohrt, Holbrook E.; Houot, Roch; Varghese, Bindu; Lin, Jack T.; Swanson, Erica; Levy, Ronald

    2012-01-01

    Adoptive immunotherapy with anti-tumor T cells is a promising novel approach to the treatment of cancer. However, T cell therapy may be limited by the co-transfer of regulatory T cells (Tregs). Here we explored this hypothesis by using two cell surface markers, CD44 and CD137, to isolate anti-tumor CD4 T cells while excluding Tregs. In a murine model of B cell lymphoma, only CD137negCD44hi CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137posCD44h...

  4. Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function.

    Science.gov (United States)

    Layman, Awo A K; Oliver, Paula M

    2016-05-15

    The human body is exposed to potentially pathogenic microorganisms at barrier sites such as the skin, lungs, and gastrointestinal tract. To mount an effective response against these pathogens, the immune system must recruit the right cells with effector responses that are appropriate for the task at hand. Several types of CD4(+) T cells can be recruited, including Th cells (Th1, Th2, and Th17), T follicular helper cells, and regulatory T cells. These cells help to maintain normal immune homeostasis in the face of constantly changing microbes in the environment. Because these cells differentiate from a common progenitor, the composition of their intracellular milieu of proteins changes to appropriately guide their effector function. One underappreciated process that impacts the levels and functions of effector fate-determining factors is ubiquitylation. This review details our current understanding of how ubiquitylation regulates CD4(+) T cell effector identity and function. PMID:27183634

  5. A novel and simple method for the generation of functional human dendritic cells from unfractionated peripheral blood mononuclear cells within 2 days: its application for induction of HIV-1-reactive CD4+ T cells in the hu-PBL SCID mice

    Directory of Open Access Journals (Sweden)

    Akira eKodama

    2013-09-01

    Full Text Available Because dendritic cells (DCs play a critical role in the regulation of adaptive immune responses, they have been ideal candidates for cell-based immunotherapy of cancers and infections in humans. Generally, monocyte-derived DCs (MDDCs were generated from purified monocytes by multiple steps of time-consuming physical manipulations for an extended period cultivation. In this study, we developed a novel, simple and rapid method for the generation of type-1 helper T cell (Th1-stimulating human DCs directly from bulk peripheral blood mononuclear cells (PBMCs. PBMCs were cultivated in the presence of 20 ng/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF, 20 ng/ml of interleukin-4 (IL-4 and 1,000 U/ml of interferon-β (IFN-β for 24 hours followed by 24 hour maturation with a cytokine cocktail containing 10 ng/ml of tumor necrosis factor-α (TNF-α, 10 ng/ml of IL-1β and 1 μg/ml of prostaglandin E2 (PGE2. The phenotype and biological activity of these new DCs for induction of allogeneic T cell proliferation and cytokine production were comparable to those of the MDDCs. Importantly, these new DCs pulsed with inactivated HIV-1 could generated HIV-1-reactive CD4+ T cell responses in humanized mice reconstituted with autologous PBMCs from HIV-1-negative donors. This simple and quick method for generation of functional DCs will be useful for future studies on DC-mediated immunotherapies.

  6. Vitamin D Actions on CD4+ T cells in Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Colleen Elizabeth Hayes

    2015-03-01

    Full Text Available This review summarizes and integrates research on vitamin D and CD4+ T lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene-environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ Treg cell and CD4+ Tr1 cell functions, and a Th1-Tr1 switch. The proposed Th1-Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell-cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, we highlight unanswered questions that potentially informative future research directions that may speed delivery of etiology-based strategies to reduce autoimmune disease.

  7. Proximal signaling control of human effector CD4 T cell function

    OpenAIRE

    Okoye, Francesca I.; Krishnan, Sandeep; Chandok, Meena R.; Tsokos, George C.; Farber, Donna L.

    2007-01-01

    The functional coupling of T cell receptor (TCR)-mediated signaling events in primary human T cells remains undefined. We demonstrate here that alterations in the expression of proximal TCR-coupled signaling subunits are associated with distinct effector capacities in differentiated human CD4 T cells. Analysis of proximal signaling profiles using biochemical and single cell approaches reveals decreased CD3ζ and ZAP-70 expression correlating with functional anergy, with increased CD3ζ/ZAP-70 e...

  8. TCR repertoire and Foxp3 expression define functionally distinct subsets of CD4+ Treg cells1

    OpenAIRE

    Kuczma, Michal; Pawlikowska, Iwona; Kopij, Magdalena; Podolsky, Robert; Rempala, Grzegorz A.; Kraj, Piotr

    2009-01-01

    Despite extensive research efforts to characterize peripheral regulatory T cells (Treg) expressing transcription factor Foxp3, their subset complexity, phenotypic characteristics, TCR repertoire and antigen specificities remain ambiguous. Here, we identify and define two subsets of peripheral Treg cells differing in Foxp3 expression level and TCR repertoires. Treg cells expressing a high level of Foxp3 and TCRs not utilized by naive CD4+ T cells present a stable suppressor phenotype and domin...

  9. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad; Issazadeh-Navikas, Shohreh; Goertsches, Robert; Martin, Roland; Comabella, Manuel

    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 ce...

  10. 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 <.001) and reduced thymic output in infants of HIV-positive mothers were found (frequency of CD4(+) cells with TRECs was 3.6% +/- 0.7% compared with 14.3% +/- 2.2% in controls, P <.001......). 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....

  11. Interdisciplinary Evaluation of Broadly-Reactive HLA Class II Restricted Epitopes Eliciting HIV-Specific CD4+T Cell Responses

    DEFF Research Database (Denmark)

    Buggert, M.; Norström, M.; Lundegaard, Claus; Lund, Ole; Nielsen, Morten; Karlsson, A. C.

    2011-01-01

    Background: CD4+ T cells orchestrate immune protection by ‘‘helping’’ other cells of our immune system to clear viral infections. It is well known that the preferential infection and depletion of CD4+ T cells contributes to hampered systemic T cell help following HIV infection. However, the funct...

  12. Heat Shock Proteins 60 and 70 Specific Proinflammatory and Cytotoxic Response of CD4+CD28null Cells in Chronic Kidney Disease

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    Ashok K. Yadav

    2013-01-01

    Full Text Available Background. CD4+CD28null T cells are expanded in peripheral blood of patients with chronic kidney disease and associated with subclinical atherosclerosis. However, triggers for the oligoclonal expansion and activation of these cells are not clear. Methods. We investigated twenty-five stage V-IV chronic kidney disease (CKD patients and eight healthy subjects (HC. Peripheral mononuclear cells were isolated and incubated with heat shock protein- (HSP 60 and 70. CD4+CD28null and CD4+CD28+ cells were sorted by flowcytometry and antigen specific response was assessed by the mRNA and protein expression of interferon (IFN-γ, perforin, and granzyme B using qRT-PCR and Elispot. Results. The basal mRNA expression of IFN-γ, perforin, and granzyme B in CD4+CD28null cells was higher in subjects with CKD compared to that in HC (P<0.0001. Subjects with CKD also showed expression of IFN-γ, perforin, and granzyme B in the CD4+CD28+ subset, but this was much weaker than that seen in the CD4+CD28null population (P<0.0001. We did not note the expression of these molecules at mRNA or protein level in either subset of CD4 cells in HC. After incubation with HSP60 and HSP70, CD4+CD28null cells showed increased expression at mRNA (P<0.001 and protein level (P<0.001. CD4+CD28+ cells also showed a weak increase in expression. No antigen-specific response was noted in HC. Conclusion. These data show that CD4+CD28null cells in subjects with CKD react with HSP60 and HSP70 by upregulating the expression of IFN-γ, perforin and granzyme B. Increased circulating level of HSP60 and HSP70 might play a role in initiation and/or progression of atherosclerosis in CKD subjects through perturbation of CD4+CD28null cells.

  13. Transcription regulates HIF-1α expression in CD4(+) T cells.

    Science.gov (United States)

    Bollinger, Thomas; Bollinger, Annalena; Gies, Sydney; Feldhoff, Lea; Solbach, Werner; Rupp, Jan

    2016-01-01

    The transcription factor hypoxia inducible factor-1α (HIF-1α) mediates the metabolic adaptation of cells to hypoxia and T-helper cell fate. However, HIF-1α regulation in CD4(+) T cells (T cells) remains elusive. Here we observed that depletion of oxygen (O2⩽2%) alone was not sufficient to induce HIF-1α expression in T cells. However, when hypoxic T cells were stimulated, HIF-1α was expressed and this was dependent on nuclear factor-κB- and nuclear factor of activated T cell (NFAT)-mediated transcriptional upregulation of Hif-1α mRNA. HIF-1α upregulation could be blocked by drugs inhibiting NF-κB, NFAT or mammalian target of rapamycin precluding CD4(+) T-cell stimulation or translation in T cells, as well as by blocking transcription. CD3, CD28, phorbol-12-myristat-13-acetat (PMA) or ionomycin-stimulated T cells did not express HIF-1α under normoxic conditions. In conclusion, regulation of HIF-1α expression in CD4(+) T cells in hypoxia gravely relies on its transcriptional upregulation and subsequent enhanced protein stabilization. PMID:26150319

  14. A novel SIV gag-specific CD4(+)T-cell clone suppresses SIVmac239 replication in CD4(+)T cells revealing the interplay between antiviral effector cells and their infected targets.

    Science.gov (United States)

    Ayala, Victor I; Trivett, Matthew T; Coren, Lori V; Jain, Sumiti; Bohn, Patrick S; Wiseman, Roger W; O'Connor, David H; Ohlen, Claes; Ott, David E

    2016-06-01

    To study CD4(+)T-cell suppression of AIDS virus replication, we isolated nine rhesus macaque SIVGag-specific CD4(+)T-cell clones. One responding clone, Gag68, produced a typical cytotoxic CD8(+)T-cell response: induction of intracellular IFN-γ, MIP-1α, MIP-1β, and CD107a degranulation. Gag68 effectively suppressed the spread of SIVmac239 in CD4(+)T cells with a corresponding reduction of infected Gag68 effector cells, suggesting that CD4(+)effectors need to suppress their own infection in addition to their targets to be effective. Gag68 TCR cloning and gene transfer into CD4(+)T cells enabled additional experiments with this unique specificity after the original clone senesced. Our data supports the idea that CD4(+)T cells can directly limit AIDS virus spread in T cells. Furthermore, Gag68 TCR transfer into CD4(+)T-cell clones with differing properties holds promise to better understand the suppressive effector mechanisms used by this important component of the antiviral response using the rhesus macaque model. PMID:27017056

  15. 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

  16. Novel function of perforin in negatively regulating CD4+T cell activation by affecting calcium signaling

    Institute of Scientific and Technical Information of China (English)

    Enguang Bi; Kairui Mao; Jia Zou; Yuhan Zheng; Bing Sun; Chunjian Huang; Yu Hu; Xiaodong Wu; Weiwen Deng; Guomei Lin; Zhiduo Liu; Lin Tian; Shuhui Sun

    2009-01-01

    Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic Tlymphocytes (CTLs) and natural killer cells. However, whether it also plays a role in conventional CD4+ T cell func-tion remains unclear. Here we report that in perforin-deficient (PKO) mice, CD4+ T cells are hyperproliferative in response to T cell receptor (TCR) stimulation. This feature of hyperproliferation is accompanied by the enhancement both in cell division and in IL-2 secretion. It seems that the perforin deficiency does not influence T cell development in thymus spleen and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell prolifera-tion and antibody production. Furthermore, PKO mice are more susceptible to experimental autoimmune uveitis. To address the molecular mechanism, we found that after TCR stimulation, CD44 T cells from PKO mice display an increased intracellular calcium flux and subsequently enhance activation of transcription factor NFATI. Our results indicate that perforin plays a negative role in regulating CD4+ T cell activation and immune response by affecting TCR-dependent Ca2+ signaling.

  17. Effector CD4+ T cell expression signatures and immune-mediated disease associated genes.

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    Full Text Available Genome-wide association studies (GWAS in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune-mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20 compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2, where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis.

  18. Maturation of Dendritic Cells & HIV Transmission to CD4(+) T cells

    OpenAIRE

    Izquierdo-Useros, Nuria

    2009-01-01

    Las células dendríticas (DCs) están especializadas en la presentación de antígeno. Sin embargo, las DCs expuestas al virus de la inmunodeficiencia humana (VIH) también son capaces de transmitir una potente infección citopática a los linfocitos T CD4+, un proceso que frecuentemente se ha relacionado con la capacidad que tiene el receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) para unirse de forma específica a la glicoproteína de la envuelta vi...

  19. Maturation of dendritic cells & HIV-1 transmission to CD4+ T cells

    OpenAIRE

    Izquierdo Useros, Nuria

    2009-01-01

    Descripció del recurs: 22 febrer de 2010 Las células dendríticas (DCs) están especializadas en la presentación de antígeno. Sin embargo, las DCs expuestas al virus de la inmunodeficiencia humana (VIH) también son capaces de transmitir una potente infección citopática a los linfocitos T CD4+, un proceso que frecuentemente se ha relacionado con la capacidad que tiene el receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) para unirse de forma esp...

  20. Induction of a virus-specific effector–memory CD4+ T cell response by attenuated SIV infection

    OpenAIRE

    Gauduin, Marie-Claire; Yu, Yi; Barabasz, Amy; Carville, Angela; Piatak, Mike; Lifson, Jeffrey D.; Desrosiers, Ronald C; Johnson, R. Paul

    2006-01-01

    We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVΔnef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4–10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5–10-fold lower in frequency and inversely correlated with the level of plasma...

  1. Duel of the fates: the role of transcriptional circuits and noise in CD4+ cells.

    Science.gov (United States)

    Hebenstreit, Daniel; Deonarine, Andrew; Babu, M Madan; Teichmann, Sarah A

    2012-06-01

    CD4+ T cells play key roles in orchestrating adaptive immune responses, and are a popular model for mammalian cell differentiation. While immune regulation would seem to require exactly adjusted mRNA and protein expression levels of key factors, there is little evidence that this is strictly the case. Stochastic gene expression and plasticity of cell types contrast the apparent need for precision. Recent work has provided insight into the magnitude of molecular noise, as well as the relationship between noise, transcriptional circuits and epigenetic modifications in a variety of cell types. These processes and their interplay will also govern gene expression patterns in the different CD4+ cell types, and the determination of their cellular fates. PMID:22498241

  2. A chimeric measles virus with a lentiviral envelope replicates exclusively in CD4+/CCR5+ cells

    International Nuclear Information System (INIS)

    We generated a replicating chimeric measles virus in which the hemagglutinin and fusion surface glycoproteins were replaced with the gp160 envelope glycoprotein of simian immunodeficiency virus (SIVmac239). Based on a previously cloned live-attenuated Schwarz vaccine strain of measles virus (MV), this chimera was rescued at high titers using reverse genetics in CD4+ target cells. Cytopathic effect consisted in the presence of large cell aggregates evolving to form syncytia, as observed during SIV infection. The morphology of the chimeric virus was identical to that of the parent MV particles. The presence of SIV gp160 as the only envelope protein on chimeric particles surface altered the cell tropism of the new virus from CD46+ to CD4+ cells. Used as an HIV candidate vaccine, this MV/SIVenv chimeric virus would mimic transient HIV-like infection, benefiting both from HIV-like tropism and the capacity of MV to replicate in dendritic cells, macrophages and lymphocytes.

  3. 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.

  4. Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy

    Directory of Open Access Journals (Sweden)

    Mark J Dobrzanski

    2013-03-01

    Full Text Available The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for "plasticity" and memory cell generation within the hostile tumor environment and their potentials in cancer treatment and adoptive immunotherapies.

  5. CD4+ T cell responses to self- and mutated p53 determinants during tumorigenesis in mice.

    Science.gov (United States)

    Fedoseyeva, E V; Boisgérault, F; Anosova, N G; Wollish, W S; Arlotta, P; Jensen, P E; Ono, S J; Benichou, G

    2000-06-01

    We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225-239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225-239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225-239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225-239 self-reactive T cells. PMID:10820239

  6. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17

    OpenAIRE

    Park, Heon; Li, Zhaoxia; Yang, Xuexian O.; Chang, Seon Hee; Nurieva, Roza; Wang, Yi-hong; Wang, Ying; Hood, Leroy; Zhu, Zhou; Tian, Qiang; Dong, Chen

    2005-01-01

    Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interfero...

  7. Innate memory CD4+ T cells suppress autoimmune graft-versus-host disease

    OpenAIRE

    Weishan Huang; Jianfang Hu; Laufer, Terri M.

    2013-01-01

    Chronic graft-versus-host disease (cGVHD) is the major complication post hematopoietic cell transplantation. Major histocompatibility complex class II (MHCII) mediated CD4+ T cell differentiation and function plays a critical role in cGVHD, and the lack of hematopoietic MHCII (H-MHCII) causes cGVHD in syngeneic irradiated murine recipients. We have studied this process using murine bone marrow transplant of MHCII deficient or sufficient donors. We find that irradiated WT recipients that recei...

  8. Electroacupuncture Attenuates Ovalbumin-Induced Allergic Asthma via Modulating CD4+CD25+ Regulatory T Cells

    OpenAIRE

    Youngjoo Kwon; Sung-Hwa Sohn; Gihyun Lee; Youngeun Kim; Hyejung Lee; Minkyu Shin; Hyunsu Bae

    2012-01-01

    A mouse pulmonary hypersensitivity experimental model that mimics human asthma was developed, and electroacupuncture (EA) treatment was shown to reduce allergic inflammatory processes. In addition, we also assessed whether the beneficial effects of EA on allergic asthma could be correlated with CD4+CD25+Foxp3+ regulatory T cells (Treg). Cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in ...

  9. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells

    OpenAIRE

    Deborah H Strickland; Stumbles, Philip A.; Zosky, Graeme R.; Subrata, Lily S.; Thomas, Jenny A.; Turner, Debra J.; Sly, Peter D.; Holt, Patrick G.

    2006-01-01

    An important feature of atopic asthma is the T cell–driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+...

  10. 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...... lymphoid tissues of transplanted SCID mice proliferate in vitro in the presence of interleukin (IL)-2 + IL-7. CD3 ligation enhances this cytokine-supported proliferation in CD4+ T cells from the spleen and the mesenteric lymph node of transplanted SCID mice; CD3 ligation suppresses the cytokine...... fraction of colitis-inducing CD4+ T cells undergo activation-induced cell death in situ and can damage other cells through Fas-dependent cytotoxicity....

