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

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    Ulysse Ateba-Ngoa

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

  3. 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

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

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    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.

  5. Cord Blood Derived CD4+CD25high T Cells Become Functional Regulatory T Cells upon Antigen Encounter

    Science.gov (United States)

    Mayer, Elisabeth; Bannert, Christina; Gruber, Saskia; Klunker, Sven; Spittler, Andreas; Akdis, Cezmi A.

    2012-01-01

    Background: Upon antigen exposure, cord blood derived T cells respond to ubiquitous environmental antigens by high proliferation. To date it remains unclear whether these “excessive” responses relate to different regulatory properties of the putative T regulatory cell (Treg) compartment or even expansion of the Treg compartment itself. Methods: Cord blood (>37 week of gestation) and peripheral blood (healthy controls) were obtained and different Treg cell subsets were isolated. The suppressive potential of Treg populations after antigen exposure was evaluated via functional inhibition assays ([3H]thymidine incorporation assay and CFSE staining) with or without allergen stimulation. The frequency and markers of CD4+CD25highFoxP3+ T cells were characterized by mRNA analysis and flow cytometry. Results: Cord blood derived CD4+CD25high cells did not show substantial suppressor capacity upon TCR activation, in contrast to CD4+CD25high cells freshly purified from adult blood. This could not be explained by a lower frequency of FoxP3+CD4+CD25highcells or FOXP3 mRNA expression. However, after antigen-specific stimulation in vitro, these cells showed strong proliferation and expansion and gained potent suppressive properties. The efficiency of their suppressive capacity can be enhanced in the presence of endotoxins. If T-cells were sorted according to their CD127 expression, a tiny subset of Treg cells (CD4+CD25+CD127low) is highly suppressive even without prior antigen exposure. Conclusion: Cord blood harbors a very small subset of CD4+CD25high Treg cells that requires antigen-stimulation to show expansion and become functional suppressive Tregs. PMID:22272233

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

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    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.

  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. Comparative Study of Regulatory T Cell Function of Human CD25+CD4+ T Cells from Thymocytes, Cord Blood, and Adult Peripheral Blood

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    Wakae Fujimaki

    2008-01-01

    Full Text Available CD25+CD4+ regulatory T cells suppress T cell activation and regulate multiple immune reactions in in vitro and in vivo studies. To define the regulatory function of human CD25+CD4+ T cells at various stages of maturity, we investigated in detail the functional differences of CD25+CD4+ T cells from thymocytes, cord blood (CB, and adult peripheral blood (APB. CB CD25+CD4+ T cells displayed low-FOXP3 protein expression level and had no suppressive activity. In contrast, CD25+CD4+ T cells from thymocytes or APB expressed high expression level of FOXP3 protein associated with significant suppressive activity. Although CB CD25+CD4+ T cells exhibited no suppressive activity, striking suppressive activity was observed following expansion in culture associated with increased FOXP3 expression and a shift from the CD45RA+ to the CD45RA− phenotype. These functional differences in CD25+CD4+ T cells from Thy, CB, and APB hence suggest a pathway of maturation for Treg in the peripheral immune system.

  9. 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.

  10. Detectable expression of IL-35 in CD4+ T cells from peripheral blood of chronic hepatitis B patients.

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    Liu, Fen; Tong, Fuyi; He, Yan; Liu, Haiyan

    2011-04-01

    Epstein-Barr virus-induced gene 3 (Ebi3) and the p35 subunit of IL-12 have been reported to form a heterodimeric cytokine, named IL-35, in human and mouse. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) and suggested to contribute to their suppressive activity. However, human CD4(+)CD25(+)Foxp3(+) Tregs do not constitutively express detectable amounts of IL-35 in both mRNA and protein levels. Circulating CD4(+)CD25(+) Treg frequency of chronic Hepatitis B patients significantly correlates with serum viral load. In this study, we investigated whether IL-35 expression could be detected in CD4(+) T cells from peripheral blood of chronic Hepatitis B patients. Using both RT-PCR and immunoprecipitation plus Western blot analysis, we demonstrated that IL-35 expression could be detected in the CD4(+) T cells from peripheral blood of Chronic Hepatitis B patients.

  11. 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

  12. 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...

  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. 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

  15. 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.

  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. CD4+/CD8+ double-positive T cells

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  18. 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.

  19. Role of the frequency of blood CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells in autoimmunity in patients with Sjoegren's syndrome

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    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.

  20. 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

  1. 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.

  2. 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

  3. [The Analysis for Probable Reasons of Cd4+ T-Cell Activation Non-Linear Dependence on Extra Cellular Calcium Ion Concentration in Human Peripheral Blood in vitro].

    Science.gov (United States)

    Litvinov, I S

    2015-01-01

    The analysis for probable reasons of CD4+ T-cell activation non-linear dependence on [Ca2+]o in HPB in vitro is the general aim of current work. At the beginning we pursued the analysis of receptor-dependent (the mixture of monoclonal antibodies (mAbs) to CD3 and CD28 molecules) and receptor-independent (phorbol-myristate-acetate and ionomycin mixture) means to activate T cells in vitro with different [Ca2+]o in HPB. The key role of intracellular T-cell signaling systems in activated T cells in their non-similar sensitivity to calcium ions in the blood was shown. The analysis of differentiation next stages of CD4+ T-cell activation in vitro relatively [Ca2+]o in PHB demonstrates the key role of the earliest induction stages in non-similar sensitivity to calcium ions in CD4+ T-cell activation in vitro. According to the pursued analysis; the non-similar sensitivity of CD4+ T-cell in vitro to activation is in no-way connected with pace differences on the primary stages of activation process. The comparison of CD4+ memory T cells with their naive T-cell precursors in the cell activation process in hypocalcemia conditions was made in the separate experimental series. The 1st maximum consists in average of 85% CD4+CD45R0high CD69+ memory T cells. Naive CD4+CD45RAlowCD69+ T cells constitute the remainder 15%. The 2nd maximum almost completely consists of CD4+CD45R0+CD69+ memory T cells. The ratio between CD4+CD69+ T cell maximums depends on donor ages and represents linear dependence with R = -0.981. The most probable candidate on the role of CD4+ T cell, being capable of activation in hypocalcemia conditions, are memory T lymphocytes, being resistant to ionomycin action (I R) subset. To check this assumption the mononuclear cells and their IR-fraction were prepared from donor PB. Then the mononuclear cells and their IR-fraction were activated by mAbs mixture at different [EGTA] values. For IR-fraction, enriched with CD4+CD45RA-CD45R0+ memory T cells, slightly seen 1st

  4. 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

  5. [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

  6. 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

  7. 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

  8. Rapid T-cell receptor CD4+ repertoire reconstitution and immune recovery in unrelated umbilical cord blood transplanted pediatric leukemia patients.

    Science.gov (United States)

    Finocchi, Andrea; Romiti, Maria Luisa; Di Cesare, Silvia; Puliafito, Pamela; Pensieroso, Simone; Rana, Ippolita; Pinto, Rita; Cancrini, Caterina; De Rossi, Giulio; Caniglia, Maurizio; Rossi, Paolo

    2006-07-01

    Umbilical cord blood transplantation has been successfully employed for treatment of many immune and hematologic disorders. The aim of this study was to evaluate the quality of immune reconstitution after umbilical cord blood transplantation in 6 leukemia children. T-cell receptor Vbeta third complementary region spectratyping was used for monitoring the contribution of the thymic pathway in patients' immune reconstitution. Absolute numbers of lymphocyte subsets (T, B, and natural killer), and lymphoproliferative in vitro response to mitogens, recovered within 12 months after transplantation. Furthermore, an overall diversification of T-cell receptor complexity in the repopulating T cells, with a polyclonal Gaussian profiles in most (74%) of total families was observed. Noteworthy, we showed a wider and more rapid reconstitution of T-cell receptor CD4+ T cell families compared with T-cell receptor CD8+ T ones still exhibiting some perturbations at 24 months. These data show that umbilical cord blood transplantation allows immune reconstitution already within 12 months with generation of newly diversified CD4+ T lymphocyte subsets.

  9. 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

  10. 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....

  11. 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)

  12. Rapid detection of dendritic cell and monocyte disorders using CD4 as a lineage marker of the human peripheral blood antigen presenting cell compartment

    Directory of Open Access Journals (Sweden)

    Laura eJardine

    2013-12-01

    Full Text Available Dendritic cells (DCs and monocytes are critical regulators and effectors of innate and adaptive immune responses. Monocyte expansion has been described in many pathological states while monocyte and DC deficiency syndromes are relatively recent additions to the catalogue of human primary immunodeficiency disorders. Clinically applicable screening tests to diagnose and monitor these conditions are lacking. Conventional strategies for identifying human DCs and monocytes have been based on the use of a lineage gate to exclude lymphocytes, thus preventing simultaneous detection of DCs, monocytes and lymphocyte subsets. Here we demonstrate that CD4 is a reliable lineage marker for the human peripheral blood antigen presenting cell compartment that can be used to identify DCs and monocytes in parallel with lymphocytes. Based on this principle, simple modification of a standard lymphocyte phenotyping assay permits simultaneous enumeration of four lymphocyte and five DC/monocyte populations from a single sample. This approach is applicable to clinical samples and facilitates the diagnosis of DC and monocyte disorders in a wide range of clinical settings, including genetic deficiency, neoplasia and inflammation.

  13. 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...

  14. 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.

  15. 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

  16. 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

  17. IL-35 expression in peripheral blood CD4(+) T cells from chronic hepatitis B virus-infected patients directly correlates with virus load.