  11. Detection and significance of CD4+ CD25+ CD127low/-Treg cells in patients with SLE%系统性红斑狼疮患者外周血CD4+CD25+CD127low/-调节性T细胞的检测及意义

    Institute of Scientific and Technical Information of China (English)

    韦月梅; 邹洪才; 崔俊; 孔建忠; 田安国; 葛建英

    2013-01-01

    Objective To investigate the feasibility of application of CD4+ CD25+ CD127low/- as an Treg cells new marker in patients with systemic lupus erythematosus (SLE). Methods The proportions of CD4+CD25+CD127low-/and CD4+CD25+ FoxP3+Treg cells in peripheral blood of SLE patients(group A) and healthy people(group B) were determined by flow cytometry. The correlation between CD4+ CD25+ CD127low/- Treg cells and CD4+ CD25+ FoxP3+ Treg cells was analyzed. Results The proportions of CD4+CD25+CD127low/- Treg cells and CD4+ CD25+ FoxP3+Treg cells in group A were significantly lower than those in group B [(3. 31 + 0. 82)% and (2. 28 + 0. 47)% vs. (6. 07 + 1. 59)% and (5. 01 + 1. 09)%](P<0. 01). The proportion of CD4+ CD25+ CD127 low/- Treg cells was positively correlated to that of CD4+ CD25+ FoxP3+ T cells in both groups(r=0. 713 and r=0. 709, P<0. 01). Conclusion The surface marker CD4+ CD25+ CD127low/- can be used to identify Treg cells. The decreases of CD4+CD25+CD127low/- Treg cells may play an important role in the pathogenesis of SLE.%目的 探讨用膜表面标志CD4+ CD25+ CD127low/-作为检测调节性T(Treg)细胞标记的可行性,并探讨其在系统性红斑狼疮(SLE)中的临床意义.方法 用流式细胞术检测SLE组及健康对照组外周血CD4+ CD25+ CD127low/-Treg细胞及CD4+ CD25+ FoxP3+ Treg细胞的比例,并分析两组CD4+ CD25+ CD127low/-Treg细胞与CD4+ CD25+ FoxP3+ Treg细胞比例之间的相关性.结果 SLE组外周血CD4+ CD25+ CD127low/-Treg细胞比例为(3.31±0.82)%CD4+ CD25+ FoxP3+ Treg细胞比例为(2.28±0.47)%,均显著低于健康对照组的(6.07±1.59)%和(5.01±1.09)%(P<0.01).SLE组及健康对照组外周血CD4+ CD25+ CD127low/-Treg细胞比例与CD4+ CD25+FoxP3+ Treg细胞比例之间呈显著正相关(r=0.713、r=0.709,P<0.01).结论 膜表面标志CD4+ CD25+ CD127low/-可以用来鉴定Treg细胞;SLE患者外周血CD4+ CD25+ CD127low/-Treg细胞的显著减少可能与SLE的发病有关.

  12. Evaluation of CD4+CD25+ regulatory T cells in patients with hepatocellular carcinoma and liver cirrhosis

    Directory of Open Access Journals (Sweden)

    Amal Abdel Aleem, ** Eman A Abdel Rahman and ***Abdel Aty M. Elgonimy

    2011-04-01

    Full Text Available The emergence of a Tumor results from the disruption of cell growth regulation as well as from failure of the host to provoke a sufficient immunological anti-tumor response. Regulatory T cells CD4+CD25+ (Tregs play an important role in maintaining peripheral self-tolerance, thus preventing autoimmune pathologies. However, in certain situations Tregs can impair effective immunity to some pathogens and tumor cells. Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related death in the world, and in developed countries it is expected to continue to increase because of the epidemic of chronic hepatitis C virus (HCV infection. Previous studies also showed that Tregs infiltrating HCC tumors were an indicator of poor prognosis. Aim: of this study was to evaluate CD4+CD25+ Treg cells in patients with HCC and liver cirrhosis and their correlation with liver tumor markers and grading. Patients and Methods: The study included 30 patients, 15 patients had HCC (group I and 15 were cirrhotic patients (group II. In addition, 10 healthy subjects were used as controls. All patients were subjected to clinical examination and laboratory investigations including liver function tests, hepatitis B markers (HBs Ag, HBeAg and HBc-Ab and HCV antibodies were detected by ELISA. and Bilharzial Abs by indirect hemagglutination test. CD4+CD25+ Tcells were quantified in the blood by flow cytometry, alpha feto protein by Cobas e 411, To evaluate HCC grading ,abdominal sonography, C.T.and liver biopsy were done. Patients were categorized into mildely differentiated (grad 1, moderately differentiated (grad 11 and poorly differentiated (grad 111. Results: There were significant increased in serum AFP, and CD4+CD25+% in patients with HCC, and in patients with liver cirrhosis when compared to control group (p<0.05, and highly significant increased in AFP, and CD4+CD25+ % in patients with HCC when compared to patients with liver cirrhosis (p<0.001. In HCC patients

  13. Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites.

    Science.gov (United States)

    Chaput, Nathalie; Darrasse-Jèze, Guillaume; Bergot, Anne-Sophie; Cordier, Corinne; Ngo-Abdalla, Stacie; Klatzmann, David; Azogui, Orly

    2007-10-15

    Natural regulatory T cells (Tregs) are present in high frequencies among tumor-infiltrating lymphocytes and in draining lymph nodes, supposedly facilitating tumor development. To investigate their role in controlling local immune responses, we analyzed intratumoral T cell accumulation and function in the presence or absence of Tregs. Tumors that grew in normal BALB/c mice injected with the 4T1 tumor cell line were highly infiltrated by Tregs, CD4 and CD8 cells, all having unique characteristics. Most infiltrating Tregs expressed low levels of CD25Rs and Foxp3. They did not proliferate even in the presence of IL-2 but maintained a strong suppressor activity. CD4 T cells were profoundly anergic and CD8 T cell proliferation and cytotoxicity were severely impaired. Depletion of Tregs modified the characteristics of tumor infiltrates. Tumors were initially invaded by activated CD4(+)CD25(-) T cells, which produced IL-2 and IFN-gamma. This was followed by the recruitment of highly cytotoxic CD8(+) T cells at tumor sites leading to tumor rejection. The beneficial effect of Treg depletion in tumor regression was abrogated when CD4 helper cells were also depleted. These findings indicate that the massive infiltration of tumors by Tregs prevents the development of a successful helper response. The Tregs in our model prevent Th cell activation and subsequent development of efficient CD8 T cell activity required for the control of tumor growth. PMID:17911581

  14. Where CD4 + CD25 + T reg cells impinge on autoimmune diabetes

    OpenAIRE

    Chen, Zhibin; Herman, Ann E.; Matos, Michael; Mathis, Diane; Benoist, Christophe

    2005-01-01

    Foxp3 is required for the generation and activity of CD4 + CD25 + regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in ...

  15. CD4+CD45RBHi Interleukin-4 Defective T Cells Elicit Antral Gastritis and Duodenitis

    OpenAIRE

    Dohi, Taeko; Fujihashi, Kohtaro; Koga, Toshiya; Etani, Yuri; Yoshino, Naoto; Kawamura, Yuki I.; Mcghee, Jerry R

    2004-01-01

    We have analyzed the gastrointestinal inflammation which develops following adoptive transfer of IL-4 gene knockout (IL-4−/−) CD4+CD45RBHi (RBHi) T cells to severe combined immunodeficient (SCID) or to T cell-deficient, T cell receptor β and δ double knockout (TCR−/−) mice. Transfer of IL-4−/− RBHi T cells induced a similar type of colitis to that seen in SCID or TCR−/− recipients of wild-type (wt) RBHi T cells as reported previously. Interestingly, transfer of both wt and IL-4−/− RBHi T cell...

  16. Immunotherapy With IL-10 and IFN-γ Producing CD4 Effector Cells Modulate “Natural” And “Inducible” CD4 TReg Cell Subpopulation Levels: Observations In Four Cases Of Patients With Ovarian Cancer

    OpenAIRE

    Dobrzanski, Mark J.; Rewers-Felkins, Kathleen A.; Samad, Khaliquzzaman A.; Quinlin, Imelda S.; Phillips, Catherine A.; Robinson, William; Dobrzanski, David J.; Wright, Stephen E.

    2011-01-01

    Adoptive T cell therapy for cancer patients optimally requires participation of CD4 T cells. In this phase I/II study, we assessed the therapeutic effects of adoptively transferred IL-10 and IFN-γ-producing CD4 effector cells in patients with recurrent ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that 3 monthly treatment cycles of autologous T cell restimulation and local intraperitoneal re-infusion modulated T cell mediated immune responses th...

  17. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination

    OpenAIRE

    Casares, N. (Noelia); L. Arribillaga; Sarobe, P.; Dotor, J. (Javier); Lopez-Diaz-de-Cerio, A. (Ascensión); Melero, I; Lasarte, J.J. (Juan José)

    2003-01-01

    CD25(+) regulatory T (T reg) cells suppress the activation/proliferation of other CD4(+) or CD8(+) T cells in vitro. Also, down-regulation of CD25(+) T reg cells enhance antitumor immune responses. In this study, we show that depletion of CD25(+) T reg cells allows the host to induce both CD4(+) and CD8(+) antitumoral responses following tumor challenge. Simultaneous depletion of CD25(+) and CD8(+) cells, as well as adoptive transfer experiments, revealed that tumor-specific CD4(+) T cells, w...

  18. Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells

    DEFF Research Database (Denmark)

    Nielsen, C H; Albertsen, L; Bendtzen, K;

    2007-01-01

    The mechanism of action of methotrexate (MTX) in autoimmune diseases (AID) is unclear. A pro-apoptotic effect has been demonstrated in mitogen-stimulated peripheral blood mononuclear cells (PBMC), but studies employing conventional antigens have disputed a pro-apoptotic effect. CD4+ T helper (Th...

  19. Importance of B cell co-stimulation in CD4+ T cell differentiation: X-linked agammaglobulinaemia, a human model

    Science.gov (United States)

    Martini, H; Enright, V; Perro, M; Workman, S; Birmelin, J; Giorda, E; Quinti, I; Lougaris, V; Baronio, M; Warnatz, K; Grimbacher, B

    2011-01-01

    We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann–Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4+CD45RO+ and CD4+CD45RO+CXCR5+ cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans. PMID:21488866

  20. Importance of B cell co-stimulation in CD4(+) T cell differentiation: X-linked agammaglobulinaemia, a human model.

    Science.gov (United States)

    Martini, H; Enright, V; Perro, M; Workman, S; Birmelin, J; Giorda, E; Quinti, I; Lougaris, V; Baronio, M; Warnatz, K; Grimbacher, B

    2011-06-01

    We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann-Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+)CD45RO(+) and CD4(+)CD45RO(+)CXCR5(+) cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans. PMID:21488866

  1. Presence of HLA-DR molecules and HLA-DRB1 mRNA in circulating CD4+ T cells

    DEFF Research Database (Denmark)

    Revenfeld, Anne Louise Schacht; Steffensen, Rudi; Pugholm, Lotte Hatting;

    2016-01-01

    The human major histocompatibility complex class II (MHCII) isotype HLA-DR is currently used as an activation marker for T cells. However, whether an endogenous protein expression or a molecular acquisition accounts for the presence of HLA-DR on T cells remains undetermined and still controversial....... In order to further characterize this phenomenon, we compared several aspects of the presence of the HLA-DR protein to the presence of associated mRNA (HLA-DRB1), focusing on human T cells from peripheral blood of healthy individuals. Using a flow cytometric approach, we determined that the HLA......-DR observed on CD4+ T cells was almost exclusively cell surface-associated, while for autologous CD19+ B cells, the protein could be located in the plasma membrane as well as in the cytoplasm. Moreover, negligible expression levels of HLA-DRB1 were found in CD4+ T cells, using an HLA-DRB1 allele-specific q...

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

    Science.gov (United States)

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

    2015-11-16

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

  3. Electroacupuncture Attenuates Ovalbumin-Induced Allergic Asthma via Modulating CD4+CD25+ Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Youngjoo Kwon

    2012-01-01

    Full Text Available A mouse pulmonary hypersensitivity experimental model that mimics human asthma was developed, and electroacupuncture (EA treatment was shown to reduce allergic inflammatory processes. In addition, we also assessed whether the beneficial effects of EA on allergic asthma could be correlated with CD4+CD25+Foxp3+ regulatory T cells (Treg. Cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in the EA-treated groups when compared to the OVA and anti-CD25 Ab-injected (Treg depletion groups. Furthermore, total BAL cells were reduced in the EA groups when compared to other groups. Interestingly, the population of CD4+CD25+Foxp3+Tregs in pneumonocytes increased in EA-treated group when compared to OVA and Treg depletion groups. These results imply that EA stimulation at ST 36 may affect CD4+CD25+Foxp3+ Treg in an OVA-induced experimental model and may enhance Treg function by suppressing other T cells and limiting the immune response.

  4. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation.

    Science.gov (United States)

    Makita, Shin; Kanai, Takanori; Nemoto, Yasuhiro; Totsuka, Teruji; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Yamamoto, Masafumi; Kiyono, Hiroshi; Watanabe, Mamoru

    2007-04-15

    It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (T(REG)) cells play an important role in the normal intestinal homeostasis, but also that its dysregulation of immune response leads to the development of inflammatory bowel disease. In this study, we demonstrate that murine CD4(+)CD25(+) T cells residing in the intestinal lamina propria (LP) constitutively express CTLA-4, glucocorticoid-induced TNFR, and Foxp3 and suppress proliferation of responder CD4(+) T cells in vitro. Furthermore, cotransfer of intestinal LP CD4(+)CD25(+) T cells prevents the development of chronic colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells into SCID mice. When lymphotoxin (LT)alpha-deficient intercrossed Rag2 double knockout mice (LTalpha(-/-) x Rag2(-/-)), which lack mesenteric lymph nodes and Peyer's patches, are transferred with CD4(+)CD45RB(high) T cells, they develop severe wasting disease and chronic colitis despite the delayed kinetics as compared with the control LTalpha(+/+) x Rag2(-/-) mice transferred with CD4(+)CD45RB(high) T cells. Of note, when a mixture of splenic CD4(+)CD25(+) T(REG) cells and CD4(+)CD45RB(high) T cells are transferred into LTalpha(-/-) x Rag2(-/-) recipients, CD4(+)CD25(+) T(REG) cells migrate into the colon and prevent the development of colitis in LTalpha(-/-) x Rag2(-/-) recipients as well as in the control LTalpha(+/+) x Rag2(-/-) recipients. These results suggest that the intestinal LP harboring CD4(+)CD25(+) T(REG) cells contributes to the intestinal immune suppression. PMID:17404275

  5. Autocrine production of beta-chemokines protects CMV-Specific CD4 T cells from HIV infection.

    Directory of Open Access Journals (Sweden)

    Joseph P Casazza

    2009-10-01

    Full Text Available Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1alpha and MIP-1beta mRNA, resulting in a rapid increase in production of MIP-1alpha and MIP-1beta after cognate antigen stimulation. Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of beta-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1beta contained 10 times less Gag DNA than did those which failed to produce MIP-1beta. These data suggest that CD4+ T cells which produce MIP-1alpha and MIP-1beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.

  6. Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3

    OpenAIRE

    Chen, Wanjun; Jin, Wenwen; Hardegen, Neil; Lei, Ke-Jian; Li, Li; Marinos, Nancy; McGrady, George; Wahl, Sharon M.

    2003-01-01

    CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25− naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transformin...

  7. Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells

    Science.gov (United States)

    Provine, Nicholas M.; Larocca, Rafael A.; Aid, Malika; Penaloza-MacMaster, Pablo; Badamchi-Zadeh, Alexander; Borducchi, Erica N.; Yates, Kathleen B.; Abbink, Peter; Kirilova, Marinela; Ng’ang’a, David; Bramson, Jonathan; Haining, W. Nicholas; Barouch, Dan H.

    2016-01-01

    CD4+ T cell help is critical for optimal CD8+ T cell memory differentiation and maintenance in many experimental systems. Additionally, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced antigen or pathogen clearance. Here we demonstrate that absence of CD4+ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8+ T cell functionality and differentiation. Unhelped CD8+ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 days of immunization. Unhelped CD8+ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4+ T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4+ T cell help is required to promote both the expansion and acquisition of effector functions by CD8+ T cells, which is accomplished by preventing immediate dysfunction. PMID:27448585

  8. The early activation marker CD69 regulates the expression of chemokines and CD4 T cell accumulation in intestine.

    Directory of Open Access Journals (Sweden)

    Katarina Radulovic

    Full Text Available Migration of naïve and activated lymphocytes is regulated by the expression of various molecules such as chemokine receptors and ligands. CD69, the early activation marker of C-type lectin domain family, is also shown to regulate the lymphocyte migration by affecting their egress from the thymus and secondary lymphoid organs. Here, we aimed to investigate the role of CD69 in accumulation of CD4 T cells in intestine using murine models of inflammatory bowel disease. We found that genetic deletion of CD69 in mice increases the expression of the chemokines CCL-1, CXCL-10 and CCL-19 in CD4(+ T cells and/or CD4(- cells. Efficient in vitro migration of CD69-deficient CD4 T cells toward the chemokine stimuli was the result of increased expression and/or affinity of chemokine receptors. In vivo CD69(-/- CD4 T cells accumulate in the intestine in higher numbers than B6 CD4 T cells as observed in competitive homing assay, dextran sodium sulphate (DSS-induced colitis and antigen-specific transfer colitis. In DSS colitis CD69(-/- CD4 T cell accumulation in colonic lamina propria (cLP was associated with increased expression of CCL-1, CXCL-10 and CCL-19 genes. Furthermore, treatment of DSS-administrated CD69(-/- mice with the mixture of CCL-1, CXCL-10 and CCL-19 neutralizing Abs significantly decreased the histopathological signs of colitis. Transfer of OT-II×CD69(-/- CD45RB(high CD4 T cells into RAG(-/- hosts induced CD4 T cell accumulation in cLP. This study showed CD69 as negative regulator of inflammatory responses in intestine as it decreases the expression of chemotactic receptors and ligands and reduces the accumulation of CD4 T cells in cLP during colitis.

  9. Hsp70 enhances presentation of FMDV antigen to bovine CD4+ T cells in vitro

    OpenAIRE

    McLaughlin, Kerry; Seago, Julian; Robinson, Lucy; Kelly, Charles; Charleston, Bryan

    2010-01-01

    International audience Foot-and-mouth disease virus (FMDV) is the causative agent of a highly contagious acute vesicular disease affecting cloven-hoofed animals, including cattle, sheep and pigs. The current vaccine induces a rapid humoral response, but the duration of the protective antibody response is variable, possibly associated with a variable specific CD4+ T cell response. We investigated the use of heat shock protein 70 (Hsp70) as a molecular chaperone to target viral antigen to th...

  10. CD4+ T cell immunity to the Burkholderia pseudomallei ABC transporter LolC in melioidosis

    OpenAIRE

    Chu, Karen K.; Tippayawat, Patcharaporn; Walker, Nicola J.; Harding, Sarah V.; Atkins, Helen S.; Maillere, Bernard; Bancroft, Gregory J; Lertmemongkolchai, Ganjana; Altmann, Daniel M

    2010-01-01

    Burkholderia pseudomallei (Bp) causes melioidosis, a disease with a wide range of possible outcomes, from seroconversion and dormancy to sepsis and death. This spectrum of host-pathogen interactions poses challenging questions about heterogeneity in immunity to Bp. Models show protection to be dependent on CD4+ cells and IFNγ, but little is known about specific target antigens. Having previously implicated the ABC transporter, LolC, in protective immunity, we here use epitope prediction, HLA ...

  11. Subsets of human CD4+ regulatory T cells express the peripheral homing receptor CXCR3

    OpenAIRE

    Hoerning, André; Koss, Kerith; Datta, Dipak; Boneschansker, Leonard; Jones, Caroline N.; Wong, Ian Y.; Irimia, Daniel; Calzadilla, Katiana; Benitez, Fanny; Hoyer, Peter F.; Harmon, William E.; Briscoe, David M.

    2011-01-01

    Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that ~30–40% of human CD25hi FOXP3+ CD4+ Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-γ production were significantly higher using CXCR3-depleted versus undeplete...

  12. Nutritional status and CD4 cell counts in patients with HIV/AIDS receiving antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Ana Celia Oliveira dos Santos

    2013-12-01

    Full Text Available Introduction Even with current highly active antiretroviral therapy, individuals with AIDS continue to exhibit important nutritional deficits and reduced levels of albumin and hemoglobin, which may be directly related to their cluster of differentiation 4 (CD4 cell counts. The aim of this study was to characterize the nutritional status of individuals with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS and relate the findings to the albumin level, hemoglobin level and CD4 cell count. Methods Patients over 20 years of age with AIDS who were hospitalized in a university hospital and were receiving antiretroviral therapy were studied with regard to clinical, anthropometric, biochemical and sociodemographic characteristics. Body mass index, percentage of weight loss, arm circumference, triceps skinfold and arm muscle circumference were analyzed. Data on albumin, hemoglobin, hematocrit and CD4 cell count were obtained from patient charts. Statistical analysis was performed using Fisher's exact test, Student's t-test for independent variables and the Mann-Whitney U-test. The level of significance was set to 0.05 (α = 5%. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS 17.0 software for Windows. Results Of the 50 patients evaluated, 70% were male. The prevalence of malnutrition was higher when the definition was based on arm circumference and triceps skinfold measurement. The concentrations of all biochemical variables were significantly lower among patients with a body mass index of less than 18.5kg/m2. The CD4 cell count, albumin, hemoglobin and hematocrit anthropometric measures were directly related to each other. Conclusions These findings underscore the importance of nutritional follow-up for underweight patients with AIDS, as nutritional status proved to be related to important biochemical alterations.

  13. Friend of GATA-1 Represses GATA-3–dependent Activity in CD4+ T Cells

    OpenAIRE

    Zhou, Meixia; Ouyang, Wenjun; Gong, Qian; Katz, Samuel G.; White, J. Michael; Orkin, Stuart H.; Murphy, Kenneth M.

    2001-01-01

    The development of naive CD4+ T cells into a T helper (Th) 2 subset capable of producing interleukin (IL)-4, IL-5, and IL-13 involves a signal transducer and activator of transcription (Stat)6-dependent induction of GATA-3 expression, followed by Stat6-independent GATA-3 autoactivation. The friend of GATA (FOG)-1 protein regulates GATA transcription factor activity in several stages of hematopoietic development including erythrocyte and megakaryocyte differentiation, but whether FOG-1 regulat...

  14. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus.

    Science.gov (United States)

    Zhang, Xiaoming; Mozeleski, Brian; Lemoine, Sebastien; Dériaud, Edith; Lim, Annick; Zhivaki, Dania; Azria, Elie; Le Ray, Camille; Roguet, Gwenaelle; Launay, Odile; Vanet, Anne; Leclerc, Claude; Lo-Man, Richard

    2014-05-28

    The T cell compartment is considered to be naïve and dedicated to the development of tolerance during fetal development. We have identified and characterized a population of fetally developed CD4 T cells with an effector memory phenotype (TEM), which are present in cord blood. This population is polyclonal and has phenotypic features similar to those of conventional adult memory T cells, such as CD45RO expression. These cells express low levels of CD25 but are distinct from regulatory T cells because they lack Foxp3 expression. After T cell receptor activation, neonatal TEM cells readily produced tumor necrosis factor-α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We also detected interferon-γ (IFN-γ)-producing T helper 1 (TH1) cells and interleukin-4 (IL-4)/IL-13-producing TH2-like cells, but not IL-17-producing cells. We used chemokine receptor expression patterns to divide this TEM population into different subsets and identified distinct transcriptional programs using whole-genome microarray analysis. IFN-γ was found in CXCR3(+) TEM cells, whereas IL-4 was found in both CXCR3(+) TEM cells and CCR4(+) TEM cells. CCR6(+) TEM cells displayed a genetic signature that corresponded to TH17 cells but failed to produce IL-17A. However, the TH17 function of TEM cells was observed in the presence of IL-1β and IL-23. In summary, in the absence of reported pathology or any major infectious history, T cells with a memory-like phenotype develop in an environment thought to be sterile during fetal development and display a large variety of inflammatory effector functions associated with CD4 TH cells at birth. PMID:24871133

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

    Science.gov (United States)

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

    2005-09-01

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

  16. Transient Treg-cell depletion in adult mice results in persistent self-reactive CD4(+) T-cell responses.

    Science.gov (United States)

    Nyström, Sofia N; Bourges, Dorothée; Garry, Sarah; Ross, Ellen M; van Driel, Ian R; Gleeson, Paul A

    2014-12-01

    Depletion of Foxp3(+) CD4(+) regulatory T cells (Treg) in adults results in chronic inflammation and autoimmune disease. However, the impact of transient Treg-cell depletion on self-reactive responses is poorly defined. Here, we studied the effect of transient depletion of Treg cells on CD4(+) T-cell responses to endogenous self-antigens. Short-term ablation of Treg cells in mice resulted in rapid activation of CD4(+) T cells, increased percentage of IFN-γ(+) and Th17 cells in lymphoid organs, and development of autoimmune gastritis. To track self-reactive responses, we analyzed the activation of naïve gastric-specific CD4(+) T cells. There was a dramatic increase in proliferation and acquisition of effector function of gastric-specific T cells in the stomach draining LNs of Treg-cell-depleted mice, compared with untreated mice, either during Treg-cell depletion or after Treg-cell reconstitution. Moreover, the hyperproliferation of gastric-specific T cells in the Treg-cell-ablated mice was predominantly antigen-dependent. Transient depletion of Treg cells resulted in a shift in the ratio of peripheral:thymic Treg cells in the reemerged Treg-cell population, indicating an altered composition of Treg cells. These findings indicate that transient Treg-cell depletion results in ongoing antigen-driven self-reactive T-cell responses and emphasize the continual requirement for an intact Treg-cell population. PMID:25231532

  17. Public T cell receptors confer high-avidity CD4 responses to HIV controllers.

    Science.gov (United States)

    Benati, Daniela; Galperin, Moran; Lambotte, Olivier; Gras, Stéphanie; Lim, Annick; Mukhopadhyay, Madhura; Nouël, Alexandre; Campbell, Kristy-Anne; Lemercier, Brigitte; Claireaux, Mathieu; Hendou, Samia; Lechat, Pierre; de Truchis, Pierre; Boufassa, Faroudy; Rossjohn, Jamie; Delfraissy, Jean-François; Arenzana-Seisdedos, Fernando; Chakrabarti, Lisa A

    2016-06-01

    The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure. PMID:27111229

  18. CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Birjandi, Shirin Z; Palchevskiy, Vyacheslav; Xue, Ying Ying; Nunez, Stefanie; Kern, Rita; Weigt, S Sam; Lynch, Joseph P; Chatila, Talal A; Belperio, John A

    2016-08-01

    Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-β) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis. PMID:27317904

  19. SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

    Directory of Open Access Journals (Sweden)

    Shravan Madireddi

    Full Text Available Tumors convert conventional CD4(+ T cells into induced CD4(+CD25(+FoxP3(+ T regulatory (iTreg cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4(+ T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4(+and CD8(+ T effector (Teff cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our knowledge, that signaling through 4-1BB inhibits antigen- and TGF-β-driven conversion of naïve CD4(+FoxP3(- T cells into iTreg cells via stimulation of IFN-γ production by CD4(+FoxP3(- T cells. Importantly, treatment with SA-4-1BBL blocked the conversion of CD4(+FoxP3(- T cells into Treg cells by EG.7 tumors. Taken together with our previous studies, these results show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i inhibiting the conversion of CD4(+FoxP3(- T cells into iTreg cells and ii endowing Teff cells refractory to inhibition by Treg cells. Given the dominant role of Treg cells in tumor immune evasion mechanisms, 4-1BB signaling represents an attractive target for favorably tipping the Teff:Treg balance toward Teff cells with important implications for cancer immunotherapy.

  20. Isolated CD39 Expression on CD4+ T Cells Denotes both Regulatory and Memory Populations

    OpenAIRE

    Zhou, Q.; Yan, J.; Putheti, P.; Wu, Y.; X. Sun; Toxavidis, V.; Tigges, J.; Kassam, N.; Enjyoji, K.; Robson, S C; Strom, T. B.; Gao, W.

    2009-01-01

    Foxp3+ regulatory T cells (Tregs) express both ectoenzymes CD39 and CD73, which in tandem hydrolyze pericellular ATP into adenosine, an immunoinhibitory molecule that contributes to Treg suppressive function. Using Foxp3GFP knockin mice, we noted that the mouse CD4+CD39+ T-cell pool contains two roughly equal size Foxp3+ and Foxp3− populations. While Foxp3+CD39+ cells are CD73bright and are the bone fide Tregs, Foxp3−CD39+ cells do not have suppressive activity and are CD44+CD62L−CD25−CD73dim...

  1. Dichotomy in the human CD4+ T-cell response to Leishmania parasites

    DEFF Research Database (Denmark)

    Kemp, M; Kurtzhals, J A; Kharazmi, A;

    1994-01-01

    Leishmania parasites cause human diseases ranging from self-healing cutaneous ulcers to fatal systemic infections. In addition, many individuals become infected without developing disease. In mice the two subsets of CD4+ T cells, Th1 and Th2, have different effects on the outcome of experimental...... Leishmania infections. Th1 cells producing interferon-gamma (IFN-gamma) mediate resistance, whereas Th2 cells producing interleukin-4 (IL-4) and IL-10 are associated with susceptibility and exacerbation. Evidence is accumulating that a Th1/Th2 dichotomy in the T-cell response to Leishmania exists also...

  2. Germinal center B cell depletion diminishes CD4+ follicular T helper cells in autoimmune mice.

    Directory of Open Access Journals (Sweden)

    Isharat Yusuf

    Full Text Available BACKGROUND: Continuous support from follicular CD4(+ T helper (Tfh cells drives germinal center (GC responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. METHODS AND FINDING: Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. CONCLUSION: These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.

  3. Identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade#

    OpenAIRE

    Pauken, Kristen E.; Nelson, Christine E; Martinov, Tijana; Spanier, Justin A.; Heffernan, James R; Sahli, Nathanael L; Quarnstrom, Clare F; Osum, Kevin C; Schenkel, Jason M.; Jenkins, Marc K.; Blazar, Bruce R; Vezys, Vaiva; Fife, Brian T.

    2015-01-01

    Programmed Death (PD)-1 promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD-L1 regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in Type 1 Diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additiona...

  4. CD4(+CD25(-Nrp1(+ T cells synergize with rapamycin to prevent murine cardiac allorejection in immunocompetent recipients.

    Directory of Open Access Journals (Sweden)

    Qing Yuan

    Full Text Available Besides CD4(+CD25(+Foxp3(+ regulatory T cells (Tregs, other immunosuppressive T cells also participated in the regulation of immune tolerance. Reportedly, neuropilin-1 (Nrp1 might be one of the molecules by which regulatory cells exert their suppressive effects. Indeed, CD4(+CD25(-Nrp1(+ T cells exhibit potent suppressive function in autoimmune inflammatory responses. Here we investigated the specific role of CD4(+CD25(-Nrp1(+ T cells in the setting of the transplant immune response. Through MLR assays, we found that CD4(+CD25(-Nrp1(+ T cells suppressed the proliferation of naive CD4(+CD25(- T cells activated by allogeneic antigen-stimulation. Adoptive transfer of CD4(+CD25(-Nrp1(+ T cells synergized with rapamycin to induce long-term graft survival in fully MHC-mismatched murine heart transplantation, which was associated with decreased IFN-γ, IL-17 and increased IL-10, TGF-β, Foxp3 and Nrp1 expression in the grafts. Importantly, our data indicated that CD4(+CD25(-Nrp1(+ T cell transfer augments the accumulation of Tregs in the recipient, and creates conditions that favored induction of hyporesponsiveness of the T effector cells. In conclusion, this translational study indicates the possible therapeutic potential of CD4(+CD25(-Nrp1(+ T cells in preventing allorejection. CD4(+Nrp1(+ T cells might therefore be used in bulk as a population of immunosuppressive cells with more beneficial properties concerning ex vivo isolation as compared to Foxp3(+ Tregs.

  5. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes.

    Science.gov (United States)

    Every, Alison L; Kramer, David R; Mannering, Stuart I; Lew, Andrew M; Harrison, Leonard C

    2006-04-15

    Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T(reg)) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ T(reg) that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+ CD25+ T(reg), CD4+ T(reg) induced by proinsulin DNA were both CD25+ and CD25- and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T(reg) and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T(reg), but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity. PMID:16585551

  6. Higher Frequency of CD4+CXCR5+ICOS+PD1+ T Follicular Helper Cells in Patients With Infectious Mononucleosis.

    Science.gov (United States)

    Liu, Jinlin; Zhou, Yonglie; Yu, Qinghua; Zhao, Zhao; Wang, Huan; Luo, Xiaoming; Chen, Yanxia; Zhu, Zhongliang; Chen, Guoqing; Wu, Mao; Qiu, Liannv

    2015-11-01

    Follicular helper T (Tfh) cells are recognized as a distinct CD4helper T cell subset, and mainly dysregulated in the autoimmune disease, whether it plays a role in the infectious mononucleosis (IM) diseases is unknown. In this study, we found that the CD4CXCR5 Tfh cells were not significantly changed, but the CD4CXCR5ICOS and CD4CXCR5ICOSPD1 Tfh subsets were significantly increased in the IM patients, and all these cells were significantly changed after antiviral therapy. Second, only the numbers of CD4CXCR5ICOSPD1 Tfh cells correlated with the Epstein-Barr virus (EBV) DNA load, negatively correlated with the numbers of naive B cells and amount of IL-21, and positively correlated with the numbers of plasma cells, memory B cells, and atypical lymphocytes. Third, the frequency of CD4CXCR5ICOSPD1 Tfh subset was significantly higher in lymphadenectasis or hepatosplenomegaly patients, and associated with the level of alanine aminotransferase (ALT). All together, our findings discovered this CD4CXCR5ICOSPD1 Tfh cell subset might play an important role in the pathogenesis of IM. PMID:26559315

  7. Biological features of intrahepatic CD4+CD25+ T cells in the naturally tolerance of rat liver transplantation

    Institute of Scientific and Technical Information of China (English)

    LU Ling; ZHANG Feng; PU Liyong; YAO Aihua; YU Yue; SUN Beicheng; LI Guoqiang

    2007-01-01

    The biological features of intrahepatic CD4+CD25+ T regulatory cells in the naturally tolerance of rat liver transplantation were explored.Orthotopic liver transplantation was performed in two allogeneic rat strain combinations,one with fatal immunosuppression despite a complete major histocompatibility complex mismatch.The subjects were divided into three groups according to different donors and recipients [Tolerance group:LEW-to-DA;Rejection group:DA-to-LEW;Syngegnic group(control group):DAto-DA].The proportion of intrahepatic CD4+CD25+ T cells from three groups was determined by flow cytometry(FCM)in different time.The intrahepaitc CD4+CD25+ T cells were isolated by magnetic activated cell sorting(MACS)method and identified by FCM.The Foxp3 mRNA was detected by reverse transcriptase polymerase chain reaction(RT-PCR).And their suppression on the proliferation of CD4+CD25- T effector cells was analyzed by cell proliferation assay in vitro.Beginning immediately after transplantation,the proportion of Treg cells increased over time in both allogeneic groups but was significantly greater in the Rejection group.The proportion of Treg cells declined after day 5,and such reduction was more dramatic in the Rejection group than in the Tolerance group.Animals in the Tolerance group showed a second increase in the proportion after day 14.Intrahepatic CD4+CD25+T cells isolated from spontaneous tolerance models inhibited the proliferation of mixed lymphocyte reaction.The purity of CD4+CD25+ T cells sorted by MACS was 86%-93%.The CD4+CD25+ T cells could specifically express the Foxp3 gene compared with CD4+CD25- T cells.In vitro,the spleen cells from LEW rats can irritate the proliferation of CD4+CD25+ T cells more obviously than the syngegnic spleen cells.CD4+CD25+ Tr cells could suppress the proliferation of CD4+CD25- T cells,but the inhibition was reversed by exogenous IL-2(200 U/mL).The CD4+CD25+ T regulatory cells specifically express the Foxp3 gene,which may play an

  8. Changes and clinical significance of CD4+CD25+Foxp3+ regulatory T cell and IL-10,TGF-β1 in steroid-resistant asthma patients of peripheral blood%激素抵抗性哮喘患者外周血CD4+CD25+Foxp3+调节性T细胞及IL-10、TGF-β1的变化及意义

    Institute of Scientific and Technical Information of China (English)

    钱一龙; 赵振中; 朱建俊; 谢中华; 王珠美

    2013-01-01

    目的 观察激素抵抗性哮喘(SRA)患者外周血CD4+CD25+Foxp3+调节性T细胞(Treg)及白介素10(IL-10)、转化生长因子β1(TGF-β1)的变化,分析其在SRA发病机制中的作用.方法 采用流式细胞术检测40例SRA患者(激素抵抗组)外周血单个核细胞CD4+CD25+Foxp3+ Treg数目,并计算CD4+CD25+Foxp3+ Treg占CD4+T淋巴细胞的百分比;酶联免疫吸附试验(ELISA)法检测其血清IL-10、TGF-β1水平,并与激素敏感性患者(激素敏感组,46例)及正常体检者(正常组,30例)进行对比.结果 激素抵抗组患者外周血CD4+CD25+Foxp3+Treg占CD4+T淋巴细胞的百分比、CD4+CD25+Foxp3+Treg绝对值及血清IL-10、TGF-β1水平均明显低于激素敏感组与正常组(P<0.01,P<0.05);激素敏感组患者外周血CD4+CD25+Foxp3+Treg占CD4+T淋巴细胞的百分比、CD4+CD25+Foxp3+Treg绝对值及血清TGF-β1水平明显低于正常组(P<0.01,P<0.05),血清IL-10无明显差异(P>0.05);CD4+CD25+Foxp3+Treg/CD4+T及CD4+CD25+Foxp3+Treg绝对数均与血清IL-10、TGF-β1水平呈明显正相关(P<0.01).结论 SRA患者外周血CD4+CD25+Foxp3+ Treg数目减少及IL-10、TGF-β1含量减低可能与SRA的发生、发展有关.