    Science.gov (United States)

    Zhou, Yali; Zhang, Hong; Li, Yumin

    2015-05-01

    Interleukin 35 (IL-35) functions in an anti-inflammatory fashion by inhibiting T-cell proliferation, whereas CD4(+) T cells play an important role in cellular immunity. In a hepatitis B virus (HBV) infection, the viral proteins stimulate the immune system to generate antiviral molecules, which correlate to HBV DNA load. We investigated the impact of HBV DNA load on the expression of IL-35 mRNA in CD4(+) T cells, and the expression of IL-35 cytokine in serum of the patients with chronic HBV infection. Here we report that the frequency of circulating CD4(+) T cells correlates with the HBV DNA load in the serum of chronic hepatitis B (CHB) patients. An increased number of CD4(+) T cells were found in those patients with higher levels of HBV DNA. Regulatory T cells (T regs) also showed this trend, but circulating cytotoxic lymphocytes (CTLs) showed a negative correlation with serum HBV DNA load. In addition, significantly more IL-35 mRNA was found in the CD4(+) T cells of CHB patients, compared to healthy controls. Patients in the high viral load group showed increased levels of IL-35 mRNA, compared with those in the low viral load group. The level of IL-35 cytokine in the serum of CHB patients was significantly higher than in the healthy controls and in those infected with HBV, the patients with a higher viral load had more serum IL-35 cytokines, compared to those with a lower viral load. Our study suggests that increased serum IL-35 could be directly related to increased levels of IL-35 mRNA in CD4(+) T cells and HBV DNA load in CHB patients. The possible role of IL-35 as an immune regulator in chronic HBV infection should be investigated further.

  18. 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.

  19. 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.

  20. 3种不同中医证型艾滋病患者外周血CD+4CD+25调节性T细胞的表达%Expression of CD+4CD+25 regulatory T cell in peripheral blood of HIV/AIDS patients with different TCM syndromes

    Institute of Scientific and Technical Information of China (English)

    陈晓蓉; 杨宗国; 沈芳; 王江蓉; 卢洪洲; 杨悦娅

    2011-01-01

    objective: To observe the expression level of CD4+CD25+ regulatory T cell in peripheral blood of HIV/AIDS patients with different TCM syndromes, and to probe the immune negative regulation ability of HIV/AIDS. Methods: Based on the symptoms,signs,tongue manifestations, pulse conditions of AIDS patients, according to the thought of TCM Treatment with syndrome differentiation ,we divided the 97 HIV/AIDS patients into 3 different syndrome type, deficiency of pulmonary and renal syndrome, qi asthenia and blood stasis syndrome, and deficiency of spleen and renal syndrome, in order to observe the expression level of CD4+ CD25+ regulatory T cell in peripheral blood of HIV/AIDS patients with different TCM syndromes and 30cases of normal in control group. Results: The statistical significance of the expression level of CD4+ CD25+ regulatory T cell was observed among the 3 kinds of syndrome and control group (P<0.001). The deficiency of spleen and renal syndrome own the highest expression level of CD4+CD25+ regulatory T cell, followed by deficiency of pulmonary and renal syndrome, and qi asthenia and blood stasis syndrome. Conclusion: The expression level of CD4+CD25+ regulatory T cell of HIV/AIDS patients with different TCM syndromes has being reduced gradually from the deficiency of spleen and renal syndrome, to the deficiency of pulmonary and renal syndrome, and to the qi asthenia and blood stasis syndrome.%目的:观察不同中医证型艾滋病患者CD+4CD+25调节性T细胞(以下简称CD+4CD+25T细胞)的表达水平,探讨不同证型艾滋病免疫负调节能力.方法:根据艾滋病患者的症状、体征、舌象、脉象,按照中医辨证论治思路,分为肺肾不足、气虚血瘀、脾肾亏虚3种证型,设正常对照组30名,收集病例97例,观察不同证型艾滋病患者及正常对照组外周血CD+4CD+25T细胞的表达水平.结果:正常对照组、脾肾亏虚、肺肾不足、气虚血瘀各组患者CD+4CD+25T细胞的表

  1. Thymic Nurse Cells Support CD4-CD8+ Thymocytes to Differentiate into CD4+CD8+ Cells

    Institute of Scientific and Technical Information of China (English)

    Aidong Li; Xueli Liu; Baochun Duan; Jie Ma

    2005-01-01

    Thymic nurse cells (TNCs) represent a unique microenvironment in the thymus for T cell maturation. In order to investigate the role of thymic nurse cells during T cell differentiation, a TNC clone, RWTE-1, which formed a typical complex with fetal thymocytes in vitro was established from normal Wistar rat. Hanging drop culture method was applied to reveal the interaction between TNCs and thymocytes. Our result revealed that eighty percent of immature CD4-CD8+ cells differentiated into CD4+CD8+ cells after a 12-hour hanging drop culture with RWTE-1. However, in a 12-hour culture of immature CD4-CD8+ cells with or without RWTE-1 supernatant, only 30% of the cells differentiated into CD4+CD8+ cells spontaneously. This observation led to the conclusion that RWTE-1 cell has the capacity to facilitate immature CD4-CD8+ thymocytes to differentiate into CD4+CD8+ T cells by direct interaction.

  2. 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。

  3. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    Science.gov (United States)

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.

  4. 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.

  5. Sialylation regulates peripheral tolerance in CD4+ T cells.

    Science.gov (United States)

    Brennan, Patrick J; Saouaf, Sandra J; Van Dyken, Steve; Marth, Jamey D; Li, Bin; Bhandoola, Avinash; Greene, Mark I

    2006-05-01

    Decreased binding by the 6C10 auto-antibody serves as a unique marker for CD4+ T cell unresponsiveness after the induction of T cell tolerance in Vbeta8.1 TCR transgenic mice. We further define the nature of the epitope recognized by the 6C10 antibody to be a subset of Thy-1 bearing incompletely sialylated N-linked glycans, and furthermore, we demonstrate that tolerant CD4+ T cells have an increased degree of cell-surface sialylation. To test the significance of the altered glycosylation state identified by the 6C10 auto-antibody in the tolerant CD4+ T cell population, surface sialic acid was cleaved enzymatically. Treatment of purified peripheral CD4+ T cells with Vibrio cholerae sialidase (VCS) leads to increased 6C10 binding, significantly enhances proliferation in the tolerant CD4+ population and corrects defects in phosphotyrosine signaling observed in the tolerant CD4+ T cell. Furthermore, in vivo administration of VCS enhances proliferation in both tolerant and naive CD4+ T cell subsets. These studies suggest that sialylation of glycoproteins on the surface of the CD4+ T cell contributes to the regulation of T cell responsiveness in the tolerant state. PMID:16291658

  6. 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;

    In a vaccine trial against Mycoplasma hyosynoviae infection, pigs were vaccinated with formalin fixed whole-cell-antigen formulated with adjuvant DDA/TDB (SSI). Placebo pigs received adjuvant with saline. Vaccinations were performed at five and eight weeks of age, followed by an intranasal M......-α were rare. However, CD4+ cells producing IFN-γ or TNF-α after Ag-stimulation were detected in vaccinated pigs, and increased IFN-γ level (iMFI) in cells co-producing IFN-γ and TNF-α was more pronounced in vaccinated pigs compared to placebo pigs in response to M. hyosynoviae challenge (day 15 p...

  7. Expressions of CD4 + CD25high regulatory T cells, TGF-β1 and COX-2 in the peripheral blood of prostate cancer patients%前列腺癌患者外周血中CD4+CD25high调节性T细胞及调节因子TGF-31和COX-2的表达

    Institute of Scientific and Technical Information of China (English)

    夏桃林; 刘涛; 吴振权; 张海滨; 杨明; 刘绍远; 何灼彬; 李辽源

    2011-01-01

    Objective: To investigate the expressions of CD4+ CD25high regulatory T cells, TGF-β1 and COX-2 in the periphe-ral blood of prostate cancer (Pca) patients, and analyze the role of CD4+ CD25high regulatory T cells in the pathogenesis of Pca and their relationship with TGF-pl and COX-2. Methods: We used flow cytometry to calculate the percentage of CD4+ CD25high regulatory T cells in the CD4 + T cells in the peripheral blood mononuelear cells ( PBMC) from 30 Pca patients (11 localized and 19 non-localized cases) and 20 healthy volunteer controls, determined the expressions of TGF-pl and COX-2 in the serum by ELISA, and analyzed their correlation with the CD4+ CD25high regulatory T cells in the Pca patients as well as the differences between the localized and non- localized cases. Results: CD4+ CD25high regulatory T cells accounted for (18.32 ±7.49) % in the CD4+ T cells in PBMCs from the Pca patients, significantly higher than (7.77 ±1.86) % from the controls (P 0.05 ). The expressions of TGF-pl and COX-2 in the peripheral blood were (215.97 ±55.16) ng/ml and (6.88 ±5.14) ng/ml in the Pca patients, in comparison with (149.75 ±47.11) ng/ml (P 0.05 ) in the controls. Multiple linear regression analysis showed no significant correlation between the expression of CD4 + CD25high regulatory T cells in PBMCs and those of TGF-pl and COX-2 in the peripheral blood of the Pca patients. There were no significant differences between the localized and non-localized Pca groups in the expressions of CD4 + CD25high regulatory T cells, TGF-pl and COX-2 (P > 0.05). Conclusion-. CD4 + CD25high regulatory T cells in in PBMCs are involved in the pathogenesis of Pca. The proliferation of CD4 + CD25 high regulatory T cells is not significantly correlated to the expressions of TGF-pl and COX-2 in the peripheral blood, but maybe to the tumor itself and the local tumor microenvironment.%目的:通过检测前列腺癌患者以及健康志愿者外周血中CD4+ CD25high

  8. 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

  9. 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

  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. 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

  12. 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.