  9. 雾化吸入变应原对支气管哮喘外周血CD4+CD25+Foxp3+Treg的影响%Effects of Desensitization of Allergen Nebulization on Blood CD4 + CD25 + Foxp3 + Treg in the Prevention and Treatment of Asthma

    Institute of Scientific and Technical Information of China (English)

    李红华; 赵娟; 张景鸿

    2012-01-01

    Objective To evaluate the effect of allergen nebulization on the ratio of blood CD4 + CD25 + Foxp3 + Treg in asthma. Methods 40 patients with Der. p and Der. f allergy and newly diagnosed uncontrolled moderate persistent bronchial asthma were randomly divided into 2 groups; group A and group B (20 per group). The patients in group B were nebulized with specific allergen twice a week for 6 months. Both groups were treated with salmeterol xinafoate and fluticasone propionate powder. The percentage of CD4 + CD25 + Foxp3 + Treg cells in peripheral blood was determined by flow cytometry. ACT, airway responsiveness and lung function were performed before and after treatment. Results The negative conversion rates of Bronchial Provocation Test in group B were higher than group A significantly. The percentage of CD4 + CD25 + Foxp3 + Treg cells increased in group B when compared with group A(P <0. 05). Conclusion CD4 + CD25 + Foxp3 + T cells played an important immunomudulatory role in immunotherapy of allergen nebulization in treatment of asthma.%目的 探讨CD4+ CD25+ Foxp3+ Treg细胞在哮喘变应原雾化吸入减敏治疗的作用.方法 粉尘螨和屋尘螨点刺阳性的支气管哮喘患者随机分为A组(常规治疗)和B组(变应原吸入减敏),各20例.B组雾化吸入特异性变应原,A组雾化吸入以生理盐水代替,两组给予相同的基础治疗.治疗前、后用流式细胞术(FCM)检测外周血中CD4+CD25+ Foxp3+T细胞占CD4 +T细胞比例;进行哮喘控制评分和肺功能、气道反应性测定.结果 治疗后B组ACT评分高于A组,两组肺功能均有明显增加.B组支气管激发试验转阴率明显高于A组.B组外周血中CD4+ CD25+Foxp3+T细胞占CD4 +T细胞比例较A组明显升高(P<0.05).结论 CD4+ CD25+ Foxp3+T细胞在变应原雾化吸入减敏防治支气管哮喘中发挥免疫调节作用.

  10. Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells

    OpenAIRE

    Meininger, Isabel; Griesbach, Richard A.; Hu, Desheng; Gehring, Torben; Seeholzer, Thomas; Bertossi, Arianna; Kranich, Jan; Oeckinghaus, Andrea; Eitelhuber, Andrea C; Greczmiel, Ute; Gewies, Andreas; Schmidt-Supprian, Marc; Ruland, Jürgen; Brocker, Thomas; Heissmeyer, Vigo

    2016-01-01

    MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4+ T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify...

  11. CD4+ FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome.

    Directory of Open Access Journals (Sweden)

    Young Ah Lee

    Full Text Available We investigated whether the frequency, phenotype, and suppressive function of CD4+ FOXP3+ regulatory T cells (Tregs are altered in young TS patients with the 45,X karyotype compared to age-matched controls.Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4-35.9 years and healthy controls (n = 16 were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (- (n = 7 and TS (+ (n = 17. Tregs sorted for CD4+ CD25bright were co-cultured with autologous CD4+ CD25- target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function.Despite a lower frequency of CD4+ T cells in the TS (- and TS (+ patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively, both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively. There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+ CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+ CD25- T cells was significantly impaired in the TS (- and TS (+ patients compared to controls (P = 0.003 and P = 0.041. Meanwhile, both the TS (- and TS (+ groups had lower frequencies of naïve cells (P = 0.001 for both but higher frequencies of effector memory cells (P = 0.004 and P = 0.002 than did the healthy control group.The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells.

  12. CD4+FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome

    Science.gov (United States)

    Lee, Young Ah; Kim, Hang-Rae; Lee, Jeong Seon; Jung, Hae Woon; Kim, Hwa Young; Lee, Gyung Min; Lee, Jieun; Sim, Ji Hyun; Oh, Sae Jin; Chung, Doo Hyun; Shin, Choong Ho; Yang, Sei Won

    2015-01-01

    Objective We investigated whether the frequency, phenotype, and suppressive function of CD4+FOXP3+ regulatory T cells (Tregs) are altered in young TS patients with the 45,X karyotype compared to age-matched controls. Design and Methods Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4–35.9 years) and healthy controls (n = 16) were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (–) (n = 7) and TS (+) (n = 17). Tregs sorted for CD4+CD25bright were co-cultured with autologous CD4+CD25− target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function. Results Despite a lower frequency of CD4+ T cells in the TS (-) and TS (+) patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively), both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively). There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+CD25− T cells was significantly impaired in the TS (–) and TS (+) patients compared to controls (P = 0.003 and P = 0.041). Meanwhile, both the TS (–) and TS (+) groups had lower frequencies of naïve cells (P = 0.001 for both) but higher frequencies of effector memory cells (P = 0.004 and P = 0.002) than did the healthy control group. Conclusions The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells. PMID:26709833

  13. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells

    OpenAIRE

    Fahlén, Linda; Read, Simon; Gorelik, Leonid; Hurst, Stephen D.; Coffman, Robert L.; Flavell, Richard A.; Powrie, Fiona

    2005-01-01

    CD4+CD25+ regulatory T (T reg) cells play a pivotal role in control of the immune response. Transforming growth factor-β (TGF-β) has been shown to be required for T reg cell activity; however, precisely how it is involved in the mechanism of suppression is poorly understood. Using the T cell transfer model of colitis, we show here that CD4+CD45RBhigh T cells that express a dominant negative TGF-β receptor type II (dnTβRII) and therefore cannot respond to TGF-β, escape control by T reg cells i...

  14. In Vivo Identification and Characterization of CD4+ Cytotoxic T Cells Induced by Virulent Brucella abortus Infection

    Science.gov (United States)

    Martirosyan, Anna; Von Bargen, Kristine; Arce Gorvel, Vilma; Zhao, Weidong; Hanniffy, Sean; Bonnardel, Johnny; Méresse, Stéphane; Gorvel, Jean-Pierre

    2013-01-01

    CD4+ T cells display a variety of helper functions necessary for an efficient adaptive immune response against bacterial invaders. This work reports the in vivo identification and characterization of murine cytotoxic CD4+ T cells (CD4+ CTL) during Brucella abortus infection. These CD4+ CTLs express granzyme B and exhibit immunophenotypic features consistent with fully differentiated T cells. They express CD25, CD44, CD62L ,CD43 molecules at their surface and produce IFN-γ. Moreover, these cells express neither the co-stimulatory molecule CD27 nor the memory T cell marker CD127. We show here that CD4+ CTLs are capable of cytolytic action against Brucella-infected antigen presenting cells (APC) but not against Mycobacterium-infected APC. Cytotoxic CD4+ T cell population appears at early stages of the infection concomitantly with high levels of IFN-γ and granzyme B expression. CD4+ CTLs represent a so far uncharacterized immune cell sub-type triggered by early immune responses upon Brucella abortus infection. PMID:24367519

  15. In vivo identification and characterization of CD4⁺ cytotoxic T cells induced by virulent Brucella abortus infection.

    Science.gov (United States)

    Martirosyan, Anna; Von Bargen, Kristine; Arce Gorvel, Vilma; Zhao, Weidong; Hanniffy, Sean; Bonnardel, Johnny; Méresse, Stéphane; Gorvel, Jean-Pierre

    2013-01-01

    CD4(+) T cells display a variety of helper functions necessary for an efficient adaptive immune response against bacterial invaders. This work reports the in vivo identification and characterization of murine cytotoxic CD4(+) T cells (CD4(+) CTL) during Brucella abortus infection. These CD4(+) CTLs express granzyme B and exhibit immunophenotypic features consistent with fully differentiated T cells. They express CD25, CD44, CD62L ,CD43 molecules at their surface and produce IFN-γ. Moreover, these cells express neither the co-stimulatory molecule CD27 nor the memory T cell marker CD127. We show here that CD4(+) CTLs are capable of cytolytic action against Brucella-infected antigen presenting cells (APC) but not against Mycobacterium-infected APC. Cytotoxic CD4(+) T cell population appears at early stages of the infection concomitantly with high levels of IFN-γ and granzyme B expression. CD4(+) CTLs represent a so far uncharacterized immune cell sub-type triggered by early immune responses upon Brucella abortus infection. PMID:24367519

  16. Antigen-Experienced CD4lo T Cells Are Linked to Deficient Contraction of the Immune Response in Autoimmune Diabetes

    Directory of Open Access Journals (Sweden)

    Sean Linkes

    2010-01-01

    Full Text Available Following proper activation, naïve “CD4lo” T cells differentiate into effector T cells with enhanced expression of CD4 -“CD4hi” effectors. Autoimmune diabetes-prone NOD mice display a unique set of antigen-experienced “CD4lo” T cells that persist after primary stimulation. Here, we report that a population of such cells remained after secondary and tertiary TCR stimulation and produced cytokines upon antigenic challenge. However, when NOD blasts were induced in the presence of rIL-15, the number of antigen-experienced “CD4lo” T cells was significantly reduced. Clonal contraction, mediated in part by CD95-dependent activation-induced cell death (AICD, normally regulates the accumulation of “CD4hi” effectors. Interestingly, CD95 expression was dramatically reduced on the AICD-resistant NOD “CD4lo” T cells. Thus, while autoimmune disease has often been attributed to the engagement of robust autoimmunity, we suggest that the inability to effectively contract the immune response distinguishes benign autoimmunity from progressive autoimmune diseases that are characterized by chronic T cell-mediated inflammation.

  17. Gut-homing CD4+ T cell receptor alpha beta+ T cells in the pathogenesis of murine inflammatory bowel disease

    DEFF Research Database (Denmark)

    Rudolphi, A; Boll, G; Poulsen, S S;

    1994-01-01

    +/+) mice. No antigen receptor-expressing lymphoid cells were found in GALT of congenic C.B-17 scid/scid (scid) mice. The heterotopic transplantation of a full-thickness gut wall graft from the ileum or colon of immunocompetent (C.B-17+/+, BALB/cdm2) donor mice onto immunodeficient scid mice selectively...... reconstituted a CD3+ T cell receptor alpha beta+ CD4+ T cell subset. CD4+ cells of this subset expressed the surface phenotype of mucosa-seeking, memory T cells. In the immunodeficient scid host, this gut-derived CD4+ T cell subset was found in spleen, peritoneal cavity, mesenteric lymph nodes (LN), epithelial...... layer and lamina propria of the small and large intestine, but not in peripheral LN. Scid mice heterotopically transplanted with gut from a congenic, immunocompetent donor developed clinical and histological signs of inflammatory bowel disease (IBD). Hence, the selective repopulation of GALT...

  18. CD4(+), CD25(+), FOXP3 (+) T Regulatory Cell Levels in Obese, Asthmatic, Asthmatic Obese, and Healthy Children.

    Science.gov (United States)

    Donma, Metin; Karasu, Erkut; Ozdilek, Burcu; Turgut, Burhan; Topcu, Birol; Nalbantoglu, Burcin; Donma, Orkide

    2015-08-01

    The aim of this prospective case control study is to determine CD4(+), CD25(+), and FoxP3(+) T regulatory cells (Tregs) and T helper cells (Ths) in obese, asthmatic, asthmatic obese, and healthy children. Obese (n = 40), asthmatic (n = 40), asthmatic obese (n = 40), and healthy children (n = 40) were included in this study. Blood samples collected from children were marked with CD4, CD25, ve Foxp3 in order to detect Tregs and Ths by flow cytometric method. Statistical analyses were performed. p ≤ 0.05 was chosen as meaningful threshold. Tregs exhibiting anti-inflammatory nature were significantly lower in obese (0.16 %; p ≤ 0.001), asthmatic (0.25 %; p ≤ 0.01), and asthmatic obese (0.29 %; p ≤ 0.05) groups than control group (0.38 %). Ths were counted higher in asthma group than control (p ≤ 0.01) and obese (p ≤ 0.001) groups. T cell immunity plays important roles in chronic inflammatory diseases such as obesity and asthma pathogeneses. Decreased numbers of Tregs found in obese, asthmatic, and asthmatic obese children might represent a challenge of these cells. PMID:25655390

  19. Naturally Occurring Self-Reactive CD4+CD25+ Regulatory T Cells: Universal Immune Code

    Institute of Scientific and Technical Information of China (English)

    Nafiseh Pakravan; Agheel Tabar Molla Hassan; Zuhair Muhammad Hassan

    2007-01-01

    Naturally occurring thymus-arisen CD4+CD25+ regulatory T (Treg) cells are considered to play a central role in self-tolerance. Precise signals that promote the development of Treg cells remain elusive, but considerable evidence suggests that costimulatory molecules, cytokines, the nature of the TCR and the niche or the context in which the T cell encounters antigen in the thymus play important roles. Analysis of TCR from Treg cells has demonstrated that a large proportion of this population has a higher avidity to self-antigen in comparison with TCR from CD4+CD25- cells and that peripheral antigen is required for their development, maintenance, or expansion. Treg cells have been shown to undergo expansion in the periphery, likely regulated by the presence of self-antigen. Many studies have shown that the involvement of Treg cells in the tolerance induction is antigen-specific, even with MHC-mismatched,in transplantation/graft versus host disease (GVHD), autoimmunity, cancer, and pregnancy. Theses studies concluded a vital role for self-reactive Treg cells in maintenance of the body integrity. Based on those studies, we hypothesize that self-reactive Treg cells are shared among all healthy individuals and recognize same self-antigens and their TCR encodes for few dominant antigens of each organ which defines the healthy self. These dominant self antigens can be regarded as "universal immune code".

  20. How Diverse-CD4 Effector T Cells and their Functions

    Institute of Scientific and Technical Information of China (English)

    Yisong Y. Wan; Richard A. Flavell

    2009-01-01

    CD4 effector T cells, also called helper T (Th) cells, are the functional cells for executing immune functions. Balanced immune responses can only be achieved by proper regulation of the differentiation and function of Th cells. Dysregulated Th cell function of ten leads to inefficient clearance of pathogens and causes inflammatory diseases and autoimmunity. Since the establishment of the Th1–Th2 dogma in the 1980s, different lineages of effector T cells have been identified that not only promote but also suppress immune responses. Through years of collective efforts, much information was gained on the function and regulation of different subsets of Th cells. In this review, we attempt to sample the essence of what has been learnt in this field over the past two decades. We will discuss the classification and immunological functions of effector T cells, the determinants for effector T cell differentiation,as well as the relationship between different lineages of effector T cells.

  1. ART therapy affect CD4+FoxP3+regulatory T cells in disease progression of HIV-1 infection%ART治疗对HIV感染者CD4+FoxP3+T细胞水平的影响

    Institute of Scientific and Technical Information of China (English)

    樊竑冶; 董冠军; 傅更锋; 还锡萍; 羊海涛; 王建军; 侯亚义

    2012-01-01

    目的:探索抗逆转录病毒疗法(ART)治疗在HIV-1疾病进程中对调节性T细胞(Treg细胞)的影响,并探讨Treg细胞频率在HIV-1疾病进程中的作用.方法:抽取114例(男96例、女18例)HIV-1阳性患者及17例健康对照者外周血,应用流式细胞术检测Treg细胞,并分析其表达水平(频率和绝对数)在 HIV-1疾病进程中的变化趋势及其与CD4+细胞绝对数之间的相关性.结果:随着HIV-1感染者病情进展,患者外周血中Treg细胞绝对数趋向下降并且与CD4+T细胞绝对数呈正相关,而Treg细胞频率趋向升高并且与CD4+T细胞绝对数呈负相关.Treg细胞频率及绝对数在ART治疗无症状HIV-1阳性感染者中显著降低,而在AIDS患者中却显著升高.结论:Treg细胞参与艾滋病免疫发病过程,并且在HIV-1感染的不同阶段,ART治疗对Treg细胞水平具有一定的影响,提示通过控制Treg细胞的水平可能有助于HIV-1感染疾病的临床控制.%Objective: To understand the changes of CD4 + FoxP3 + regulatory T cells during disease progression of HIV-1 infection with anti-retroviral therapy (ART). Methods: 114 patients HIV-1 positively infected and 17 healthy controls were randomly enrolled. The percentages and absolute counts of Treg cells were detected by using flow cytometry and the correlation of Treg cells with the absolute CD4 + T cells was analyzed in the process of disease progression of HIV-1 infection with ART. Results: With HIV-1 disease progression, the absolute counts of Treg cells in HIV-1 positive peripheral blood tended to decrease and positively correlated with the absolute counts of CD4 + T cells, while the frequency of Treg cells increased and negatively correlated with the absolute counts of CD4 + T cells. Both the frequency and absolute number of Treg cells in HIV-1 positive infected asymptomatic patients with ART treatment were significantly reduced, on the contrary they were significantly higher in patients with AIDS

  2. Selective Priming and Expansion of Antigen-Specific Foxp3- CD4+ T cells during Listeria monocytogenes infection

    OpenAIRE

    Ertelt, James M.; Rowe, Jared H.; Johanns, Tanner M.; Lai, Joseph C.; McLachlan, James B.; Way, Sing Sing

    2009-01-01

    The Foxp3-expressing subset of regulatory CD4+ T cells have defined antigen-specificity and play essential roles in maintaining peripheral tolerance by suppressing the activation of self-reactive T cells. Similarly during chronic infection, pathogen-specific Foxp3-expressing CD4+ T cells expand and actively suppress pathogen-specific effector T cells. Herein, we used MHC class II tetramers and Foxp3gfp knock-in mice to track the kinetics and magnitude whereby pathogen-specific Foxp3+CD4+ and ...

  3. Changes in Th1 cells and CD4+CD25+Treg cells in non-obese diabetic mice at early stage of diabetes

    Directory of Open Access Journals (Sweden)

    Hong-jun WANG

    2013-11-01

    Full Text Available Objective To investigate the changes in Th1 cells and CD4+CD25+Treg cells in non-obese diabetic (NOD mice at early stage of diabetes, and to evaluate the significance of these changes. Methods Four week- (group A, 8 week- (group B and 16 week-old (group C female NOD mice (8 each were used in present study. The spleen, thymus and pancreas were harvested. Th1 and CD4+CD25+Treg cells in spleen were determined by flow cytometer, and the ratios of Th1/CD4+T, CD4+CD25+Treg/CD4+T and Th1/CD4+CD25+Treg were calculated. Subsequently, CD4–CD8–T, CD4+CD8+T, CD4–CD8+T and CD4+CD8–T cells in thymus were determined by flow cytometer, and the ratio of CD25+Treg/CD4+CD8–T was calculated. The histopathological changes in pancreas were also evaluated by HE staining and immunohistochemistry staining. Results The proportion of Th1 cells in spleen and the ratios of Th1/CD4+T and Th1/CD4+CD25+Treg were higher significantly in group C than in group A and B. However, no significant differences were found in the proportion of spleen CD4+CD25+Treg cells and the ratio of CD4+CD25+Treg/CD4+T among the three groups. Compared with group A, no obvious changes were found in thymus CD4–CD8–T, CD4+CD8+T, CD4–CD8+T and CD4+CD8–T cells in group B and C, but the ratio of thymus CD25+Treg/CD4+CD8–T increased significantly in group B and C. Lymphocytic infiltration was observed in pancreatic islets of group B and C as shown with HE staining, but Foxp3+T cells were not seen in pancreatic islets by immunohistochemistry. Conclusion Th1 cells are gradually increased at early stage of diabetes in NOD mice, but CD4+CD25+Treg cells are relatively default. These changes may play an important role in the progress of diabetes. DOI: 10.11855/j.issn.0577-7402.2013.11.004

  4. High-throughput sequencing reveals restricted TCR Vβ usage and public TCRβ clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes.