  13. 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 ...

  14. 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.

  15. 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

  16. 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

  17. Morbidly obese human subjects have increased peripheral blood CD4 + T cells with skewing toward a Treg- and Th2-dominated phenotype

    NARCIS (Netherlands)

    K. van der Weerd (Kim); W.A. Dik (Willem); B. Schrijver (Benjamin); D.H. Schweitzer (Dave ); A.W. Langerak (Ton); H.A. Drexhage (Hemmo); R.M. Kiewiet-Kemper (Rosalie); M.O. van Aken (Maarten); A. van Huisstede (Astrid); J.J.M. van Dongen (Jacques); A.J. van der Lelij (Aart Jan); F.J.T. Staal (Frank); P.M. van Hagen (Martin)

    2012-01-01

    textabstractObesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We

  18. Reconstitution of CD4 T Cells in Bronchoalveolar Lavage Fluid after Initiation of Highly Active Antiretroviral Therapy▿

    Science.gov (United States)

    Knox, Kenneth S.; Vinton, Carol; Hage, Chadi A.; Kohli, Lisa M.; Twigg, Homer L.; Klatt, Nichole R.; Zwickl, Beth; Waltz, Jeffrey; Goldman, Mitchell; Douek, Daniel C.; Brenchley, Jason M.

    2010-01-01

    The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells. PMID:20610726

  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. Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64(+) cells.

    Science.gov (United States)

    Vogel, Stephanie; Grabski, Elena; Buschjäger, Daniela; Klawonn, Frank; Döring, Marius; Wang, Junxi; Fletcher, Erika; Bechmann, Ingo; Witte, Torsten; Durisin, Martin; Schraven, Burkhart; Mangsbo, Sara M; Schönfeld, Kurt; Czeloth, Niklas; Kalinke, Ulrich

    2015-12-16

    Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64(+) monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients' inflamed joints that comprised enhanced numbers of CD64(+) cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64(+) cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64(+) cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions.

  1. 大肠癌患者外周血CD4+ CD25+ CD127-调节性T细胞表达及其临床意义%Expression and clinical significance of CD4+ CD25+ CD127- regulatory T cells in peripheral blood in patients of colon cancer

    Institute of Scientific and Technical Information of China (English)

    任红; 樊静; 张凤春; 康文喜

    2011-01-01

    目的:探讨CD4+ CD25+ CD127-调节性T细胞在大肠癌患者外周血中的表达水平及临床意义.方法:应用流式细胞仪检测200例大肠癌患者外周血CD4+ CD25+CD127-调节性T细胞占CD4+T细胞的百分比,并分析其与大肠癌组织的分化程度、淋巴结转移和临床分期的关系.结果:大肠癌患者外周血CD4+ CD25+ CD127-调节性T细胞占CD4+T细胞的百分率[(4.84±1.35)%]明显高于健康对照组[(0.85±0.25)%],差异有统计学意义,P<0.05.低分化者外周血调节性T细胞[(4.21±0.42)%]明显高于高分化者[(3.92±0.41)%],差异有统计学意义,P<0.05;有淋巴结转移者外周血调节T细胞[(4.57±1.44)%]明显高于无淋巴结转移者[(2.36±0.68)%],差异有统计学意义,P<0.01;Ⅲ和Ⅳ期患者外周血调节性T细胞[(3.53±1.41)%和(4.38±1.32)%]明显高于Ⅰ~Ⅱ期[(1.90±0.86)%],差异有统计学意义,P<0.01.结论:大肠癌患者外周血CD4+CD25+ CD127调节性T细胞占CD4+T细胞的百分率明显升高,可能在大肠癌的免疫耐受和免疫逃逸中发挥重要作用,检测其结果对于判断大肠癌的病程进展及预后有一定参考价值.%OBJECTIVE: To investigate the levels and clini-cal significance of the CD4+ CD25 + CD127- regulatory T cells in the peripheral blood of the patients of colon cancer. METHODS: To analysis the percentage of CD4 + CD25 + CD127- regulatory T cells in the peripheral blood of 200 patients of colon cancer with flow cytometry. And to study the relations between the percent-age of the regulatory T cells and the differentiation of colon canc-er tissues,lymphatic metastasis and clinical stages of colon canc-er. RESULTS: The percentage of CD4+ CD25 + CD127~ regula-tory T cells in the peripheral blood of the patients of colon cancer was (4. 84 ± 1. 35)% and was significantly higher than that (0.85 ± 0.25)% in healthy control group(P<0. 05). The per-centage of regulatory T cells in poorly differentiated tissues

  2. 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

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

    Directory of Open Access Journals (Sweden)

    Alexandra A Lambert

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

  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. Transcriptional regulatory networks for CD4 T cell differentiation.

    Science.gov (United States)

    Christie, Darah; Zhu, Jinfang

    2014-01-01

    CD4(+) T cells play a central role in controlling the adaptive immune response by secreting cytokines to activate target cells. Naïve CD4(+) T cells differentiate into at least four subsets, Th1Th1 , Th2Th2 , Th17Th17 , and inducible regulatory T cellsregulatory T cells , each with unique functions for pathogen elimination. The differentiation of these subsets is induced in response to cytokine stimulation, which is translated into Stat activation, followed by induction of master regulator transcription factorstranscription factors . In addition to these factors, multiple other transcription factors, both subset specific and shared, are also involved in promoting subset differentiation. This review will focus on the network of transcription factors that control CD4(+) T cell differentiation.

  6. Study on the relationship between regulatory T cell CD 4+ CD25+ and CD8+ CD28- in the peripheral blood between graves disease%外周血中 CD4+CD25+与 CD8+CD28-调节性 T 细胞与Graves 病的关系研究

    Institute of Scientific and Technical Information of China (English)

    韦巍; 林英辉; 黄小琪

    2015-01-01

    目的:分析Graves病(GD)患者外周血中CD4+ CD25+和CD8+ CD28-调节性 T (Tr)细胞的变化。方法选择该院内分泌科门诊或住院部43例GD患者为研究对象,其中内分泌科门诊确诊的19例GD患者为试验初发组。接受治疗且甲状腺功能恢复正常的24例GD患者为治疗缓解组;选择同期健康体检者20例为健康对照组。采用流式细胞术检测3组外周血中CD4+ CD25+和CD8+ CD28- T r细胞水平。结果试验初发组外周血CD4+CD25+ T r细胞水平为(4.56±4.14)%,明显低于健康对照组的(8.84±4.45)%,差异有统计学意义( P<0.05),CD8+CD28- T r细胞水平为(14.95±5.38)%,与健康对照组的(10.65±6.37)%比较,差异无统计学意义(P>0.05)。治疗缓解组外周血中CD4+CD25+ Tr细胞水平为(6.99±6.35)%,与健康对照组比较,差异无统计学意义( P>0.05),但其CD8+ CD28- T r细胞水平为(20.48±6.07)%,高于健康对照组,差异有统计学意义( P<0.05)。结论 CD4+CD25+ T r细胞水平可能与GD发病有关,CD8+CD28-T r细胞可能与GD病程发展有关。%Objective To analyze the changes of the levels of CD4+CD25+ and CD8+CD28- T cells in the pe‐ripheral blood in patients with graves disease(GD) .Methods A total of 43 patients with GD were selected as objects in this study ,19 cases who were diagnosis in outpatient department were selected into incipience group ,24 cases who were treated and the thyroid function return to normal status were selected into alleviation group ,meanwhile 20 healthy persons were recruited into control group .The levels of CD4+ CD25+ and CD8+ CD28- regulator T cells in the peripheral blood were detected by flow cytometry .Results The CD4+CD25+ regulatory T cell levels in incipience group were (4 .56 ± 4 .14)% ,which was significant lower than(8 .84 ± 4 .45)% in the

  7. 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...

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. IL-2 AND IFN-g, BUT NOT IL-4 SECRETION BY PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC ARE RELATED TO CD4+ T CELLS AND CLINICAL STATUS IN BRAZILIAN HIV-1-INFECTED SUBJECTS

    Directory of Open Access Journals (Sweden)

    Marisa A. HONG

    1998-11-01

    Full Text Available It has been reported that production of IL-2 and IFN-g, known as T-helper type 1 cytokines, by peripheral mononuclear cells (PBMC decreases with progression of HIV infection. In contrast, IL-4 and IL-10 production, Th2 cytokine profile, increases with HIV disease progression. PBMC were evaluated from 55 HIV-infected subjects from Divisão de Imunologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, to "in vitro" cytokines production after 24 hours of stimulation with PHA. Low levels of IL-4 production in both HIV- infected patients and normal subjects, were detected. The patients with CD4+ T cell counts g production compared to controls. Patients with higher counts of CD4+ T cells (either between 200-500 or >500 cells/mm3 also showed decreased production of IL-2 that was not statistically significant. There was a correlation between IL-2 and IFN-g release with CD4+ T cells counts. HIV-1-infected individuals with CD4+ T cells >500 cells/mm3 showed increased levels of IL-2 and IFN-g, than individuals with CD4+ T cells g production at advanced HIV disease. IL-4 production was not affected during HIV infection. Taken together, these findings suggest that the cytokine profile might be influenced by the HIV infection rather than the cause of disease progression.