    Science.gov (United States)

    Marrero, Idania; Aguilera, Carlos; Hamm, David E; Quinn, Anthony; Kumar, Vipin

    2016-06-01

    Islet-reactive memory CD4(+) T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCRβ repertoire of memory CD4(+) T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCRβ repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCRβ overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCRβ clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (Vβ8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR Vβ8.2 chain led to protection from diabetes, suggesting a critical role for Vβ8.2(+) CD4(+) memory T cells in T1D. These results suggest that memory CD4(+) T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D. PMID:27161799

  5. Human rotavirus specific T cells: quantification by ELISPOT and expression of homing receptors on CD4+ T cells

    International Nuclear Information System (INIS)

    Using an intracellular cytokine assay, we recently showed that the frequencies of rotavirus (RV)-specific CD4+ and CD8+ T cells secreting INFγ, circulating in RV infected and healthy adults, are very low compared to the frequencies of circulating cytomegalovirus (CMV) reactive T cells in comparable individuals. In children with acute RV infection, these T cells were barely or not detectable. In the present study, an ELISPOT assay enabled detection of circulating RV-specific INFγ-secreting cells in children with RV diarrhea but not in children with non-RV diarrhea without evidence of a previous RV infection. Using microbead-enriched CD4+ and CD8+ T cell subsets, IFNγ-secreting RV-specific CD8+ but not CD4+ T cells were detected in recently infected children. Using the same approach, both CD4+ and CD8+ RV-specific T cells were detected in healthy adults. Furthermore, stimulation of purified subsets of PBMC that express lymphocyte homing receptors demonstrated that RV-specific INFγ-secreting CD4+ T cells from adult volunteers preferentially express the intestinal homing receptor α4β7, but not the peripheral lymph node homing receptor L-selectin. In contrast, CMV-specific INFγ-secreting CD4+ T cells preferentially express L-selectin but not α4β7. These results suggest that the expression of homing receptors on virus-specific T cells depends on the organ where these cells were originally stimulated and that their capacity to secrete INFγ is independent of the expression of these homing receptors

  6. The Transmembrane E3 Ligase GRAIL Ubiquitinates and Degrades CD83 on CD4 T Cells1

    OpenAIRE

    Su, Leon L.; Iwai, Hideyuki; Lin, Jack T; Fathman, C. Garrison

    2009-01-01

    Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes, including T cell activation and tolerance. We have previously demonstrated that GRAIL (gene related to anergy in lymphocytes), a transmembrane RING finger ubiquitin E3 ligase, initially described as induced during the induction of CD4 T cell anergy, is also expressed in resting CD4 T cells. In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marke...

  7. Separation and Amplification of CD4 + CD25 + Regulatory T Cells from Sensitized Mice%致敏小鼠CD4+CD25+调节性T细胞磁珠分选及体外扩增

    Institute of Scientific and Technical Information of China (English)

    潘莉; 翁文骏; 许吕宏; 魏菁; 方建培

    2012-01-01

    The aim of this study was to separate and amplify CD4 + CD25 + Treg cells from splenocytes of sensitized nrice. The percentage of CD4 + CD25 + Treg cells was detected by flow cytometty in sensitized and normal control mice. CD4 + T, CD4 + CD25 + Treg and CD4' CD25" T cells were isolated from mouse splenocytes by MACS. CD4 + CD25+ Treg cells were expanded in vitro cultures in addition of CD3/CD28 MACSiBead and IL-2. The activity of cells was detected with 0.4% trypan blue staining. The purity of cells after sorting, the main surface marker and the level of Foxp3 were detected by flow cytometry. The results showed that CD4 + CD25 + Treg cell proportion was higher in sensitized mice than normal control mice ( P 0.05). It is concluded that the sorting of CD4 + CD25 + Treg cells is isolated successfully by MACS without affecting the vitality of target cells. The amplification of CD4 + CD25 + Treg cells is successral in vitro. Expression of surface markers and Faxp3 gene does not obviously change after amplification, so that to establish a practical method to recover and enlarge the amount of CD4 + CD25 + Treg cells in good condition.%本研究探讨致敏小鼠CD4+ CD25+调节性T细胞的分选及体外扩增.流式细胞术检测致敏小鼠及正常小鼠体内CD4+ CD25+ Treg细胞水平,免疫磁珠分选方法从小鼠脾细胞中分选出CD4+T细胞、CD4+ CD25+ Treg细胞和CD4+ CD25-T细胞,负载抗CD3/CD28单克隆抗体MACSiBead联合IL-2共同刺激CD4+ CD25+ Treg细胞进行体外扩增培养,用0.4%台盼蓝染色并计数检测细胞的活性,流式细胞术检测分选后细胞纯度、主要表面标记及Foxp3基因的表达.结果表明:致敏小鼠体内CD4+ CD25+ Treg水平较正常小鼠升高(P<0.05).分选出CD4+ CD25+Treg细胞纯度平均达到87%,细胞活性大于97%,高表达Foxp3基因.体外扩增2周后细胞数扩增倍数能够达到42倍,CD4+ CD25+ Treg细胞所占比例为85.32%,Foxp3表达由(76.92±1.72)%稍下降至(75

  8. Percentage of CD4+, CD8+, and CD25+ T lymphocytes in peripheral blood of pigs in the course of experimental burns and necrectomy

    Directory of Open Access Journals (Sweden)

    Aleksiewicz Roman

    2015-09-01

    Full Text Available The aim of the study was the evaluation of changes in the percentage profile of CD4+, CD8+, and CD25+ T lymphocytes, and their predictive value with respect to the course of experimental skin burns and early necrectomy in pigs. Thirty Large White Landrace pigs of both genders, weighing 50 kg (±2 kg, were used. Burns to their skin were performed with the use of a computer-controlled heating plate, applied to the animal’s body and heated to 2000°C, using 2.5 kg pressure for 10 s. It produced a burn of 30% (±2% of body surface with a range of damage between II b° and III°. In animals of each experimental group fascial necrectomy was performed, according to the testing module. Blood from experimental and non-treated control animals was collected from the external jugular vein before the beginning of the experiment (hour 0 and at 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 h of the experiment. An immune response profile was evaluated using flow cytometry analysis of the level and expression dynamics of CD4+, CD8+, and CD25+ particles on the surface of T lymphocytes. The study demonstrated that experimentally-induced burns in pigs caused cell-mediated immune response reflected in the changes in the percentage of CD4+, CD8+, and CD25+ T lymphocytes, and that early necrectomy in burnt pigs acted in a protective manner for the organism, based on the immunological index values. The study also proved that the dynamics of cell-mediated immunological response intensification determined on the basis of the percentage of CD4+, CD8+, and CD25+ T lymphocytes is conditioned by the size of the burnt surface and the time of necrectomy procedure.

  9. Peripheral CD4+ T cell cytokine responses following human challenge and re-challenge with Campylobacter jejuni.

    Directory of Open Access Journals (Sweden)

    Kelly A Fimlaid

    Full Text Available Campylobacter jejuni is a leading cause of human gastroenteritis worldwide; however, our understanding of the human immune response to C. jejuni infection is limited. A previous human challenge model has shown that C. jejuni elicits IFNγ production by peripheral blood mononuclear cells, a response associated with protection from clinical disease following re-infection. In this study, we investigate T lymphocyte profiles associated with campylobacteriosis using specimens from a new human challenge model in which C. jejuni-naïve subjects were challenged and re-challenged with C. jejuni CG8421. Multiparameter flow cytometry was used to investigate T lymphocytes as a source of cytokines, including IFNγ, and to identify cytokine patterns associated with either campylobacteriosis or protection from disease. Unexpectedly, all but one subject evaluated re-experienced campylobacteriosis after re-challenge. We show that CD4+ T cells make IFNγ and other pro-inflammatory cytokines in response to infection; however, multifunctional cytokine response patterns were not found. Cytokine production from peripheral CD4+ T cells was not enhanced following re-challenge, which may suggest deletion or tolerance. Evaluation of alternative paradigms or models is needed to better understand the immune components of protection from campylobacteriosis.

  10. Sequential Dysfunction and Progressive Depletion of Candida albicans-Specific CD4 T Cell Response in HIV-1 Infection

    Science.gov (United States)

    Liu, Fengliang; Fan, Xiuzhen; Auclair, Sarah; Ferguson, Monique; Sun, Jiaren; Soong, Lynn; Hou, Wei; Redfield, Robert R.; Birx, Deborah L.; Ratto-Kim, Silvia; Robb, Merlin L.; Kim, Jerome H.; Michael, Nelson L.; Hu, Haitao

    2016-01-01

    Loss of immune control over opportunistic infections can occur at different stages of HIV-1 (HIV) disease, among which mucosal candidiasis caused by the fungal pathogen Candida albicans (C. albicans) is one of the early and common manifestations in HIV-infected human subjects. The underlying immunological basis is not well defined. We have previously shown that compared to cytomegalovirus (CMV)-specific CD4 cells, C. albicans-specific CD4 T cells are highly permissive to HIV in vitro. Here, based on an antiretroviral treatment (ART) naïve HIV infection cohort (RV21), we investigated longitudinally the impact of HIV on C. albicans- and CMV-specific CD4 T-cell immunity in vivo. We found a sequential dysfunction and preferential depletion for C. albicans-specific CD4 T cell response during progressive HIV infection. Compared to Th1 (IFN-γ, MIP-1β) functional subsets, the Th17 functional subsets (IL-17, IL-22) of C. albicans-specific CD4 T cells were more permissive to HIV in vitro and impaired earlier in HIV-infected subjects. Infection history analysis showed that C. albicans-specific CD4 T cells were more susceptible to HIV in vivo, harboring modestly but significantly higher levels of HIV DNA, than CMV-specific CD4 T cells. Longitudinal analysis of HIV-infected individuals with ongoing CD4 depletion demonstrated that C. albicans-specific CD4 T-cell response was preferentially and progressively depleted. Taken together, these data suggest a potential mechanism for earlier loss of immune control over mucosal candidiasis in HIV-infected patients and provide new insights into pathogen-specific immune failure in AIDS pathogenesis. PMID:27280548

  11. CD4+CD25+ regulatory T cells: I. Phenotype and physiology

    DEFF Research Database (Denmark)

    Holm, Thomas Lindebo; Nielsen, Janne; Claesson, Mogens H

    2004-01-01

    it has become increasingly clear that regulatory CD4+CD25+ T cells (Treg cells) play an important role in the maintenance of immunological self-tolerance, and that this cell subset exerts its function by suppressing the proliferation or function of autoreactive T cells. Based on human and murine...... observations, this review presents a characterization of the phenotype and functions of the Treg cells in vitro and in vivo. An overview of the surface molecules associated with and the cytokines produced by the Treg cells is given and the origin, activation requirements and mode of action of the Treg cells...... are discussed. Finally, we address the possibility that Treg cells may play a central role in immune homeostasis, regulating not only autoimmune responses, but also immune responses toward foreign antigens....

  12. Elevated IL-6 Receptor Expression on CD4+ T Cells contributes to the increased Th17 Responses in patients with Chronic Hepatitis B

    Directory of Open Access Journals (Sweden)

    Gao Zhiliang

    2011-06-01

    Full Text Available Abstract Background Increased numbers of Interleukin-17-producing CD4+ T cells (Th17 have been found in association with hepatitis B virus (HBV-induced liver injury. However, the mechanism underlying the increase of Th17 responses in patients with HBV infection remains unclear. In this study, we investigate the possible regulatory mechanisms of increased Th17 responses in patients with chronic hepatitis B(CHB. Methods Th17 response and IL-6R expression on CD4+ T cells in peripheral blood samples were determined by flow cytometry. Cytokines TGF-β, IL-1β, IL-6 and IL-17 in plasma and/or supernatant samples were determined by ELISA and the IL-17 and IL-6R mRNA levels were quantified by quantitative real-time reverse polymerase chain reaction. Results All these data indicated that the frequency of periphery Th17 cells is significantly correlated with the percentage of CD4+ T cells expressing IL-6R in CHB patients. CD4+ T cells from patients with CHB, but not those from healthy donors, produced higher levels of IL-17 and had more IL-6R expression upon stimulation with the HBV core antigen (HBcAg in vitro. The PMA/ionomycin and HBcAg -stimulated up-regulation of IL-17 production by CD4+ T cells could be reversed by a neutralizing antibody against IL-6R. Conclusion we showed that enhancement of IL-6R expression on CD4+ T cells upon HBV infection contributes to increased Th17 response in patients with CHB.

  13. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite

    OpenAIRE

    Combe, Crescent L; Moretto, Magali M.; Schwartzman, Joseph D; Gigley, Jason P.; Bzik, David J.; Khan, Imtiaz A.

    2006-01-01

    IFN-γ-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-γ-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15−/− mice reversed inhibition of gu...

  14. Role of Circulating CD4+ CD25high Foxp3+ Regulatory T-Cells in Paediatric Asthma

    OpenAIRE

    Ensaf Khalil Mohammed*, Zeinab Farag Asheiba

    2011-01-01

    Background: The role of T-Helper 2 (Th2) cells in the pathogenesis of allergy and asthma has been well described. However, the immunologic mechanisms that down modulate and protect against the development of these disorders are poorly characterized. A spectrum of CD4+ T cells, including, FOXP3-positive CD4+CD25+ T regulatory cells (Tregs) might play a critical role in regulating these diseases. Objective: To investigate the role of CD4+CD25high FoxP3 Tregs in the pathogenesis of pediatric ast...

  15. FOXP3 Inhibits HIV-1 Infection of CD4 T-cells via Inhibition of LTR Transcriptional Activity

    OpenAIRE

    Selliah, Nithianandan; Zhang, Mingce; White, Sara; Zoltick, Philip; Sawaya, Bassel E.; Finkel, Terri H.; Cron, Randy Q

    2008-01-01

    FOXP3 is a necessary transcription factor for the development and function of CD4+ regulatory T-cells (Tregs). The role of Tregs in HIV-1 infection remains unclear. Here, we show expression of FOXP3 in primary human CD4 T-cells significantly inhibits HIV-1 infection. Since FOXP3 inhibits NFAT activity, and NFAT proteins contribute to HIV-1 transcription, we explore a transcriptional repressive function of HIV-1 LTR by FOXP3. Over-expression of FOXP3 in primary CD4 T-cells inhibits wild-type H...

  16. CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller

    Directory of Open Access Journals (Sweden)

    Burwitz Benjamin J

    2012-11-01

    Full Text Available Abstract Background Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. Results Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. Conclusions Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.

  17. Analysis of the In Vivo Turnover of CD4+ T-Cell Subsets in Chronically SIV-Infected Sooty Mangabeys.

    Science.gov (United States)

    Ortiz, Alexandra M; Carnathan, Diane G; Yu, Joana; Sheehan, Katherine M; Kim, Peter; Reynaldi, Arnold; Vanderford, Thomas H; Klatt, Nichole R; Brenchley, Jason M; Davenport, Miles P; Silvestri, Guido

    2016-01-01

    Aberrant turnover of memory CD4+ T-cells is central to Acquired Immunodeficiency Syndrome (AIDS) progression. Understanding the relationship between the turnover of CD4+ subsets and immunological homeostasis during simian immunodeficiency virus (SIV) infection in natural hosts may provide insight into mechanisms of immune regulation that may serve as models for therapeutic intervention in Human Immunodeficiency Virus (HIV)-infected persons. Sooty mangabeys (SMs) have naturally evolved with SIV to avoid AIDS progression while maintaining healthy peripheral CD4+ T-cell counts and thus represent a model by which therapeutic interventions for AIDS progression might be elucidated. To assess the relationship between the turnover of CD4+ subsets and immunological homeostasis during SIV infection in non-progressive hosts, we treated 6 SIV-uninfected and 9 SIV-infected SMs with 2'-bromo-5'-deoxyuridine (BrdU) for 14 days and longitudinally assessed CD4+ T-cell subset turnover by polychromatic flow cytometry. We observed that, in SIV-infected SMs, turnover of CD4+ T-cell naïve and central, transitional, and effector memory subsets is comparable to that in uninfected animals. Comparable turnover of CD4+ T-cell subsets irrespective of SIV-infection status likely contributes to the lack of aberrant immune activation and disease progression observed after infection in non-progressive hosts. PMID:27227993

  18. Analysis of the In Vivo Turnover of CD4+ T-Cell Subsets in Chronically SIV-Infected Sooty Mangabeys.

    Directory of Open Access Journals (Sweden)

    Alexandra M Ortiz

    Full Text Available Aberrant turnover of memory CD4+ T-cells is central to Acquired Immunodeficiency Syndrome (AIDS progression. Understanding the relationship between the turnover of CD4+ subsets and immunological homeostasis during simian immunodeficiency virus (SIV infection in natural hosts may provide insight into mechanisms of immune regulation that may serve as models for therapeutic intervention in Human Immunodeficiency Virus (HIV-infected persons. Sooty mangabeys (SMs have naturally evolved with SIV to avoid AIDS progression while maintaining healthy peripheral CD4+ T-cell counts and thus represent a model by which therapeutic interventions for AIDS progression might be elucidated. To assess the relationship between the turnover of CD4+ subsets and immunological homeostasis during SIV infection in non-progressive hosts, we treated 6 SIV-uninfected and 9 SIV-infected SMs with 2'-bromo-5'-deoxyuridine (BrdU for 14 days and longitudinally assessed CD4+ T-cell subset turnover by polychromatic flow cytometry. We observed that, in SIV-infected SMs, turnover of CD4+ T-cell naïve and central, transitional, and effector memory subsets is comparable to that in uninfected animals. Comparable turnover of CD4+ T-cell subsets irrespective of SIV-infection status likely contributes to the lack of aberrant immune activation and disease progression observed after infection in non-progressive hosts.

  19. Antigen presentation by small intestinal epithelial cells uniquely enhances IFN-γ secretion from CD4+ intestinal intraepithelial lymphocytes

    International Nuclear Information System (INIS)

    Highlights: •Small intestinal epithelial cells (sIECs). •sIECs are able to induce antigen specific proliferation of CD4+ IELs. •sIECs induce markedly enhanced IFN-γ secretion by CD4+ IELs. •Induction of enhanced IFN-γ secretion by sIECs is uniquely observed in CD4+ IELs. -- Abstract: Small intestinal epithelial cells (sIECs) express major histocompatibility complex class II molecules even in a normal condition, and are known to function as antigen presenting cells (APCs) at least in vitro. These findings raised the possibility that sIECs play an important role in inducing immune responses against luminal antigens, especially those of intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). We herein showed that antigenic stimulation with sIECs induced markedly greater secretion of interferon-gamma (IFN-γ) by CD4+ IELs, but not interleukin (IL)-4, IL-10 and IL-17 although the proliferative response was prominently lower than that with T cell-depleted splenic APCs. In contrast, no enhanced IFN-γ secretion by CD4+ LPLs and primed splenic CD4+ T cells was observed when stimulated with sIECs. Taken together, these results suggest that sIECs uniquely activate CD4+ IELs and induce remarkable IFN-γ secretion upon antigenic stimulation in vivo

  20. Antigen presentation by small intestinal epithelial cells uniquely enhances IFN-γ secretion from CD4{sup +} intestinal intraepithelial lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Hatano, Ryo; Yamada, Kiyoshi; Iwamoto, Taku; Maeda, Nana; Emoto, Tetsuro; Shimizu, Makoto; Totsuka, Mamoru, E-mail: atotuka@mail.ecc.u-tokyo.ac.jp

    2013-06-14

    Highlights: •Small intestinal epithelial cells (sIECs). •sIECs are able to induce antigen specific proliferation of CD4{sup +} IELs. •sIECs induce markedly enhanced IFN-γ secretion by CD4{sup +} IELs. •Induction of enhanced IFN-γ secretion by sIECs is uniquely observed in CD4{sup +} IELs. -- Abstract: Small intestinal epithelial cells (sIECs) express major histocompatibility complex class II molecules even in a normal condition, and are known to function as antigen presenting cells (APCs) at least in vitro. These findings raised the possibility that sIECs play an important role in inducing immune responses against luminal antigens, especially those of intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). We herein showed that antigenic stimulation with sIECs induced markedly greater secretion of interferon-gamma (IFN-γ) by CD4{sup +} IELs, but not interleukin (IL)-4, IL-10 and IL-17 although the proliferative response was prominently lower than that with T cell-depleted splenic APCs. In contrast, no enhanced IFN-γ secretion by CD4{sup +} LPLs and primed splenic CD4{sup +} T cells was observed when stimulated with sIECs. Taken together, these results suggest that sIECs uniquely activate CD4{sup +} IELs and induce remarkable IFN-γ secretion upon antigenic stimulation in vivo.

  1. Interdisciplinary Evaluation of Broadly-Reactive HLA Class II Restricted Epitopes Eliciting HIV-Specific CD4+T Cell Responses

    DEFF Research Database (Denmark)

    Buggert, M.; Norström, M.; Lundegaard, Claus; Lund, Ole; Nielsen, Morten; Karlsson, A. C.

    2011-01-01

    Background: CD4+ T cells orchestrate immune protection by ‘‘helping’’ other cells of our immune system to clear viral infections. It is well known that the preferential infection and depletion of CD4+ T cells contributes to hampered systemic T cell help following HIV infection. However, the...... functional and immunodominant discrepancies of CD4+ T cell responses targeting promiscuous MHC II restricted HIV epitopes remains poorly defined. Thus, utilization of interdisciplinary approaches might aid revealing broadly- reactive peptides eliciting CD4 + T cell responses. Methods: We utilized the novel...... bioinformatic prediction program NetMHCIIpan to select 64 optimized MHC II restricted epitopes located in the HIV Gag, Pol, Env, Nef and Tat regions. The epitopes were selected to cover the global diversity of the virus (multiple subtypes) and the human immune system(diverse MHC II types). Optimized...

  2. Oral immunization with a Salmonella enterica serovar typhi vaccine induces specific circulating mucosa-homing CD4(+) and CD8(+) T cells in humans.

    Science.gov (United States)

    Lundin, B Samuel; Johansson, Camilla; Svennerholm, Ann-Mari

    2002-10-01

    The kinetics and homing characteristics of T-cell responses in humans after mucosal immunizations have not been well characterized. Therefore, we have investigated the magnitude and duration of such responses as well as the homing receptor expression of antigen-specific peripheral blood T cells by using an oral model vaccine, i.e., the live, attenuated Salmonella enterica serovar Typhi vaccine (Ty21a). Eight volunteers were each given three doses of the vaccine 2 days apart, and blood samples, from which CD4(+) and CD8(+) T cells were selected by the use of magnetic beads, were collected before vaccination and at regular intervals thereafter. To purify the potentially antigen-specific gut-homing T cells, CD45RA(-) integrin beta(7)(+) cells were further sorted by flow cytometry. The sorted cells were then stimulated in vitro with the serovar Typhi vaccine strain, and the proliferation of cells and the cytokine production were measured. Following vaccination, there was a large increase in both the proliferation of and the gamma interferon (IFN-gamma) production by blood T cells stimulated with the vaccine strain. The responses were seen among both CD4(+) and CD8(+) T cells, although the CD8(+) cells produced the largest amounts of IFN-gamma. Peak responses were seen 7 to 14 days after the onset of vaccination. Furthermore, most of the IFN-gamma produced by both CD4(+) and CD8(+) cells emanated from cells with the potential to home to mucosal tissues, as the integrin beta(7)-expressing memory T cells produced around 10-fold more IFN-gamma than the remaining populations. In conclusion, we demonstrate that oral vaccination with a live oral bacterial vaccine induces antigen-specific CD4(+) and CD8(+) memory T cells, almost all of which express the gut-homing integrin beta(7). PMID:12228290

  3. The relationship between RTS,S vaccine-induced antibodies, CD4⁺ T cell responses and protection against Plasmodium falciparum infection.

    Directory of Open Access Journals (Sweden)

    Michael T White

    Full Text Available Vaccination with the pre-erythrocytic malaria vaccine RTS,S induces high levels of antibodies and CD4(+ T cells specific for the circumsporozoite protein (CSP. Using a biologically-motivated mathematical model of sporozoite infection fitted to data from malaria-naive adults vaccinated with RTS,S and subjected to experimental P. falciparum challenge, we characterised the relationship between antibodies, CD4(+ T cell responses and protection from infection. Both anti-CSP antibody titres and CSP-specific CD4(+ T cells were identified as immunological surrogates of protection, with RTS,S induced anti-CSP antibodies estimated to prevent 32% (95% confidence interval (CI 24%-41% of infections. The addition of RTS,S-induced CSP-specific CD4(+ T cells was estimated to increase vaccine efficacy against infection to 40% (95% CI, 34%-48%. This protective efficacy is estimated to result from a 96.1% (95% CI, 93.4%-97.8% reduction in the liver-to-blood parasite inoculum, indicating that in volunteers who developed P. falciparum infection, a small number of parasites (often the progeny of a single surviving sporozoite are responsible for breakthrough blood-stage infections.

  4. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite.

    Science.gov (United States)

    Combe, Crescent L; Moretto, Magali M; Schwartzman, Joseph D; Gigley, Jason P; Bzik, David J; Khan, Imtiaz A

    2006-04-25

    IFN-gamma-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-gamma-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15-/- mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Down-regulated CD4+ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4+ T cells from IL-15-/- mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4+ T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4+ T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4+ T cell-mediated autoimmune diseases. PMID:16614074

  5. A New Humanized HLA Transgenic Mouse Model of Multiple Sclerosis Expressing Class II on Mouse CD4 T Cells

    OpenAIRE

    Mangalam, Ashutosh; Rodriguez, Moses; David, Chella

    2007-01-01

    Among all the genetic factors associated with MS susceptibility, strongest association has been seen with expression of certain MHC class II molecules, although analysis of their exact function remains complicated. In general expression of class II is restricted to professional antigen presenting cells, however human but not mice CD4+ T cells express class II on their surface. Functional studies of classII+CD4+ T cells have been hampered due to lack of proper animal model. Here we describe de...

  6. CD4+CD25−Foxp3+ T cells play a role in tuberculous hydrothorax rather than malignant hydrothorax

    OpenAIRE

    Tang, Ying; Peng, Li-Ping; Qin, Gui-Xiang; Sun, Jing-Ting; Xu, Li-Jun; Jiang, Yan-Fang

    2015-01-01

    Background Foxp3+ T cells regulate inflammation and tumorigenesis. However, little is known about the role of different subsets of Foxp3+ T cells in malignant or tuberculous hydrothorax. Methods The numbers of CD4+CD25+Foxp3+, CD4+CD25−Foxp3+ T cells and the levels of some inflammatory cytokines in patients with tuberculous hydrothorax, malignant hydrothorax, and healthy controls (HCs) were examined by flow cytometry and ELISA. The potential association between the numbers of different subset...

  7. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

    Science.gov (United States)

    Martins, Karen A.O.; Cooper, Christopher L.; Stronsky, Sabrina M.; Norris, Sarah L.W.; Kwilas, Steven A.; Steffens, Jesse T.; Benko, Jacqueline G.; van Tongeren, Sean A.; Bavari, Sina

    2015-01-01

    Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development. PMID:26870818

  8. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

    Directory of Open Access Journals (Sweden)

    Karen A.O. Martins

    2016-01-01

    Full Text Available Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol, MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development.

  9. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity.

    Science.gov (United States)

    Martins, Karen A O; Cooper, Christopher L; Stronsky, Sabrina M; Norris, Sarah L W; Kwilas, Steven A; Steffens, Jesse T; Benko, Jacqueline G; van Tongeren, Sean A; Bavari, Sina

    2016-01-01

    Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development. PMID:26870818

  10. Proliferation and apoptosis of lamina propria CD4+ T cells from scid mice with inflammatory bowel disease

    DEFF Research Database (Denmark)

    Bregenholt, S; Reimann, J; Claesson, Mogens Helweg

    1998-01-01

    Scid mice transplanted with low numbers of syngeneic CD4+ T cells, develop a chronic and lethal inflammatory bowel disease (IBD) within 4-6 months. We have used in vivo 5-bromo2-deoxy-uridine (BrdU) labeling to assess the proliferation of lamina propria-derived CD4+ T cells in diseased scid mice....... The hourly rate of renewal of colonic lamina propria CD4+ T cells in diseased mice was 7% compared with 1.5% in normal BALB/c control mice. Transplantation of scid mice with in vitro activated CD4+ T cells accelerated the disease onset and development in a cell dose-dependent fashion when compared...

  11. Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(-/-) mice

    DEFF Research Database (Denmark)

    Riberdy, J M; Christensen, Jan Pravsgaard; Branum, K; Doherty, P C

    2000-01-01

    Optimal expansion of influenza virus nucleoprotein (D(b)NP(366))-specific CD8(+) T cells following respiratory challenge of naive Ig(-/-) microMT mice was found to require CD4(+) T-cell help, and this effect was also observed in primed animals. Absence of the CD4(+) population was consistently...... correlated with diminished recruitment of virus-specific CD8(+) T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8(+) set generated during the recall response in Ig(-/-) mice primed at least 6 months previously showed a normal profile of gamma interferon...... production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4(+) T-cell response. Both the magnitude and the localization profiles of virus-specific CD8(+) T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4(+) T...

  12. Comparative contribution of CD1 on the development of CD4+ and CD8+ T cell compartments.

    Science.gov (United States)

    Wang, B; Chun, T; Wang, C R

    2000-01-15

    CD1 molecules are MHC class I-like glycoproteins whose expression is essential for the development of a unique subset of T cells, the NK T cells. To evaluate to what extent CD1 contributes to the development of CD4+ and CD8+ T cells, we generated CD1oIIo and CD1oTAPo mice and compared the generation of T cells in these double-mutant mice and IIo or TAPo mice. FACS analysis showed that the number of CD4+ T cells in CD1oIIo mice was reduced significantly compared with the corresponding population in IIo mice. Both CD4+ NK1.1+ and the CD4+ NK1.1- population were reduced in CD1oIIo mice, suggesting that CD1 can select not only CD4+ NK1.1+ T cells but also some NK1.1- CD4+ T cells. Functional analysis showed that the residual CD4+ cells in CD1oIIo can secrete large amounts of IFN-gamma and a significant amount of IL-4 during primary stimulation with anti-CD3, suggesting that this population may be enriched for NK T cells restricted by other class I molecules. In contrast to the CD4+ population, no significant differences in the CD8+ T cell compartment can be detected between TAPo and CD1oTAPo mice in all lymphoid tissues tested, including intestinal intraepithelial lymphocytes. Our data suggest that, unlike other MHC class I molecules, CD1 does not contribute in a major way to the development of CD8+ T cells. PMID:10623818

  13. TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation.

    Directory of Open Access Journals (Sweden)

    Sejin Ahn

    2008-08-01

    Full Text Available Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT-expressing thymic stromal cells (TDLacZ. The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII. When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR transgenic reactive against LacZ (BgII, there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45- and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells.

  14. CD4+CD25+ regulatory T cells: II. Origin, disease models and clinical aspects

    DEFF Research Database (Denmark)

    Nielsen, Janne; Holm, Thomas Lindebo; Claesson, Mogens H

    2004-01-01

    Autoimmune diseases afflict approximately 5% of the population and reflect a failure in the immune system to discriminate between self and non-self resulting in the breakdown of self-tolerance. Regulatory CD4+CD25+ T cells (Treg cells) have been shown to play an important role in the maintenance of...... immune homeostasis and self-tolerance by counteracting the development and effector functions of potentially autoreactive T cells. We have in the previous APMIS review described the phenotype and physiology of Treg cells. The present overview deals with the thymic origin of Treg cells and their role in...... disease models such as autoimmune gastritis and inflammatory bowel disease. Finally, we will consider some aspects of the therapeutic potential of Treg cells....

  15. Immunology Mechanism of CD4+ CD25 T Regulatory Cells Acting on Effector T Cells

    Institute of Scientific and Technical Information of China (English)

    FENGNing-han; WUHong-fei; WUJun; ZHANGWei; SUIYuan-gen; HEHou-guang; ZHANGChun-lei; ZHENGJun-song

    2004-01-01

    Objective: To detect the inhibiting co-stimulating molecule CTLA4 and cytokines secreted by Treg cells, and explore the immunology mechanism of T regulatory cells acting on effector T cells in co-cultured system(CCS) and separating-cultured system(SCS). Methods: Detecting the percentage of CTLA4 and CD28 expressed on the Treg ceils and effector T ceils, and then adding Treg cells to mixed lymphocyte reaction(MLR) system in CCS and TransWeil Milliceil-PCF SCS, at the same time, adding or not adding anti-IL-10 or anti-TGF.II1 to the reacting systems, examining the inhibitory capacity of Treg ceils exerting on the MLR. Results: Compared with effector T cells, Treg cells expressed higher level CTLA4 and secreted much more IL-10 and TGF-β(P<0.01). The inhibitory capacity of Treg cells co-cultured with effector T ceils is much stronger than that in separating cultured group(P<0.01). Moreover, the inhibiting rate of Treg ceils exerting on effector T ceils through secretin_g IL-10 was more powerful than that through secreting TGF-β1 (P<0.01). Coaclusion: Both ceil-to-ceil contact and cytokines secretion mechanisms are involved in CD4+ CD25+ Treg ceils operating function. However, the former is more important. Intresfingly, we for the first time pointfound that IL-10 plays more powerful roles than TGF-β1 in the cytokines secretion mechanism.

  16. Distinct functions of the transcription factors Gata3 and ThPOK during intrathymic CD4 T cell differentiation*

    OpenAIRE

    Wang, Lie; Wildt, Kathryn F.; Zhu, Jinfang; Zhang, Xianyu; Feigenbaum, Lionel; Tessarollo, Lino; Paul, William E.; Fowlkes, B.J.; Bosselut, Rémy

    2008-01-01

    The transcription factors Gata3 and Zbtb7b are required for intrathymic CD4 T cell differentiation, but their precise roles in this process remain unclear. Here we show that, contrary to previous findings, Gata3 disruption blocked CD4 T cell lineage differentiation before CD4 lineage commitment, and in some contexts permitted ‘redirection’ of MHC class II-restricted thymocytes into the CD8 lineage. We found that Gata3 promotes Zbtb7b expression, and binds within a region of the Zbtb7b locus e...

  17. High Circulating Frequencies of Tumor Necrosis Factor Alpha- and Interleukin-2-Secreting Human T-Lymphotropic Virus Type 1 (HTLV-1)-Specific CD4+ T Cells in Patients with HTLV-1-Associated Neurological Disease

    OpenAIRE

    Goon, Peter K. C.; Igakura, Tadahiko; Hanon, Emmanuel; Angelina J Mosley; Asquith, Becca; Gould, Keith G.; Taylor, Graham P.; Weber, Jonathan N.; Bangham, Charles R M

    2003-01-01

    Significantly higher frequencies of tumor necrosis factor alpha- and interleukin-2-secreting human T-lymphotropic virus type 1 (HTLV-1)-specific CD4+ T cells were present in the peripheral blood mononuclear cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in those of asymptomatic carriers with similar provirus loads. The data suggest that HTLV-1-specific CD4+ T cells play a role in the pathogenesis of HAM/TSP.

  18. Impaired NK cells' activity and increased numbers of CD4 + CD25+ regulatory T cells in multidrug-resistant Mycobacterium tuberculosis patients.

    Science.gov (United States)

    Fan, Renhua; Xiang, Yangen; Yang, Li; Liu, Yanke; Chen, Pingsheng; Wang, Lei; Feng, Wenjun; Yin, Ke; Fu, Manjiao; Xu, Yixin; Wu, Jialin

    2016-05-01

    Multidrug-resistant tuberculosis (MDR-TB) often causes persistent infection and chemotherapy failure, which brings heavy burden of society and family. Many immune cell subsets and regulatory mechanisms may operate throughout the various stages of infection. The presence of regulatory T cells (Tregs) is thought to be an important mechanism that TB successfully evades the immune system. Tregs play a central role in the prevention of autoimmunity and in the control of immune responses. The role of Tregs in MDR-TB infection and persistence is inadequately documented. The current study was designed to determine whether CD4 + CD25+ regulatory T cells may modulate innate immunity (such as NK cells) against human tuberculosis. Our results indicated that the numbers of CD4 + CD25+ Treg cells increased in MDR-TB patients' blood, and the cytokine production of IL-10 increased from MDR-patients compared with healthy subjects, along with the lower activity and low CD69 expression of NK cells in patients. These results suggested that immunity to MDR-TB patients induced circulating CD4 + CD25+ T regulatory cells expansion, which may be related to the persistence of Mycobacterium tuberculosis (M. tb) infection, and to the balance between effectors immune responses and suppression immune responses. PMID:27156613

  19. Selective Loss of Early Differentiated, Highly Functional PD1high CD4 T Cells with HIV Progression.

    Science.gov (United States)

    Paris, Robert M; Petrovas, Constantinos; Ferrando-Martinez, Sara; Moysi, Eirini; Boswell, Kristin L; Archer, Eva; Yamamoto, Takuya; Ambrozak, David; Casazza, Joseph P; Haubrich, Richard; Connors, Mark; Ake, Julie; Kim, Jerome H; Koup, Richard A

    2015-01-01

    The role of PD-1 expression on CD4 T cells during HIV infection is not well understood. Here, we describe the differential expression of PD-1 in CD127high CD4 T cells within the early/intermediate differentiated (EI) (CD27highCD45RAlow) T cell population among uninfected and HIV-infected subjects, with higher expression associated with decreased viral replication (HIV-1 viral load). A significant loss of circulating PD-1highCTLA-4low CD4 T cells was found specifically in the CD127highCD27highCD45RAlow compartment, while initiation of antiretroviral treatment, particularly in subjects with advanced disease, reversed these dynamics. Increased HIV-1 Gag DNA was also found in PD-1high compared to PD-1low ED CD4 T cells. In line with an increased susceptibility to HIV infection, PD-1 expression in this CD4 T cell subset was associated with increased activation and expression of the HIV co-receptor, CCR5. Rather than exhaustion, this population produced more IFN-g, MIP1-a, IL-4, IL-10, and IL-17a compared to PD-1low EI CD4 T cells. In line with our previous findings, PD-1high EI CD4 T cells were also characterized by a high expression of CCR7, CXCR5 and CCR6, a phenotype associated with increased in vitro B cell help. Our data show that expression of PD-1 on early-differentiated CD4 T cells may represent a population that is highly functional, more susceptible to HIV infection and selectively lost in chronic HIV infection. PMID:26678998

  20. Selective Loss of Early Differentiated, Highly Functional PD1high CD4 T Cells with HIV Progression.

    Directory of Open Access Journals (Sweden)

    Robert M Paris

    Full Text Available The role of PD-1 expression on CD4 T cells during HIV infection is not well understood. Here, we describe the differential expression of PD-1 in CD127high CD4 T cells within the early/intermediate differentiated (EI (CD27highCD45RAlow T cell population among uninfected and HIV-infected subjects, with higher expression associated with decreased viral replication (HIV-1 viral load. A significant loss of circulating PD-1highCTLA-4low CD4 T cells was found specifically in the CD127highCD27highCD45RAlow compartment, while initiation of antiretroviral treatment, particularly in subjects with advanced disease, reversed these dynamics. Increased HIV-1 Gag DNA was also found in PD-1high compared to PD-1low ED CD4 T cells. In line with an increased susceptibility to HIV infection, PD-1 expression in this CD4 T cell subset was associated with increased activation and expression of the HIV co-receptor, CCR5. Rather than exhaustion, this population produced more IFN-g, MIP1-a, IL-4, IL-10, and IL-17a compared to PD-1low EI CD4 T cells. In line with our previous findings, PD-1high EI CD4 T cells were also characterized by a high expression of CCR7, CXCR5 and CCR6, a phenotype associated with increased in vitro B cell help. Our data show that expression of PD-1 on early-differentiated CD4 T cells may represent a population that is highly functional, more susceptible to HIV infection and selectively lost in chronic HIV infection.