  13. 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. ...

  14. 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...

  15. CD+4CD+25调节性T细胞与肿瘤的相关性研究%CD+4 CD+25 regulatory T cells and lung cancer

    Institute of Scientific and Technical Information of China (English)

    翟晋芳; 韩福才

    2009-01-01

    通过了解CD+4 CD+25调节性T细胞(CD+4 CD+25Treg)表面分子的特性和CD+4 CD+25Treg在外周血和组织中的表达,认识CD+4 CD+25 Treg在肿瘤免疫凋节中的作用,探索其作用的分子机制.%To know CD+4 CD+25 regulatory T cells' s function in tumor immunological regulation and to search for its functionary molecule mechanism by reviewing researches associated with the characteristics of CD+4 CD+25 regulatory T cells surface molecules and the expression of CD+4 CD+25 regulatory T cells in the peripheral blood and tissues.

  16. 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

  17. Association of progressive CD4(+ T cell decline in SIV infection with the induction of autoreactive antibodies.

    Directory of Open Access Journals (Sweden)

    Takeo Kuwata

    2009-04-01

    Full Text Available The progressive decline of CD4(+ T cells is a hallmark of disease progression in human immunodeficiency virus (HIV and simian immunodeficiency virus (SIV infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+ T cells, chronic infection is often associated with a progressive decline of total CD4(+ T cells, including the naïve subset. The mechanism of this second phase of CD4(+ T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+ T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+ T cells demonstrated two patterns of CD4(+ T cell depletion, primarily affecting either naïve or memory CD4(+ T cells. Progressive decline of total CD4(+ T cells was observed only in macaques with naïve CD4(+ T cell depletion (ND, though the depletion of memory CD4(+ T cells was profound in macaques with memory CD4(+ T cell depletion (MD. ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4(+ T cells was associated with plasma antibodies autoreactive with CD4(+ T cells, increasing numbers of IgG-coated CD4(+ T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa, dsDNA, and phospholipid (aPL. Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4(+ T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+ T cell decline

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  7. 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.

  8. 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.

  9. IL-2 and IFN-gamma, but not IL-4 secretion by peripheral blood mononuclear cells (PBMC) are related to CD4+ T cells and clinical status in Brazilian HIV-1-infected subjects.

    Science.gov (United States)

    Hong, M A; Wakim, V L; Salomão, S J; Camargo, L S; Casseb, J; Duarte, A J

    1998-01-01

    It has been reported that production of IL-2 and IFN-gamma, known as T-helper type 1 cytokines, by peripheral mononuclear cells (PBMC) decreases with progression of HIV infection. In contrast, IL-4 and IL-10 production, Th2 cytokine profile, increases with HIV disease progression. PBMC were evaluated from 55 HIV-infected subjects from Divisão de Imunologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, to "in vitro" cytokines production after 24 hours of stimulation with PHA. Low levels of IL-4 production in both HIV-infected patients and normal subjects, were detected. The patients with CD4+ T cell counts 500 cells/mm3) also showed decreased production of IL-2 that was not statistically significant. There was a correlation between IL-2 and IFN-gamma release with CD4+ T cells counts. HIV-1-infected individuals with CD4+ T cells > 500 cells/mm3 showed increased levels of IL-2 and IFN-gamma, than individuals with CD4+ T cells < 500 cells/mm3. In conclusion, we observed a decline of IL-2 and IFN-gamma production at advanced HIV disease. IL-4 production was not affected during HIV infection. Taken together, these findings suggest that the cytokine profile might be influenced by the HIV infection rather than the cause of disease progression.

  10. 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

  11. Memory T follicular helper CD4 T cells

    Directory of Open Access Journals (Sweden)

    J. Scott eHale

    2015-02-01

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

  12. 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...

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  13. 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

  14. 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.

  15. PD-1/PD-Ls pathways between CD4(+) T cells and pleural mesothelial cells in human tuberculous pleurisy.

    Science.gov (United States)

    Yin, Wen; Tong, Zhao-Hui; Cui, Ai; Zhang, Jian-Chu; Ye, Zhi-Jian; Yuan, Ming-Li; Zhou, Qiong; Shi, Huan-Zhong

    2014-03-01

    Programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and PD-L2 have been demonstrated to be involved in tuberculosis immunity, however, the expression and regulation of PD-1/PD-Ls pathways in pleural mesothelial cells (PMCs) and CD4(+) T cells in tuberculous pleural effusion (TPE) have not been investigated. Expression of PD-1 on CD4(+) T cells and expressions of PD-L1 and PD-L2 on PMCs in TPE were determined. The impacts of PD-1/PD-Ls pathways on proliferation, apoptosis, adhesion, and migration of CD4(+) T cells were explored. Concentrations of soluble PD-l, but not of soluble PD-Ls, were much higher in TPE than in serum. Expressions of PD-1 on CD4(+) T cells in TPE were significantly higher than those in blood. Expressions of PD-Ls were much higher on PMCs from TPE when compared with those from transudative effusion. Interferon-γ not only upregulated the expression of PD-1 on CD4(+) T cells, but also upregulated the expressions of PD-Ls on PMCs. Blockage PD-1/PD-Ls pathways abolished the inhibitory effects on proliferation and adhesion activity of CD4(+) T cells induced by PMCs. PD-1/PD-Ls pathways on PMCs inhibited proliferation and adhesion activity of CD4(+) T cells, suggesting that Mycobacterium tuberculosis might exploit PD-1/PD-Ls pathways to evade host cell immune response in human.

  16. The Fc and not CD4 Receptor Mediates Antibody Enhancement of HIV Infection in Human Cells

    Science.gov (United States)

    Homsy, Jacques; Meyer, Mia; Tateno, Masatoshi; Clarkson, Sarah; Levy, Jay A.

    1989-06-01

    Antibodies that enhance human immunodeficiency virus (HIV) infectivity have been found in the blood of infected individuals and in infected or immunized animals. These findings raise serious concern for the development of a safe vaccine against acquired immunodeficiency syndrome. To address the in vivo relevance and mechanism of this phenomenon, antibody-dependent enhancement of HIV infectivity in peripheral blood macrophages, lymphocytes, and human fibroblastoid cells was studied. Neither Leu3a, a monoclonal antibody directed against the CD4 receptor, nor soluble recombinant CD4 even at high concentrations prevented this enhancement. The addition of monoclonal antibody to the Fc receptor III (anti-FcRIII), but not of antibodies that react with FcRI or FcRII, inhibited HIV type 1 and HIV type 2 enhancement in peripheral blood macrophages. Although enhancement of HIV infection in CD4+ lymphocytes could not be blocked by anti-FcRIII, it was inhibited by the addition of human immunoglobulin G aggregates. The results indicate that the FcRIII receptor on human macrophages and possibly another Fc receptor on human CD4+ lymphocytes mediate antibody-dependent enhancement of HIV infectivity and that this phenomenon proceeds through a mechanism independent of the CD4 protein.

  17. Early Postseroconversion CD4 Cell Counts Independently Predict CD4 Cell Count Recovery in HIV-1–Postive Subjects Receiving Antiretroviral Therapy

    Science.gov (United States)

    Kulkarni, Hemant; Okulicz, Jason F.; Grandits, Greg; Crum-Cianflone, Nancy F.; Landrum, Michael L.; Hale, Braden; Wortmann, Glenn; Tramont, Edmund; Polis, Michael; Dolan, Matthew; Lifson, Alan R.; Agan, Brian K.; Ahuja, Sunil K.; Marconi, Vincent C.

    2013-01-01

    Background The relationship between CD4+ T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown. Methods Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4+ T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well-characterized cohort. The association of baseline with post-HAART CD4+ T-cell count was determined after adjustment for other relevant covariates. Results A higher baseline CD4+ T-cell count predicted a greater post- HAART CD4+ T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4+ count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/baseline count ratio was consistently ≥0.6. Conclusions Among viral load suppressing seroconverters, the absolute CD4+ T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4+ T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons. PMID:21546844

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

    Energy Technology Data Exchange (ETDEWEB)

    Schols, D.; Baba, M.; Pauwels, R.; Desmyter, J.; De Clercq, E. (Katholieke Universiteit Leuven (Belgium))

    1989-05-01

    The triphenylmethane derivative aurintricarboxylic acid (ATA), but not aurin, selectively prevented the binding of OKT4A/Leu-3a monoclonal antibody (mAb) and, to a lesser extent, OKT4 mAb to the CD4 cell receptor for human immunodeficiency virus type 1 (HIV-1). The effect was seen within 1 min at an ATA concentration of 10 {mu}M in various T4{sup +} 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.

  19. Effect of Natalizumab on Circulating CD4(+) T-Cells in Multiple Sclerosis

    DEFF Research Database (Denmark)

    Börnsen, Lars; Christensen, Jeppe Romme; Ratzer, Rikke;

    2012-01-01

    In multiple sclerosis (MS), treatment with the monoclonal antibody natalizumab effectively reduces the formation of acute lesions in the central nervous system (CNS). Natalizumab binds the integrin very late antigen (VLA)-4, expressed on the surface of immune cells, and inhibits VLA-4 dependent......-cells due to reduced extravasation of activated and pro-inflammatory T-cells or due to induction of VLA-4 mediated co-stimulatory signals by natalizumab. In this study we examined how natalizumab treatment altered the distribution of effector and memory T-cell subsets in the blood compartment and if T......(HIGH) T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26(HIGH)CD4(+) T-cells in vitro. Otherwise CD4(+) T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. In conclusion natalizumab treatment selectively increased...

  20. 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.

  1. 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...

  2. 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...

  3. 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...

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  5. 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

  6. KI and WU polyomaviruses and CD4+ cell counts in HIV-1-infected patients, Italy.

    Science.gov (United States)

    Babakir-Mina, Muhammed; Ciccozzi, Massimo; Farchi, Francesca; Bergallo, Massimiliano; Cavallo, Rossana; Adorno, Gaspare; Perno, Carlo Federico; Ciotti, Marco

    2010-09-01

    To investigate an association between KI and WU polyomavirus (KIPyV and WUPyV) infections and CD4+ cell counts, we tested HIV-1-positive patients and blood donors. No association was found between cell counts and virus infections in HIV-1-positive patients. Frequency of KIPyV infection was similar for both groups. WUPyV was more frequent in HIV-1-positive patients.

  7. Effects of Points Transplantation on Allogeneic Cord Blood Stem Cell in Rheumatoid Arthritis in Peripheral Blood CD4+CD25+ Regulatory T Cells%异基因脐血干细胞穴位移植对类风湿关节炎大鼠外周血CD4+CD25+调节性T细胞的影响

    Institute of Scientific and Technical Information of China (English)

    姜兆荣; 高明利; 牛广华; 高玉杰; 刘东武

    2015-01-01

    目的:观察异基因脐血干细胞(hUCBSCs)穴位移植对类风湿关节炎大鼠外周血CD4+CD25+调节性T细胞(CD4+ CD25+ Treg)的干预作用及相关机制.方法:先进行脐血CD34+细胞分选,将100只大鼠随机分为正常对照组、模型组对照组、hUCBSC尾静脉注射治疗组、hUCBSCs外关穴注射治疗组、甲氨喋呤(MTX)灌胃治疗组,每组20只.采用邓安梅法建立胶原诱导性关节炎(CIA)大鼠模型.于大鼠免疫后第31天(除正常组及模型组用等体积蒸馏水)向外关穴、尾静脉注射0.5 mL氯化钠注射液和0.5mL hUCBSCs悬液(含干细胞2×107/mL),4周后采用流式细胞仪,对外周血CD4+ CD25+细胞的百分含量及其在CD4+T淋巴细胞中所占的比例进行检测.结果:hUCBSCs外关穴注射治疗组外周血CD4+ CD25+细胞的百分含量及其在CD4+T淋巴细胞中所占的比例与甲氨喋呤组比较明显增高,差异有统计学意义(P<0.01),hUCBSC尾静脉注射治疗组与甲氨喋呤组比较,无显著性差异(P>0.05).结论:hUCBSCs外关穴穴位注射治疗可能通过上调CD4+ CD25+调节性T细胞水平,抑制关节炎症和关节骨破坏吸收,有助于类风湿关节炎的治疗.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies

    Science.gov (United States)

    Zarling, Joyce M.; Moran, Patricia A.; Haffar, Omar; Sias, Joan; Richman, Douglas D.; Spina, Celsa A.; Myers, Dorothea E.; Kuebelbeck, Virginia; Ledbetter, Jeffrey A.; Uckun, Fatih M.

    1990-09-01

    FUNCTIONAL impairment and selective depletion of CD4+ T cells, the hallmark of AIDS, are at least partly caused by human immunodeficiency virus (HIV-1) type 1 binding to the CD4 molecule and infecting CD4+ cells1,2. It may, therefore, be of therapeutic value to target an antiviral agent to CD4+ cells to prevent infection and to inhibit HIV-1 production in patients' CD4+ cells which contain proviral DNA3,4. We report here that HIV-1 replication in normal primary CD4+ T cells can be inhibited by pokeweed antiviral protein, a plant protein of relative molecular mass 30,000 (ref. 5), which inhibits replication of certain plant RNA viruses6-8, and of herpes simplex virus, poliovirus and influenza virus9-11. Targeting pokeweed antiviral protein to CD4+ T cells by conjugating it to monoclonal antibodies reactive with CDS, CD7 or CD4 expressed on CD4+ cells, increased its anti-HIV potency up to 1,000-fold. HIV-1 replication is inhibited at picomolar concentrations of conjugates of pokeweed antiviral protein and monoclonal antibodies, which do not inhibit proliferation of normal CD4+ T cells or CD4-dependent responses. These conjugates inhibit HIV-1 protein synthesis and also strongly inhibit HIV-1 production in activated CD4+ T cells from infected patients.

  13. 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...

  14. 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.

  15. Antigen presenting B cells facilitate CD4 T cell cooperation resulting in enhanced generation of effector and memory CD4 T cells.

    Directory of Open Access Journals (Sweden)

    David R Kroeger

    Full Text Available We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII-binding peptide of hen egg lysozyme (HEL is facilitated when mice are immunized with splenic antigen presenting cells (APC pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs, can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252 interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of "epitope-spreading" seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation.

  16. 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...

  17. CD4 Variability in Malawi: Implications for Use of a CD4 Threshold of 500 Cells/mm3 Versus Universal Eligibility for Antiretroviral Therapy

    Science.gov (United States)

    Schooley, Alan L.; Kamudumuli, Pocha Samuel; Vangala, Sitaram; Tseng, Chi-hong; Soko, Chifundo; Parent, Julie; Phiri, Khumbo; Jahn, Andreas; Namarika, Dan; Hoffman, Risa M.

    2016-01-01

    Background. Given the uncertainty about the ability of a single CD4 count to accurately classify a patient as antiretroviral therapy (ART) eligible, we sought to understand the extent to which CD4 variability results in misclassification at a CD4 threshold of 500 cells/mm3. Methods. We performed a prospective study of CD4 variability in Malawian human immunodeficiency virus-infected, ART-naive, World Health Organization (WHO) stage 1 or 2, nonpregnant adults. CD4 counts were performed daily for 8 days. We fit a Bayesian linear mixed-effects model of log-transformed CD4 cell counts to the data. We used Monte Carlo approximations to estimate misclassification rates for different observed values of CD4. The misclassification rate was calculated based on the conditional probability of true CD4 given the geometric mean of observed CD4 measurements. Results. Fifty patients were enrolled from 2 sites. The median age was 33.5 years (interquartile range, 27.5–40.0) and 34 (68%) were female. Misclassification rates were <1% when the observed CD4 counts were ≤250 or ≥750 cells/mm3. Rates of misclassification were high at observed CD4 counts between 350 and 650 cells/mm3, particularly when a single measurement was used (up to 46.7%). Conclusions. Our data show that ART eligibility based on a single CD4 count results in highest risk of misclassification when observed CD4 counts are in the range of 350–650 cells/mm3. Given the benefits of early ART, countries should weigh the costs and complexity of CD4 testing using a 500 cell/mm3 threshold against the cost savings and public health benefits of universal eligibility. PMID:27704028

  18. 呼吸道合胞病毒毛细支气管炎患儿外周血CD4+CD25+调节性T细胞与Th17细胞功能变化及意义%Changes and the clinical significance of CD4+ CD25+ regulatory T cells and Th17 cells in peripheral blood of infants with respiratory syncytial virus bronchiolitis

    Institute of Scientific and Technical Information of China (English)

    李宾; 吴福玲; 冯学斌; 孙大康; 崔晴晴; 赵志旭

    2012-01-01

    AIM: To observe the percentages of CD4 + CD25+ regulatory T cells (Tregs) and Thl7 cells and the levels of IL-10, TGF-p and IL-17 in peripheral blood of infants with respiratory syncytial virus ( RSV) bronchiolitis. The relationship between above cells, cytokines and RSV bronchiolitis was determined. METHODS: Thirty-three infants with RSV bronchiolitis, twenty-eight infants with non-RSV pneumonia and twenty-six healthy infants were enrolled. The percentages of Tregs and Thl7 cells in peripheral blood were detected by flow cytometer (FCM), and the levels of IL-10, TGF-pand IL-17 in plasma were determined by ELISA. RESULTS: The percentage of Tregs and the levels of IL-10 and TGF-pin infants with RSV bronchiolitis were significantly lower than those in infants with non-RSV pneumonia and healthy infants ( P < 0. 05), while the percentage of Thl7 cells and the level of IL-17 in infants with RSV bronchiolitis were significantly higher than those in infants with non-RSV pneumonia and healthy infants ( P < 0. 05). CONCLUSION: The imbalance between Tregs and Thl7 cells in peripheral blood of infants with RSV bronchiolitis may be one of the pathogenesis of RSV bronchiolitis.%目的:探讨呼吸道合胞病毒(RSV)毛细支气管炎患儿外周血CD4+ CD25+调节性T细胞和Th17细胞及其分泌细胞因子IL-10、TGF-β、IL-17水平变化与RSV毛细支气管炎发病的关系.方法:收集2010-09/2011-04在滨州医学院附属医院儿科住院的33例RSV毛细支气管炎患儿、28例做为阳性对照的非RSV感染性肺炎患儿(肺炎组)及26例正常对照组的健康体检儿外周血,采用流式细胞术(FCM)检测外周血CD4+ CD25+调节性T细胞、Th17细胞百分率,酶联免疫吸附(ELISA)法检测血浆IL-10、TGF-β、IL-17的水平.结果:RSV毛细支气管炎患儿外周血CD4+ CD25+调节性T细胞、IL-10、TGF-β水平显著低于肺炎患儿及健康体检儿(P<0.05),而Th17、IL-17水平则显著高于肺炎患儿与健康体检儿(P<0

  19. 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.

  20. 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

  1. 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...