  1. CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.

    Science.gov (United States)

    O'Brien, Meagan; Manches, Olivier; Wilen, Craig; Gopal, Ramya; Huq, Rumana; Wu, Vernon; Sunseri, Nicole; Bhardwaj, Nina

    2016-04-01

    Plasmacytoid dendritic cells (pDC) are innate immune cells that sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We showed previously that HIV-1 (HIV) localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. This divergent signaling may contribute to disease progression through production of pro-apoptotic and pro-inflammatory IFN and inadequate maturation of pDCs. We now demonstrate that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype. PMID:27082754

  2. Chemokines involved in protection from colitis by CD4+CD25+ regulatory T cells

    DEFF Research Database (Denmark)

    Kristensen, Nanna Ny; Brudzewsky, Dan; Gad, Monika;

    2006-01-01

    /chemokine receptor-specific gene expression profiling system of 67 genes, the authors have determined the expression profile of chemokine and chemokine receptor genes in the rectum of colitic mice and in mice that have been protected fromcolitis by CD4CD25 regulatory T cells. In mice protected from colitis, the...... authors found down regulation of the mRNA expression of the inflammatory chemokine receptors CCR1 and CXCR3 and their ligands CXCL9, CXCL10, CCL5, and CCL7. Also the transcripts for CCR9, CCL25, CCL17, and CXCL1 are found down regulated in protected compared with colitic animals. In addition, the authors...

  3. Fusion as a mediator of cytolysis in mixtures of uninfected CD4+ lymphocytes and cells infected by human immunodeficiency virus

    International Nuclear Information System (INIS)

    The authors describe an unusual type of cytopathology in which uninfected CD4+ (helper/inducer) cells (cells expressing the human leukocyte antigen CD4) interact with cells persistently infected with the human immunodeficiency virus (HIV). Prior antigenic stimulation was not required, since CD4+ cells taken either from healthy persons without anti-HIV antibodies or from individuals with anti-HIV antibodies were capable in inducing cytolysis. Neither CD8+ (suppressor/cytotoxic) nor CD16+ (natural killer) cells mediated the reaction. Light microscopic and autoradiographic studies revealed that, prior to cytolysis, multinucleated giant cells were formed from fusions between HIV-infected cells and large numbers of uninfected CD4+ lymphocytes. These data may explain the paradox that exists in vivo in which a dramatic depletion of CD4+ lymphocytes occurs in the presence of a small number of HIV-infected CD4+ cells. These new insights into the pathogenesis of acquired immunodeficiency syndrome (AIDS) may lead to future therapeutic strategies

  4. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm.

    Science.gov (United States)

    Hirahara, Kiyoshi; Nakayama, Toshinori

    2016-04-01

    CD4(+)T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (Th1) and Th2 cells, unexpected increases in the numbers of CD4(+)T-cell subsets, including Th17, Th9, T follicular-helper (Tfh) and T-regulatory (Treg) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique sub-populations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type Th2 cells, which are involved in the pathogenesis of chronic type-2 immune-related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the Th1/Th2 balance. To this end, we propose another model--the pathogenic T-helper population disease-induction model--as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases. PMID:26874355

  5. HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells.

    Science.gov (United States)

    Riou, Catherine; Strickland, Natalie; Soares, Andreia P; Corleis, Björn; Kwon, Douglas S; Wherry, E John; Wilkinson, Robert J; Burgers, Wendy A

    2016-04-01

    HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-α (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets. PMID:26927799

  6. Telomere Length, Telomerase Activity, and Replicative Potential in HIV Infection: Analysis of CD4+ and CD8+T Cells from HIV-discordant Monozygotic Twins

    OpenAIRE

    Palmer, Larry D.; Weng, Nan-ping; Levine, Bruce L.; June, Carl H; Lane, H. Clifford; Hodes, Richard J.

    1997-01-01

    To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV− donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from...

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

    International Nuclear Information System (INIS)

    To track epitope-specific CD4+ T cells at a single-cell level during influenza infection, the MHC class II-restricted OVA323-339 epitope was engineered into the neuraminidase stalk of influenza/A/WSN, creating a surrogate viral antigen. The recombinant virus, influenza A/WSN/OVAII, 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 OVA323-339 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

  8. Models of HIV-1 persistence in the CD4+ T cell compartment: past, present and future.

    Science.gov (United States)

    Tyagi, Mudit; Romerio, Fabio

    2011-12-01

    The limitations of current anti-retroviral therapies (ART) and the lack of a valid anti-HIV-1 vaccine candidate underscore the need for new therapeutic concepts aiming at the eradication of HIV-1, which represents at the same time an ideal goal and a major challenge for AIDS research. At present, this aim is unattainable due to the existence of cellular and anatomical reservoirs of persistent infection. Memory CD4(+) T cells comprise the largest pool of cells harboring silent, stably integrated HIV-1, which remains undetected by the immune system and refractory to conventional anti-retroviral drugs. The eradication of latent HIV-1 reservoirs will require new, potent and specific therapeutic strategies, which in turn must rely upon a deeper understanding of HIV-1 latency. To facilitate the advancement of our knowledge in this new area of research, several in vitro models of HIV-1 latency in CD4(+) T cells have been established. Here, we dissect and critically compare the rationale behind each experimental approach. Furthermore, we outline new avenues of research that will benefit from these models, including the push toward the development of new classes of viral eradication drugs. PMID:22211662

  9. 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.

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

    International Nuclear Information System (INIS)

    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.

  11. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma

    OpenAIRE

    Cabrera, Roniel; Ararat, Miguel; Xu, Yiling; Brusko, Todd; Wasserfall, Clive; Atkinson, Mark A.; Chang, Lung Ji; Liu, Chen; Nelson, David R.

    2012-01-01

    Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25− effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from periphe...

  12. Blocking interaction of viral gp120 and CD4-expressing T cells by single-stranded DNA aptamers

    OpenAIRE

    Zhao, Nianxi; Pei, Sung-nan; Parekh, Parag; Salazar, Eric; Zu, Youli

    2014-01-01

    To investigate the potential clinical application of aptamers to prevention of HIV infection, single- stranded DNA (ssDNA) aptamers specific for CD4 were developed using the systematic evolution of ligands by exponential enrichment approach and next generation sequencing. In contrast to RNA-based aptamers, the developed ssDNA aptamers were stable in human serum up to 12 hr. Cell binding assays revealed that the aptamers specifically targeted CD4-expressing cells with high binding affinity (Kd...

  13. In Vitro Immune Toxicity of Depleted Uranium: Effects on Murine Macrophages, CD4+ T Cells, and Gene Expression Profiles

    OpenAIRE

    Wan, Bin; Fleming, James T.; Schultz, Terry W.; Sayler, Gary S.

    2005-01-01

    Depleted uranium (DU) is a by-product of the uranium enrichment process and shares chemical properties with natural and enriched uranium. To investigate the toxic effects of environmental DU exposure on the immune system, we examined the influences of DU (in the form of uranyl nitrate) on viability and immune function as well as cytokine gene expression in murine peritoneal macrophages and splenic CD4+ T cells. Macrophages and CD4+ T cells were exposed to various concentrations of DU, and cel...

  14. Quantitative analysis of the acute and long-term CD4(+) T-cell response to a persistent gammaherpesvirus

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Doherty, P C

    1999-01-01

    compensatory response. The peak frequency within the splenic CD4(+) T-cell population may reach 1:50 in the acute response; it then drops to 1:400 to 1:500 within 4 months and stays at that level in the very long term. Sorting for L-selectin (CD62L) expression established that all virus-specific CD4(+) T cells...

  15. Long-term exposure to high levels of decabrominated diphenyl ether inhibits CD4 T-cell functions in C57Bl/6 mice.

    Science.gov (United States)

    Feng, Yan; Zeng, Weihong; Wang, Ying; Shen, Hao; Wang, Yan

    2016-09-01

    In recent years, the adverse health effects of decabrominated diphenyl ether (BDE-209) have raised more concerns as a growing number of studies reported its persistence in the environment and abundance in the human population, especially in occupational environmental compartments and exposed personnel. This study applies our previous animal model simulating occupational exposure to BDE-209 to investigate its potential adverse effects on CD4 T cells. Female C57Bl/6 mice were orally gavaged with BDE-209 at a dose of 800 mg kg(-1) every 2 days for 10 months and the blood of each mouse was collected for analysis. Kinetic changes of the peripheral immune system were investigated from 1 to 5 months of exposure. The chronic effects on cytokine production, proliferation and the antigen-specific responses of CD4 T cells were evaluated at 7, 9 and 10 months, respectively. The results have shown that impaired proliferation and cytokine (IFN-γ, IL-2 or TNF-α) production of CD4 T cells were observed in BDE-209-exposed mice, accompanied by increased T regulatory cells in the blood. BDE-209 exposure in vitro also suppressed the reactivity of CD4 T cells at concentrations of 0.01, 0.1, 1 and 10 μM. Furthermore, we observed weaker antigen-specific CD4 T-cell responses to Listeria monocytogenes infection in the mice exposed to BDE-209, suggesting decreased resistance to exogenous pathogens. Taken together, these observations indicate an impaired cellular immunity after long-term and relative high-dose exposure to BDE-209 in adult mice. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26682527

  16. Numerical status of CD4+CD25+FoxP3+ and CD8+CD28- regulatory T cells in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Ebrahim Kouchaki

    2014-04-01

    Full Text Available Objective(s: Regulatory T cells, including CD4+CD25+Fox3+ and CD8+CD28- cells play an important role in regulating the balance between immunity and tolerance. Since multiple sclerosis is an inflammatory autoimmune disease, regulatory T cells are considered to be involved in its pathogenesis. In this study, we investigated the circulatory numbers of the two mentioned types of regulatory T cells and also their association with different clinical characteristics in 84 multiple sclerosis patients. Materials and Methods: 84 patients with multiple sclerosis and 75 normal individuals were studied. Demographic and clinical information of all participants were collected via questionnaire and clinical examination as well as MRI. The peripheral blood frequency of two different subgroups of regulatory T cells (CD4+ CD25+Foxp3+ and CD8+CD28- cells were analyzed by flow cytometry using anti-human antibodies conjugated with CD4-FITC / CD25-PE/Foxp3-PE-Cy5, CD3-PE/CD8a-PE-Cy5/CD28-FITC. Results: The frequency of CD4+CD25+Foxp3+ cells in multiple sclerosis patients was significantly less than that in healthy controls (P=0.006 and in mild forms less than that in sever forms (P=0.003. There was not any correlation between the frequency of regulatory T cells and different clinical variables. Conclusion: Our results showed that the number of CD4+CD25+Foxp3+ cells decreases significantly in multiple sclerosis patients, which probably shows the regulatory role of these cells in multiple sclerosis.

  17. Protein kinase C θ regulates the phenotype of murine CD4+ Th17 cells.

    Directory of Open Access Journals (Sweden)

    Katarzyna Wachowicz

    Full Text Available Protein kinase C θ (PKCθ is involved in signaling downstream of the T cell antigen receptor (TCR and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures and in vivo (experimental autoimmune encephalomyelitis model, EAE techniques, we demonstrated that PKCθ-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt, accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation.

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

    Directory of Open Access Journals (Sweden)

    Lindsay R Ancelet

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

  19. A specific assay measuring binding of 125I-Gp 120 from HIV to T4+/CD4+ cells

    International Nuclear Information System (INIS)

    The HIV (HTLV-III) envelope glycoprotein, Gp120, was isolated from virus-infected tissue culture cells using affinity chromatography. A radioimmunoassay was developed to determine the degree of iodinated Gp120 to target CD4+ (T4+) cells. 125I-Gp120 could be shown to selectively bind to CD4+ cells only. The Gp120 remained bound to these cells after repeated washes. Monoclonal anti-CD4 antibodies block the binding of Gp120 to CD4+ cells. Monoclonal antibodies to other cell surface components do not interfere with 125I-Gp120 binding. All IgG antibodies from HIV seropositive donors tested block 125I-GP120 binding, though with variable titers. The authors believe that this assay provides further proof for the use of CD4 (T4) as a component of the receptor for HIV. It represents a safe, objective and sensitive method for the analysis of Gp120-CD4 interactions, as well as the potential of antibodies to interfere with this binding. (Auth.)

  20. Immunity to experimental Salmonella typhimurium infections in rats. Transfer of immunity with primed CD45RC+ and CD45RC- CD4 T-cell subpopulations

    DEFF Research Database (Denmark)

    Thygesen, P; Christensen, H B; Hougen, H P;

    1996-01-01

    The protective effect of primed CD4 T cells against a lethal dose of Salmonella typhimurium was studied in Lewis rats. Primed CD4 T cells were obtained by inoculating Lewis rats with a non-lethal dose of S. typhimurium. Four weeks after the infection, spleen CD4 T cells were separated by antibody...

  1. Different Immunological Phenotypes Associated with Preserved CD4+ T Cell Counts in HIV-Infected Controllers and Viremic Long Term Non-Progressors

    DEFF Research Database (Denmark)

    Gaardbo, Julie Christine; Hartling, Hans J; Ronit, Andreas;

    2013-01-01

    HIV-infected controllers control viral replication and maintain normal CD4+ T cell counts. Long Term Non-Progressors (LTNP) also maintain normal CD4+ T cell counts, but have on-going viral replication. We hypothesized that different immunological mechanisms are responsible for preserved CD4+ T cell...... counts in controllers and LTNP....

  2. PD-1HIGH Follicular CD4 T Helper Cell Subsets Residing in Lymph Node Germinal Centers Correlate with B Cell Maturation and IgG Production in Rhesus Macaques

    OpenAIRE

    Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A; Veazey, Ronald S.

    2014-01-01

    CD4+ T follicular helper (TFH) cells guide development and maturation of B cells and are crucial for effective antibody responses. Here we found rhesus macaque TFH cells, defined as CXCR5+CD4 T cells, contain two major populations: PD-1INT and PD-1HIGH cells. Of these, PD-1HIGHCD4+ T cells highly co-express ICOS but little CCR7, and reside in lymph node germinal centers (GCs), but not in blood. These cells secrete IL-21 and express transcriptional factor Bcl-6 at higher levels than CXCR5+PD-1...

  3. Co-culture of placental explants with isolated CD4 and CD8 T cells: a functional model to define the consequences of placental inflammation

    Directory of Open Access Journals (Sweden)

    Hayley Derricott

    2015-11-01

    Full Text Available Appropriate placental function is essential for successful pregnancy and placental dysfunction is associated with fetal growth restriction (FGR and stillbirth. Villitis of unknown etiology (VUE and chronic intervillositis of unknown etiology (CIUE are immune-mediated conditions characterised by placental infiltrates of macrophages, CD4 and CD8 T cells. VUE and CIUE occur more frequently in the placentas of pregnancies complicated by FGR. The mechanisms by which this inflammation induces placental dysfunction are yet to be defined. We aimed to develop an in vitro model of placental inflammation to investigate functional consequences of immune cells in the placental environment. Fragments of placental tissue were co-cultured with CD4 and CD8 T cells isolated from whole blood. CellTrackerTM fluorescence was used to identify T cells in cultured explants. Tissue histology, endocrine and nutrient transport function was assessed using established methods. This novel preparation will enable future investigations into immune cell interactions with placenta.

  4. Evidence implicating the Ras pathway in multiple CD28 costimulatory functions in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Sujit V Janardhan

    Full Text Available CD28 costimulation is a critical event in the full activation of CD4(+ T cells that augments cytokine gene transcription, promotes cytokine mRNA stability, prevents induction of anergy, increases cellular metabolism, and increases cell survival. However, despite extensive biochemical analysis of the signaling events downstream of CD28, molecular pathways sufficient to functionally replace the diverse aspects of CD28-mediated costimulation in normal T cells have not been identified. Ras/MAPK signaling is a critical pathway downstream of T cell receptor stimulation, but its role in CD28-mediated costimulation has been controversial. We observed that physiologic CD28 costimulation caused a relocalization of the RasGEF RasGRP to the T cell-APC interface by confocal microscopy. In whole cell biochemical analysis, CD28 cross-linking with either anti-CD28 antibody or B7.1-Ig augmented TCR-induced Ras activation. To determine whether Ras signaling was sufficient to functionally mimic CD28 costimulation, we utilized an adenoviral vector encoding constitutively active H-Ras (61L to transduce normal, Coxsackie-Adenovirus Receptor (CAR transgenic CD4(+ T cells. Like costimulation via CD28, active Ras induced AKT, JNK and ERK phosphorylation. In addition, constitutive Ras signaling mimicked the ability of CD28 to costimulate IL-2 protein secretion, prevent anergy induction, increase glucose uptake, and promote cell survival. Importantly, we also found that active Ras mimicked the mechanism by which CD28 costimulates IL-2 production: by increasing IL-2 gene transcription, and promoting IL-2 mRNA stability. Finally, active Ras was able to induce IL-2 production when combined with ionomycin stimulation in a MEK-1-dependent fashion. Our results are consistent with a central role for Ras signaling in CD28-mediated costimulation.

  5. Cutting edge: TNFR-shedding by CD4+CD25+ regulatory T cells inhibits the induction of inflammatory mediators.

    NARCIS (Netherlands)

    Mierlo, G.J. van; Scherer, H.U.; Hameetman, M.; Morgan, M.E.; Flierman, R.; Huizinga, T.W.J.; Toes, R.E.

    2008-01-01

    CD4+CD25+ regulatory T (Treg) cells play an essential role in maintaining tolerance to self and nonself. In several models of T cell-mediated (auto) immunity, Treg cells exert protective effects by the inhibition of pathogenic T cell responses. In addition, Treg cells can modulate T cell-independent

  6. Infection with host-range mutant adenovirus 5 suppresses innate immunity and induces systemic CD4+ T cell activation in rhesus macaques.