  2. 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

  3. Human CD4+ T cell epitopes from vaccinia virus induced by vaccination or infection.

    Directory of Open Access Journals (Sweden)

    J Mauricio Calvo-Calle

    2007-10-01

    Full Text Available Despite the importance of vaccinia virus in basic and applied immunology, our knowledge of the human immune response directed against this virus is very limited. CD4(+ T cell responses are an important component of immunity induced by current vaccinia-based vaccines, and likely will be required for new subunit vaccine approaches, but to date vaccinia-specific CD4(+ T cell responses have been poorly characterized, and CD4(+ T cell epitopes have been reported only recently. Classical approaches used to identify T cell epitopes are not practical for large genomes like vaccinia. We developed and validated a highly efficient computational approach that combines prediction of class II MHC-peptide binding activity with prediction of antigen processing and presentation. Using this approach and screening only 36 peptides, we identified 25 epitopes recognized by T cells from vaccinia-immune individuals. Although the predictions were made for HLA-DR1, eight of the peptides were recognized by donors of multiple haplotypes. T cell responses were observed in samples of peripheral blood obtained many years after primary vaccination, and were amplified after booster immunization. Peptides recognized by multiple donors are highly conserved across the poxvirus family, including variola, the causative agent of smallpox, and may be useful in development of a new generation of smallpox vaccines and in the analysis of the immune response elicited to vaccinia virus. Moreover, the epitope identification approach developed here should find application to other large-genome pathogens.

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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...

  9. 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

  10. Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35.

    Science.gov (United States)

    Bardel, Emilie; Larousserie, Frédérique; Charlot-Rabiega, Pascaline; Coulomb-L'Herminé, Aurore; Devergne, Odile

    2008-11-15

    EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3(+) nor CD25(+) cells coexpressed EBI3. Similarly, Foxp3(+) cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4(+) T cells, CD8(+) and gammadelta T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8(+) and gammadelta T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4(+) T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35.

  11. 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

  12. CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART

    Science.gov (United States)

    Fromentin, Rémi; Bakeman, Wendy; Lawani, Mariam B.; Khoury, Gabriela; Hartogensis, Wendy; DaFonseca, Sandrina; Killian, Marisela; Epling, Lorrie; Hoh, Rebecca; Sinclair, Elizabeth; Hecht, Frederick M.; Bacchetti, Peter; Deeks, Steven G.; Lewin, Sharon R.; Sékaly, Rafick-Pierre; Chomont, Nicolas

    2016-01-01

    HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals. PMID:27415008

  13. 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.

  14. 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.

  15. Peripheral canine CD4(+)CD8(+) double-positive T cells - unique amongst others.

    Science.gov (United States)

    von Buttlar, Heiner; Bismarck, Doris; Alber, Gottfried

    2015-12-15

    T lymphocytes co-expressing CD4 and CD8 ("double-positive T cells") are commonly associated with a thymic developmental stage of T cells. Their first description in humans and pigs as extrathymic T cells with a memory phenotype almost 30 years ago came as a surprise. Meanwhile peripheral double-positive T cells have been described in a growing number of different species. In this review we highlight novel data from our very recent studies on canine peripheral double-positive T cells which point to unique features of double-positive T cells in the dog. In contrast to porcine CD4(+)CD8(+) T cells forming a homogenous cellular population based on their expression of CD4 and CD8α, canine CD4(+)CD8(+) T cells can be divided into three different cellular subsets with distinct expression levels of CD4 and CD8α. Double-positive T cells expressing CD8β are present in humans and dogs but absent in swine. Moreover, canine CD4(+)CD8(+) T cells can not only develop from CD4(+) single-positive T cells but also from CD8(+) single-positive T cells. Together, this places canine CD4(+)CD8(+) T cells closer to their human than porcine counterparts since human double-positive T cells also appear to be heterogeneous in their CD4 and CD8α expression and have both CD4(+) and CD8(+) T cells as progenitor cells. However, CD4(+) single-positive T cells are the more potent progenitors for canine double-positive T cells, whereas CD8(+) single-positive T cells are more potent progenitors for human double-positive T cells. Canine double-positive T cells have an activated phenotype and may have as yet unrecognized roles in vivo in immunity to infection or in inflammatory diseases such as chronic infection, autoimmunity, allergy, or cancer.

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    Lifescience Database Archive (English)

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

    Lifescience Database Archive (English)

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

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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

    Science.gov (United States)

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

    2014-01-01

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

  8. 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.

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

    OpenAIRE

    Tullius, Estefan G.; Biefer, Hector Rodriguez Cetina; Li, Suyan; Trachtenberg, Alexander J.; Edtinger, Karoline; Quante, Markus; Krenzien, Felix; Uehara, Hirofumi; Yang, Xiaoyong; Kissick, Haydn T.; Kuo, Winston P.; Ghiran, Ionita; Fuente García, Miguel Ángel de la; Arredouani, Mohamed S.; Camacho, Virginia

    2014-01-01

    Producción Científica CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNγ(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation th...

  10. 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.

  11. 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....

  12. 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

  13. 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

  14. 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.

  15. 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)

  16. 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.

  17. 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...

  18. 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

  19. 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

  20. Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis.

    Directory of Open Access Journals (Sweden)

    Zili Zhang

    Full Text Available BACKGROUND: T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2 plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function. DESIGN AND METHODS: Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU models. RESULTS: In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis. CONCLUSION: These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis.

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

    Institute of Scientific and Technical Information of China (English)

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

    2010-01-01

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

  2. 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 ...

  3. Rapamycin combined with allogenic immature dendritic cells selectively expands CD4+CD25+Foxp3+ regulatory T cells in rats

    Institute of Scientific and Technical Information of China (English)

    Guo-YingWang; QiZhang; YangYang; Wen-JieChen; WeiLiu; NanJiang; Gui-HuaChen

    2012-01-01

    BACKGROUND: Dendriticcells(DCs)caninitiatetheexpansion of regulatory T cells (Tregs), which play an indispensable role in inducing transplantation tolerance. Some studies have investigated the effect of the immunosuppressant rapamycin (Rapa) on Tregs in vitro. However, the in vivo effect of Rapa combined with immature DCs (iDCs) on Tregs is unknown. This study was undertaken to determine whether allogenic iDCs combined with a short course of Rapa have the ability to selectivelyexpandtheCD4+CD25+Foxp3+ Tregsinarat model. METHODS: Brown Norway rats were injected intravenously with 2×106 Lewis iDCs followed by 1 mg/kg per day Rapa intraperitoneally for 7 consecutive days. On day 8, the levels of CD4+CD25+Foxp3+ Treg cells in peripheral blood and spleen cells were analyzed by flow cytometry. IL-2, IL-4, TGF-β1, and IFN-γ levels in serum were assessed by ELISA. The experimental animals were divided into four groups: control, Rapa-treated, iDC-treated,andcombination-treated. RESULTS: CD4+CD25+Foxp3+ Tregs comprised 7%-8% of CD4+T cells in control rats. Rapa combined with iDCs enhanced this percentage in the peripheral blood and spleen. However, the levels of Tregs did not significantly change after treatment with Rapa or iDCs alone. The levels of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3- T cells in CD4+ T cells did not significantly change in the combined group. The TGF-β1 level in serum from the combined group increased significantly compared with the other groups. CONCLUSIONS: A significantly higher percentage of CD4+CD25+ Foxp3+ Tregs was found in rats treated with allogenic iDCs and a short course of Rapa, along with an increase in the TGF-β1 level in serum. This improved protocol may be a promising therapeutic strategy to increase Tregs, which are beneficial to the induction of peritransplant tolerance.

  4. 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.

  5. 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...

  6. 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. ...

  7. Circulating subsets and CD4(+)CD25(+) regulatory T cell function in chronic inflammatory demyelinating polyradiculoneuropathy.

    Science.gov (United States)

    Sanvito, Lara; Makowska, Anna; Gregson, Norman; Nemni, Raffaello; Hughes, Richard A C

    2009-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory disease of the peripheral nervous system that is probably autoimmune in origin. Different components of the adaptive and innate immunity may be responsible for the aberrant response towards nerve antigens. To investigate this, we examined lymphocyte subsets and regulatory T cell (Treg) function in the blood of CIDP patients, healthy controls (HC) and subjects with non-immune mediated neuropathies (other neuropathies, ON). We used flow cytometry to determine the frequency of monocytes, B cells, natural killer (NK) and NK-T cells, total and activated CD4(+) and CD8(+) T cells, effector memory and central memory CD4(+) and CD8(+) T cells, and CD4(+)CD25(high)Foxp3(+) Tregs. Treg function was studied after polyclonal stimulation and antigen specific stimulation with myelin protein peptides in CIDP and HC. There was an increased frequency of monocytes (p = 0.02) and decreased frequency of NK cells (p = 0.02) in CIDP compared with HC but not ON. There were no significant differences in other populations. Treg function was impaired in CIDP compared to HC (p = 0.02), whilst T cell proliferation to myelin protein peptides before and after depletion of Tregs was not different between patients and controls. This study shows increased circulating monocytes and reduced NK cells in CIDP. Although Treg frequency was not altered, we confirm that Tregs display a defect of suppressive function. Myelin protein peptides were not the target of the altered peripheral regulation of the immune response. The mechanisms of peripheral immune tolerance in CIDP and their relevance to the pathogenesis deserve further exploration.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Megan KL Macleod

    2015-09-01

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

  10. 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

  11. Advanced glycation end products promote differentiation of CD4(+) T helper cells toward pro-inflammatory response.

    Science.gov (United States)

    Han, Xiao-qun; Gong, Zuo-jiong; Xu, San-qing; Li, Xun; Wang, Li-kun; Wu, Shi-min; Wu, Jian-hong; Yang, Hua-fen

    2014-02-01

    This study investigated the effect of advanced glycation end products (AGEs) on differentiation of naïve CD4(+) T cells and the role of the receptor of AGEs (RAGE) and peroxisome proliferator-activated receptors (PPARs) activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin (BSA) with glucose. Human naïve CD4(+) T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin (sh) RNA knock-down experiment, naïve CD4(+) T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-X(TM) 293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4(+) T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T (Treg) cells was determined by a [(3)H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from naïve CD4(+) T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in naïve CD4(+) T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4(+) T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα PPARγ agonist, PGJ2, inhibited the effect of AGEs on naïve CD4(+) T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It

  12. Expression of chemokine recepter CCR4 and CCR5 on peripheral blood CD4+T cells in systemic lupus erythematosus patients%趋化因子受体CCR4、CCR5在系统性红斑狼疮患者外周血CD4+T淋巴细胞上的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    程慧玲; 刘建伟; 马万山; 迟伟玲

    2008-01-01

    目的 探讨系统性红斑狼疮(SLE)患者趋化因子受体CCR4和CCR5在外周血淋巴细胞表面的表达及其意义.方法 流式细胞仪计数法对113例SLE患者和50例健康体检者外周血淋巴细胞表面CCR4和CCR5的表达情况进行检测,分析及评价SLE患者外周血淋巴细胞中CCR4+和CCR5+T淋巴细胞的百分数.结果 非狼疮性肾炎(nLN)SLE组外周血CCR4+CD4+T%明显高于健康对照组(P<0.01);狼疮性肾炎SLE组外周血CCR4+CD4+T%明显高于健康对照组(P<0.001);LN SLE组外周血CCR4+CD4+T%明显高于nLN SLE组(P<0.01);nLN SLE组外周血CCR5+CD4+T%高于健康对照组(P<0.05);LN SLE组外周血CCR5+CD4+T%明显高于健康对照组(P<0.001);LN SLE组外周血CCR5+CD4+T%明显高于nLN SLE组(P<0.01).SLE活动组血清CCR4+CD4+T%与CCR5+CD4+T%较非活动组和对照组明显升高(P<0.01);活动性狼疮性肾炎(LN)与活动性无肾损伤组及对照组比较,其差异具有显著统计学意义(P<0.01).nLN SLE组外周血CCR4+CD4+T%与CCR5+CD4+T%有相关性(r=0.619,P<0.05);LN SLE组外周血CCR4+CD4+T%与CCR5+CD4+T%有明显相关性(r=0.68,P<0.01);血清CCR4+CD4+T%水平随着SLE疾病活动水平明显升高,与总的系统性红斑狼疮疾病活动性指数(SLEDAI)评分密切相关(r=0.6382,P<0.001);与SLEDAI肾评分亦密切相关(r=0.6980,P<0.001);而CCR5+CD4+T%与疾病活动度不相关(r=0.16,P>0.05).结论 以上结果表明CCR4和CCR5在T细胞趋化至病变部位的过程中可能发挥重要作用,CCR4+CD4+T%与CCR5+CD4+T%可能在肾损伤中起着十分重要的作用,血清CCR4+CD4+T%、CCR5+CD4+T%与SLE疾病活动密切相关,可作为SLE疾病活动,尤其是监测狼疮性肾损伤的重要指标.

  13. 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

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

    Science.gov (United States)

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

    2016-01-01

    CD4(+) T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4(+) T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4(-)CD8(-)NK1.1(-) double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4(+) rather than CD8(+) T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4(+) T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases. PMID:27077809

  15. Targeting of liposomes to HIV-1-infected cells by peptides derived from the CD4 receptor.

    Science.gov (United States)

    Slepushkin, V A; Salem, I I; Andreev, S M; Dazin, P; Düzgüneş, N

    1996-10-23

    Liposomes can be targeted to HIV-infected cells by either reconstituting transmembrane CD4 in the membrane or covalently coupling soluble CD4 to modified lipids. We investigated whether synthetic peptides could be used as ligands for targeting liposomes. A synthetic peptide from the complementarity determining region 2 (CDR-2)-like domain of CD4 could bind specifically to HIV-infected cells and mediate the binding of peptide-coupled liposomes to these cells. A peptide from the CDR-3-like domain of CD4 inhibited HIV-induced syncytia formation, but failed to target liposomes to infected cells. This apparent discrepancy may be due to the requirement for a conformational change in the CD4 receptor for the CDR-3 region to interact with the HIV envelope protein. Our results demonstrate the feasibility of using synthetic peptides to target liposomes containing antiviral drugs to HIV-infected cells.

  16. Lack of Suppressive CD4+CD25+FOXP3+ T Cells in Advanced Stages of Primary Cutaneous T-Cell Lymphoma

    OpenAIRE

    Tiemessen, Machteld M.; Mitchell, Tracey J.; Hendry, Lisa; Whittaker, Sean J; Taams, Leonie S.; John, Susan

    2006-01-01

    Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common primary cutaneous T-cell lymphomas (CTCLs). In an ex vivo study, we investigated the percentage, phenotype, and suppressive function of CD4+CD25+ regulatory T cells (Tregs) from peripheral blood of CTCL patients. The percentage of Tregs did not differ significantly between patients and controls. Functional assays demonstrated a dichotomy in Treg function: in four out of 10 patients CD4+CD25+ T cells were incapabl...

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. 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

  20. Periodontal status in HIV-positive individuals and its possible correlation with CD4+T cell count

    Directory of Open Access Journals (Sweden)

    K Asif

    2012-01-01

    Full Text Available Background : Infection with human immunodeficiency virus (HIV results in loss of immunologic functions, especially those coordinated by CD4+ T-helper cells and consequent impairment of immune response. Periodontal disease has been associated with HIV infection, and HIV infection has been considered a modifier of periodontal disease. Aim: The aim of this study was to report the severity of periodontal disease in HIV-positive individuals and its association between clinical periodontal indices and CD4+T-cell count. Materials and Methods: 25 HIV-positive individuals were recruited and medical history was recorded. To evaluate periodontal disease, clinical attachment loss (CAL, oral hygiene index (OHI, and gingival bleeding index (GI were recorded. Immune suppression was measured by peripheral blood CD4+T cells/mm 3 as analyzed by flow cytometry. Statistical Analysis: Association between CD4+ T levels and clinical parameters were determined using correlation coefficient test. Results: When all subjects were evaluated, a negative correlation was obtained between CD4+ T-cell count and clinical attachment loss (r = -0.68226. In individuals with CD4+cell counts <200 cells/ mm 3 , a negative correlation was obtained between clinical attachment loss (-0.35467 and GI (-0.35202. In patients with CD4 count <200, a negative correlation was obtained between CAL (-0.30361, GI (-0.29711, and OHI (-0.14669. Conclusion: Immune suppression in combination with risk factors may increase progression of periodontal disease. Hence, these individuals should practice better oral hygiene and regular follow-up.

  1. Reduced Plasmodium Parasite Burden Associates with CD38+ CD4+ T Cells Displaying Cytolytic Potential and Impaired IFN-γ Production

    Science.gov (United States)

    Burel, Julie G.; Apte, Simon H.; Groves, Penny L.; Klein, Kerenaftali; McCarthy, James S.; Doolan, Denise L.

    2016-01-01

    Using a unique resource of samples from a controlled human malaria infection (CHMI) study, we identified a novel population of CD4+ T cells whose frequency in the peripheral blood was inversely correlated with parasite burden following P. falciparum infection. These CD4+ T cells expressed the multifunctional ectoenzyme CD38 and had unique features that distinguished them from other CD4+ T cells. Specifically, their phenotype was associated with proliferation, activation and cytotoxic potential as well as significantly impaired production of IFN-γ and other cytokines and reduced basal levels of activated STAT1. A CD38+ CD4+ T cell population with similar features was identified in healthy uninfected individuals, at lower frequency. CD38+ CD4+ T cells could be generated in vitro from CD38- CD4+ T cells after antigenic or mitogenic stimulation. This is the first report of a population of CD38+ CD4+ T cells with a cytotoxic phenotype and markedly impaired IFN-γ capacity in humans. The expansion of this CD38+ CD4+ T population following infection and its significant association with reduced blood-stage parasite burden is consistent with an important functional role for these cells in protective immunity to malaria in humans. Their ubiquitous presence in humans suggests that they may have a broad role in host-pathogen defense. Trial Registration ClinicalTrials.gov clinical trial numbers ACTRN12612000814875, ACTRN12613000565741 and ACTRN12613001040752 PMID:27662621

  2. 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

  3. 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.

  4. 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)

  5. 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.

  6. 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

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

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad;

    2006-01-01

    OBJECTIVE: To evaluate whether T cells expressing CCR5 and CXCR3 from multiple sclerosis (MS) patients are more resistant to apoptosis. METHODS: Expression of CD69, TNF-R1, Fas, FasL, bcl-2, and bax was investigated in 41 MS patients and 12 healthy controls by flow cytometry in CD4+ and CD8+ T...... cells expressing CCR5 and CXCR3. RESULTS: In MS patients, the percentage of CD69 was increased and Fas expression decreased in CD4+ CCR5+ T cells. INTERPRETATION: The lower Fas expression in activated CD4+ CCR5+ T cells might contribute to disease pathogenesis by prolonging cell survival and favoring...