    Science.gov (United States)

    Qureshi, Huma; Genescà, Meritxell; Fritts, Linda; McChesney, Michael B; Robert-Guroff, Marjorie; Miller, Christopher J

    2014-01-01

    Ad5 is a common cause of respiratory disease and an occasional cause of gastroenteritis and conjunctivitis, and seroconversion before adolescence is common in humans. To gain some insight into how Ad5 infection affects the immune system of rhesus macaques (RM) 18 RM were infected with a host-range mutant Ad5 (Ad5hr) by 3 mucosal inoculations. There was a delay of 2 to 6 weeks after the first inoculation before plasmacytoid dendritic cell (pDC) frequency and function increased in peripheral blood. Primary Ad5hr infection suppressed IFN-γ mRNA expression, but the second Ad5hr exposure induced a rapid increase in IFN-gamma mRNA in peripheral blood mononuclear cells (PBMC). Primary Ad5hr infection suppressed CCL20, TNF and IL-1 mRNA expression in PBMC, and subsequent virus exposures further dampened expression of these pro-inflammatory cytokines. Primary, but not secondary, Ad5hr inoculation increased the frequency of CXCR3+ CD4+ T cells in blood, while secondary, but not primary, Ad5hr infection transiently increased the frequencies of Ki67+, HLADR+ and CD95+/CCR5+ CD4+ T cells in blood. Ad5hr infection induced polyfunctional CD4 and CD8+ T cells specific for the Ad5 hexon protein in all of the animals. Thus, infection with Ad5hr induced a complex pattern of innate and adaptive immunity in RM that included transient systemic CD4+ T cell activation and suppressed innate immunity on re-exposure to the virus. The complex effects of adenovirus infection on the immune system may help to explain the unexpected results of testing Ad5 vector expressing HIV antigens in Ad5 seropositive people. PMID:25203111

  7. Role of CD4 molecule in the induction of interleukin 2 and interleukin 2 receptor in class II major histocompatibility complex-restricted antigen-specific T helper clones. T cell receptor/CD3 complex transmits CD4-dependent and CD4-independent signals.

    OpenAIRE

    Oyaizu, N; Chirmule, N; Pahwa, S.

    1992-01-01

    The CD4 molecule plays an essential role in antigen-induced activation of T helper (Th) cells, but its contribution to signal transduction events resulting in physiologic T cell function is ill defined. By utilizing anti-CD4 monoclonal antibodies (MAbs) that recognize distinct epitopes of CD4, we have investigated the role of CD4 molecule in antigen-induced interleukin 2 (IL-2) and IL-2 receptor (IL-2R) alpha chain expression in class II major histocompatibility complex-restricted antigen-spe...

  8. Bistability analyses of CD4+ T follicular helper and regulatory cells during Helicobacter pylori infection.

    Science.gov (United States)

    Leber, Andrew; Abedi, Vida; Hontecillas, Raquel; Viladomiu, Monica; Hoops, Stefan; Ciupe, Stanca; Caughman, John; Andrew, Tricity; Bassaganya-Riera, Josep

    2016-06-01

    T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori. PMID:26947272

  9. Internalization, lysosomal degradation and new synthesis of surface membrane CD4 in phorbol ester-activated T-lymphocytes and U-937 cells

    DEFF Research Database (Denmark)

    Petersen, C M; Christensen, E I; Andresen, B S;

    1992-01-01

    degradation was low in resting cells. Endocytosis and/or degradation of anti-CD4 mAb was suppressed by H7, and by inhibitors of membrane traffic (Monensin) and lysosome function (methylamine, chloroquine). Immunocytochemistry localized CD4 to the surface of unstimulated T-cells. Upon PMA stimulation...... occasional labeling was seen in endosomes but whole cell CD4 decreased dramatically. However, methylamine-treated PMA blasts showed accumulation of CD4 in lysosomes and accordingly, pulse-chase experiments in biolabeled cell cultures suggested a manifest reduction of CD4 half-life in response to PMA. Despite...... lysosomal degradation of membrane CD4. Transport of CD4 to the cell surface and CD4 synthesis is unaffected by activation....

  10. Nuclear localization of Vpr is crucial for the efficient replication of HIV-1 in primary CD4+ T cells

    International Nuclear Information System (INIS)

    The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr appears to make a substantial contribution to the replication of HIV-1 in established T cell lines when HIV-1 is present at very low multiplicities of infection. However, the role of Vpr in viral replication in primary CD4+ T cells remains to be clarified. In this study, we generated a panel of viruses that encoded mutant forms of Vpr that lacked either the ability to accumulate in the nucleus and induce G2 arrest or the ability to induce apoptosis, which has been shown to occur independently of G2 arrest of the cell cycle. We demonstrate here that the nuclear localization of Vpr and consequent G2 arrest but not the induction of apoptosis by Vpr are important for viral replication in primary CD4+ T cells at both high and low multiplicities of infection. Viruses that encoded mutant forms of Vpr that failed to be imported into the nucleus in the presence of cytoplasmic extracts from primary CD4+ T cells in an in vitro nuclear import assay replicated at drastically reduced rates. Thus, Vpr might be a key regulator of the viral nuclear import process during infection in primary CD4+ T cells. By contrast, a mutant form of Vpr that exhibited diffuse cytosolic staining exclusively in an immunofluorescence assay of HeLa cells and was not imported into nucleus by the cytosol from HeLa cells was effectively imported into the nucleus by cytosol from primary CD4+ T cells. This Vpr mutant virus replicated well in primary CD4+ T cells, indicating that cellular factors in primary CD4+ T cells are indispensable for the accumulation of Vpr in the nucleus and, thus, for viral replication. Our results suggest that the nuclear import of Vpr might be a good target in efforts to block the early stages of replication of HIV-1

  11. Correspondence of Neutralizing Humoral Immunity and CD4 T Cell Responses in Long Recovered Sudan Virus Survivors

    Directory of Open Access Journals (Sweden)

    Ariel Sobarzo

    2016-05-01

    Full Text Available Robust humoral and cellular immunity are critical for survival in humans during an ebolavirus infection. However, the interplay between these two arms of immunity is poorly understood. To address this, we examined residual immune responses in survivors of the Sudan virus (SUDV outbreak in Gulu, Uganda (2000–2001. Cytokine and chemokine expression levels in SUDV stimulated whole blood cultures were assessed by multiplex ELISA and flow cytometry. Antibody and corresponding neutralization titers were also determined. Flow cytometry and multiplex ELISA results demonstrated significantly higher levels of cytokine and chemokine responses in survivors with serological neutralizing activity. This correspondence was not detected in survivors with serum reactivity to SUDV but without neutralization activity. This previously undefined relationship between memory CD4 T cell responses and serological neutralizing capacity in SUDV survivors is key for understanding long lasting immunity in survivors of filovirus infections.

  12. Gene-engineered varicella-zoster virus reactive CD4+ cytotoxic T cells exert tumor-specific effector function.

    Science.gov (United States)

    Landmeier, Silke; Altvater, Bianca; Pscherer, Sibylle; Eing, Bodo R; Kuehn, Joachim; Rooney, Cliona M; Juergens, Heribert; Rossig, Claudia

    2007-09-01

    T cells with grafted specificities for surface antigens provide an avenue for rapidly producing immune effector cells with tumor specificity. However, the function of chimeric receptor (chRec) gene-modified T cells is limited by lack of T-cell expansion and persistence. We propose to use varicella zoster virus (VZV)-reactive T cells as host for the chRec because these cells can be expanded both in vitro and in vivo by stimulation of their native receptor during endogenous reexposure to the virus or by administration of VZV vaccine. We obtained human T cells reactive with VZV from the peripheral blood of seropositive donors by stimulation with VZV lysate and evaluated their characteristics after genetic modification with two tumor-specific model chRecs. Cultures dominated by cytolytic CD4(+) T cells (VZV-CTL) could be expanded and maintained in vitro. Gene-modified VZV-CTL recognized and lysed tumor targets in a MHC-independent manner while maintaining functional, MHC-restricted interaction with VZV antigen through their native receptor. Thus, chRec-transduced VZV-CTL may provide a source of potent tumor-reactive cells for adoptive immunotherapy of cancer. The availability of a safe and effective VZV vaccine provides the option of repeated in vivo stimulation to maintain high T-cell numbers until the tumor is eliminated. PMID:17804749

  13. 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; Nyazema, N; Friis, Henrik

    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...

  14. Crohn's disease intestinal CD4+ T cells have impaired interleukin-10 productionwhich is not restored by probiotic bacteria

    DEFF Research Database (Denmark)

    Hvas, Christian L; Kelsen, Jens; Agnholt, Jørgen;

    2007-01-01

    OBJECTIVE: Crohn's disease (CD) has been associated with low mucosal interleukin (IL)-10 production, but the mechanism behind this deficiency remains unclear. The aim of this study was to investigate IL-10 and interferon (IFN)-gamma production in intestinal CD4+ T cells from CD patients and healthy...... volunteers (HV) and to examine how this was affected by bacterial products and the presence or absence of autologous dendritic cells. MATERIAL AND METHODS: We cultured intestinal CD4+ T cells from CD patients (n=9) and HV (n=6) and differentiated dendritic cells from their peripheral monocytes. Intestinal T...... imbalance in CD, but tended to do so in HV. When there were no dendritic cells, CD intestinal T cells responded to autologous bacteria with an increased IFN-gamma production (2.3+/-1.3 ng/ml) compared with HV intestinal T cells (0.3+/-0.2 ng/ml). CONCLUSIONS: Crohn's disease intestinal CD4+ T cells display...

  15. Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.

    Science.gov (United States)

    Liu, Haibo; Gao, Wei; Yuan, Jie; Wu, Chaoneng; Yao, Kang; Zhang, Li; Ma, Leilei; Zhu, Jianbing; Zou, Yunzeng; Ge, Junbo

    2016-02-01

    CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-γ and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs. PMID:26746143

  16. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism.

    Science.gov (United States)

    Oida, Takatoku; Zhang, Xingmin; Goto, Masao; Hachimura, Satoshi; Totsuka, Mamoru; Kaminogawa, Shuichi; Weiner, Howard L

    2003-03-01

    Murine CD4(+)CD25(+) regulatory cells have been reported to express latency-associated peptide (LAP) and TGF-beta on the surface after activation, and exert regulatory function by the membrane-bound TGF-beta in vitro. We have now found that a small population of CD4(+) T cells, both CD25(+) and CD25(-), can be stained with a goat anti-LAP polyclonal Ab without being stimulated. Virtually all these LAP(+) cells are also positive for thrombospondin, which has the ability to convert latent TGF-beta to the active form. In the CD4(+)CD45RB(high)-induced colitis model of SCID mice, regulatory activity was exhibited not only by CD25(+)LAP(+) and CD25(+)LAP(-) cells, but also by CD25(-)LAP(+) cells. CD4(+)CD25(-)LAP(+) T cells were part of the CD45RB(low) cell fraction. CD4(+)CD25(-)LAP(-)CD45RB(low) cells had minimal, if any, regulatory activity in the colitis model. The regulatory function of CD25(-)LAP(+) cells was abrogated in vivo by anti-TGF-beta mAb. These results identify a new TGF-beta-dependent regulatory CD4(+) T cell phenotype that is CD25(-) and LAP(+). PMID:12594277

  17. The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis

    DEFF Research Database (Denmark)

    Krakowski, M L; Owens, T

    1997-01-01

    In experimental allergic encephalomyelitis (EAE), CD4+ T cells infiltrate the central nervous system (CNS). We derived CD4+ T cell lines from SJL/J mice that were specific for encephalitogenic myelin basic protein (MBP) peptides and produced both Th1 and Th2 cytokines. These lines transferred EAE...... to naive mice. Peptide-specific cells re-isolated from the CNS only produced Th1 cytokines, whereas T cells in the lymph nodes produced both Th1 and Th2 cytokines. Mononuclear cells isolated from the CNS, the majority of which were microglia, presented antigen to and stimulated MBP-specific T cell...

  18. Histone modifications of Notch1 promoter affect lung CD4+ T cell differentiation in asthmatic rats.

    Science.gov (United States)

    Cui, Z-L; Gu, W; Ding, T; Peng, X-H; Chen, X; Luan, C-Y; Han, R-C; Xu, W-G; Guo, X-J

    2013-01-01

    Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4+ T cells. Chromatin immunoprecipitation analysis showed that the acetylation levels of total H3, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notch1 gene promoter were increased significantly in asthmatic lung CD4+ T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4+ T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, IL-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-κB and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notch1 promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma. PMID:23755752

  19. A Differential Equation Model of HIV Infection of CD4+ T-Cells with Delay

    Directory of Open Access Journals (Sweden)

    2009-02-01

    Full Text Available An epidemic model of HIV infection of CD4+ T-cells with cure rate and delay is studied. We include a baseline ODE version of the model, and a differential-delay model with a discrete time delay. The ODE model shows that the dynamics is completely determined by the basic reproduction number R0<1. If R0<1, the disease-free equilibrium is asymptotically stable and the disease dies out. If R0>1, a unique endemic equilibrium exists and is globally stable in the interior of the feasible region. In the DDE model, the delay stands for the incubation time. We prove the effect of that delay on the stability of the equilibria. We show that the introduction of a time delay in the virus-to-healthy cells transmission term can destabilize the system, and periodic solutions can arise through Hopf bifurcation.

  20. CD44 expression positively correlates with Foxp3 expression and suppressive function of CD4+ Treg cells

    Directory of Open Access Journals (Sweden)

    König Rolf

    2009-10-01

    Full Text Available Abstract Background CD4+CD25+ regulatory T (Treg cells develop in the thymus and can suppress T cell proliferation, modulated by Foxp3 and cytokines; however, the relevance of CD44 in Treg cell development is less clear. To address this issue, we analyzed Foxp3 expression in CD44+ Treg cells by using multiple parameters, measured the levels of the immunoregulatory cytokine interleukin (IL-10 in various thymocyte subsets, and determined the suppressor activity in different splenic Treg cell populations. Results Within mouse thymocytes, we detected Treg cells with two novel phenotypes, namely the CD4+CD8-CD25+CD44+ and CD4+CD8-CD25+CD44- staining features. Additional multi-parameter analyses at the single-cell and molecular levels suggested to us that CD44 expression positively correlated with Foxp3 expression in thymocytes, the production of IL-10, and Treg activity in splenic CD4+CD25+ T cells. This suppressive effect of Treg cells on T cell proliferation could be blocked by using anti-IL-10 neutralizing antibodies. In addition, CD4+CD25+CD44+ Treg cells expressed higher levels of IL-10 and were more potent in suppressing effector T cell proliferation than were CD4+CD25+CD44- cells. Conclusion This study indicates the presence of two novel phenotypes of Treg cells in the thymus, the functional relevance of CD44 in defining Treg cell subsets, and the role of both IL-10 and Foxp3 in modulating the function of Treg cells. Reviewers This article was reviewed by Dr. M. Lenardo, Dr. L. Klein & G. Wirnsberger (nominated by Dr. JC Zungia-Pfluker, and Dr. E.M. Shevach.

  1. In vitro Th1 and Th2 cell polarization is severely influenced by the initial ratio of naïve and memory CD4+ T cells

    DEFF Research Database (Denmark)

    Blom, Lars; Poulsen, Lars K.

    even small percentages (99% naïve CD4+ T cells resulted in better Th1 and Th2 polarization with significant reduced fractions of IL-4+ and IFN-γ+ CD4+ T cells, respectively. Moreover, the Th2 primed >99% naïve CD4+ T cells showed significantly higher ratio of IL-4+:IFN-γ+ (>4 fold) and GATA-3:+T...

  2. 哮喘患儿外周血CD4+CD25+调节性T细胞的测定及临床意义%The level of CD4+CD25+regulatory T cells and its clinical significance in children with asthma

    Institute of Scientific and Technical Information of China (English)

    湛洁谊; 卢慧敏; 林穗玲

    2014-01-01

    Objective To explore the proportion change of CD4+CD25+regulatory T cells (Treg) in peripheral blood of children with asthma and to analyze its significance. Methods A total of 150 asthmatic children were divided into three groups according to their clinical features50 subjects in acute asthma attack group, 50 subjects in clinical re-mission of asthma group and 50 subjects in cough variant asthma group,meanwhile, 50 healthy children were enrolled in the control group. The levels of CD4+CD25+Treg in peripheral blood of all children were detected by flow cytometer. Results The CD4+CD25+Treg level in acute attack group were lowest of the four groups (P0.05). Conclusion The CD4+CD25+regulatory T cells may be involved in the pathogenesis of asthma,the level of CD4+CD25+regulatory T cells correlated with the severity of asthma in children.%目的:探讨CD4+CD25+调节性T细胞在哮喘儿童外周血中的比例改变,并探讨其临床意义。方法150例哮喘患儿按临床表现分为急性发作组(50例)、临床缓解期组(50例)和咳嗽变异性哮喘组(50例),另选择50名健康儿童为正常对照组。应用流式细胞仪检测上述各组外周血CD4+CD25+调节性T细胞占CD4+T细胞的百分比。结果急性发作期组患儿外周血CD4+CD25+调节性T细胞水平较缓解组、咳嗽变异性哮喘组及健康对照组明显下降(P0.05)。结论CD4+CD25+调节性T细胞可能参与了哮喘的发生与发展,哮喘的严重程度可能与CD4+CD25+调节性T细胞的水平相关。

  3. Monocyte-derived macrophages exhibit distinct and more restricted HIV-1 integration site repertoire than CD4(+) T cells.

    Science.gov (United States)

    Kok, Yik Lim; Vongrad, Valentina; Shilaih, Mohaned; Di Giallonardo, Francesca; Kuster, Herbert; Kouyos, Roger; Günthard, Huldrych F; Metzner, Karin J

    2016-01-01

    The host genetic landscape surrounding integrated HIV-1 has an impact on the fate of the provirus. Studies analysing HIV-1 integration sites in macrophages are scarce. We studied HIV-1 integration site patterns in monocyte-derived macrophages (MDMs) and activated CD4(+) T cells derived from seven antiretroviral therapy (ART)-treated HIV-1-infected individuals whose cells were infected ex vivo with autologous HIV-1 isolated during the acute phase of infection. A total of 1,484 unique HIV-1 integration sites were analysed. Their distribution in the human genome and genetic features, and the effects of HIV-1 integrase polymorphisms on the nucleotide selection specificity at these sites were indistinguishable between the two cell types, and among HIV-1 isolates. However, the repertoires of HIV-1-hosting gene clusters overlapped to a higher extent in MDMs than in CD4(+) T cells. The frequencies of HIV-1 integration events in genes encoding HIV-1-interacting proteins were also different between the two cell types. Lastly, HIV-1-hosting genes linked to clonal expansion of latently HIV-1-infected CD4(+) T cells were over-represented in gene hotspots identified in CD4(+) T cells but not in those identified in MDMs. Taken together, the repertoire of genes targeted by HIV-1 in MDMs is distinct from and more restricted than that of CD4(+) T cells. PMID:27067385

  4. Monocyte-derived macrophages exhibit distinct and more restricted HIV-1 integration site repertoire than CD4+ T cells

    Science.gov (United States)

    Kok, Yik Lim; Vongrad, Valentina; Shilaih, Mohaned; Di Giallonardo, Francesca; Kuster, Herbert; Kouyos, Roger; Günthard, Huld