  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. 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

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

    Directory of Open Access Journals (Sweden)

    Deborah M. Brown

    2016-03-01

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

  11. 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...

  12. 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...

  13. 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-...

  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. Phenotypic characteristics of the CD4+CD28- T cell subsets in peripheral blood of patients with Graves disease and its clinical significance%GD患者外周血CD4+CD28-T细胞亚群的表型特征及临床意义

    Institute of Scientific and Technical Information of China (English)

    孙治平; 陈蕾; 淤葛华; 朱一蓓; 仲维学; 施毕旻; 陈冰; 周春刚; 张学光

    2007-01-01

    检测Graves病(GD)患者外周血CD4+ CD28-T细胞水平及其表面CD45RO/CD45RA及ICOS的表达,探讨CD4+ CD28-T细胞亚群在GD免疫致病机制中的作用.采用三色荧光抗体染色及流式细胞术检测了42例初发GD患者和30例健康者外周血中CD4+ CD28-T细胞的百分率及其表面CD45RO/CD45RA和ICOS表达水平,同时检测其甲状腺功能并进行相关性分析.结果GD患者外周血中CD4+ CD28-T细胞百分率明显高于健康对照组,并高表达ICOS分子,与FT3水平显著正相关;与健康对照组相比,GD患者CD4+ CD28- CD45RO+ T细胞百分率也显著增高,而CD4+ CD28- CD45RA+ T细胞呈下降趋势,FT3、FT4水平与CD4+ CD28-T细胞表面CD45RO的表达率呈正相关,而FT3水平与CD45RA表达呈负相关.结论GD患者外周血CD4+ CD28-T细胞异常增高,表面高表达ICOS分子,具有记忆性细胞的表型特征,与甲状腺功能异常有一定的相关性,CD4+ CD28-T细胞可能是参与GD免疫病理反应的自身反应性T细胞.

  16. The role of cytokines in the production of IL-17 and IFN-γvia the induction of normal human peripheral blood mononuclear cells and CD4+T cells%细胞因子直接诱导正常人CD4+T细胞产生IL-17和IFN-γ

    Institute of Scientific and Technical Information of China (English)

    范艳莹; 吴长有

    2007-01-01

    目的:探讨细胞因子(IL-23、IL-2和IL-15)对正常人外周血单个核细胞(PBMC)和CD4+T细胞IL-17产生的诱导作用和调节因素.方法:将正常人PBMC和纯化的CD4+T细胞在不同条件下与IL-23、IL-2和IL-15进行培养,采用ELISA法检测细胞培养液中IL-17和IFN-γ的水平;采用酶联免疫斑点试验(ELISPOT)在单个细胞水平上检测IL-17和IFN-γ产生细胞的频率.结果:IL-23可诱导PBMC产生IL-17和IFN-γ;Th2细胞因子和抗IL-12受体β1(IL-12Rβ1)mAb可抑制IL-23诱导的IL-17和IFN-γ产生.IL-2和IL-15均可诱导IL-17和IFN-γ产生,并与IL-23具有共同诱导作用.IL-12可诱导PBMC产生大量的IFN-γ,但不产生IL-17.进一步研究表明,IL-23、IL-2和IL-15可直接诱导纯化的CD4+T细胞产生IL-17和IFN-γ.结论:IL-23、IL-2和IL-15可直接作用于正常人CD4+T细胞诱导其产生IL-17和IFN-γ;Th2细胞因子和抗IL-12Rβ1 mAb可抑制IL-23诱导的IL-17和IFN-γ产生.为探讨自身免疫性疾病等的发生机制和治疗提供了新的靶点.

  17. The generation and antigen-specificity of CD4+CD25+ regulatory T cells.

    Science.gov (United States)

    Taams, Leonie S; Curnow, S John; Vukmanovic-Stejic, M; Akbar, Arne N

    2006-09-01

    CD4+CD25+ regulatory T cells are essential components of the immune system. They help to maintain immune tolerance by exerting suppressive effects on cells of the adaptive and innate immune system. In the last few years there has been an abundance of papers addressing the suppressive effects of CD4+CD25+ regulatory T cells and their putative role in various experimental disease models and human diseases. Despite the enormous amounts of data on these cells a number of controversial issues still exists. CD4+CD25+ regulatory T cells were originally described as thymus-derived anergic/suppressive T cells. Recent papers however indicate that these cells might also be generated in the periphery. Due to the thymic development of CD4+CD25+ regulatory T cells it was thought that these cells were specific for self-antigens. Indeed it was shown that CD4+CD25+ regulatory T cells could be positively selected upon high affinity interaction with self-antigens. However, evidence is accumulating that these cells might also interact with non-self antigens. Finally, in the literature there is conflicting evidence regarding the role of soluble factors versus cell-contact in the mechanism of suppression. The aim of this review is to summarize the evidence supporting these opposing viewpoints and to combine them into a general model for the origin, function and antigen-specificity of CD4+CD25+ regulatory T cells. PMID:16918478

  18. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo.

    Science.gov (United States)

    Simonetti, Francesco R; Sobolewski, Michele D; Fyne, Elizabeth; Shao, Wei; Spindler, Jonathan; Hattori, Junko; Anderson, Elizabeth M; Watters, Sarah A; Hill, Shawn; Wu, Xiaolin; Wells, David; Su, Li; Luke, Brian T; Halvas, Elias K; Besson, Guillaume; Penrose, Kerri J; Yang, Zhiming; Kwan, Richard W; Van Waes, Carter; Uldrick, Thomas; Citrin, Deborah E; Kovacs, Joseph; Polis, Michael A; Rehm, Catherine A; Gorelick, Robert; Piatak, Michael; Keele, Brandon F; Kearney, Mary F; Coffin, John M; Hughes, Stephen H; Mellors, John W; Maldarelli, Frank

    2016-02-16

    Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4(+)T cells. Some of these CD4(+)T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4(+) T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1-infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4(+)T cells can be a reservoir of infectious HIV-1.

  19. 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...

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

    Science.gov (United States)

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

    2011-01-01

    SUMMARY 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 (200 μg) of a murine anti-mouse CD4 monoclonal IgG (clone GK1·5). CD4+ T-cell-depleted hamsters infected with the hookworm Ancylostoma ceylanicum exhibited a threefold higher mean intestinal worm burden and more severe anaemia than animals that received isotype control IgG. In addition, depletion of CD4+ T cells was associated with impaired cellular and humoral (serum and mucosal) immune responses to hookworm antigens. These data demonstrate an effector role for CD4+ T cells in hookworm immunity and disease pathogenesis. Ultimately, these studies may yield important insights into the relationship between intestinal nematode infections and diseases that are associated with CD4+ T-cell depletion, including HIV. PMID:20500671

  1. 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

    SCID mice express the Fas ligand on the surface. Gut lamina propria CD4+ T cells show Fas-dependent cytotoxicity. A large fraction of gut lamina propria CD4+ T cells that infiltrate the inflamed colon in transplanted SCID mice are activated in situ and many CD4+ T cells are apoptotic. Hence, a large...... fraction of colitis-inducing CD4+ T cells undergo activation-induced cell death in situ and can damage other cells through Fas-dependent cytotoxicity....

  2. 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...

  3. 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...

  4. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing?

    Directory of Open Access Journals (Sweden)

    Kathrin Maly

    2015-01-01

    Full Text Available CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

  5. The story of CD4+ CD28- T cells revisited: solved or still ongoing?

    Science.gov (United States)

    Maly, Kathrin; Schirmer, Michael

    2015-01-01

    CD4(+)CD28(-) T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4(+) T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4(+)CD28(-) T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4(+)CD28(-) T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4(+)CD28(-) T cell level. The clinical relevance of targeting CD4(+)CD28(-) T cells as a therapeutic option has not been examined so far. PMID:25834833

  6. 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

  7. 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.

  8. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics.

    Science.gov (United States)

    Zanetti, Maurizio

    2015-03-01

    Cellular immune responses that protect against tumors typically have been attributed to CD8 T cells. However, CD4 T cells also play a central role. It was shown recently that, in a patient with metastatic cholangiocarcinoma, CD4 T cells specific for a peptide from a mutated region of ERBB2IP could arrest tumor progression. This and other recent findings highlight new opportunities for CD4 T cells in cancer immunotherapy. In this article, I discuss the role and regulation of CD4 T cells in response to tumor Ags. Emphasis is placed on the types of Ags and mechanisms that elicit tumor-protective responses. I discuss the advantages and drawbacks of cancer immunotherapy through personalized genomics. These considerations should help to guide the design of next-generation therapeutic cancer vaccines.

  9. FIV establishes a latent infection in feline peripheral blood CD4+ T lymphocytes in vivo during the asymptomatic phase of infection

    Directory of Open Access Journals (Sweden)

    Murphy Brian

    2012-02-01

    Full Text Available Abstract Background Feline immunodeficiency virus (FIV is a lentivirus of cats that establishes a lifelong persistent infection with immunologic impairment. Results In an approximately 2 year-long experimental infection study, cats infected with a biological isolate of FIV clade C demonstrated undetectable plasma viral loads from 10 months post-infection onward. Viral DNA was detected in CD4+CD25+ and CD4+CD25- T cells isolated from infected cats whereas viral RNA was not detected at multiple time points during the early chronic phase of infection. Viral transcription could be reactivated in latently infected CD4+ T cells ex vivo as demonstrated by detectable FIV gag RNA and 2-long terminal repeat (LTR circle junctions. Viral LTR and gag sequences amplified from peripheral blood mononuclear cells during early and chronic stages of infection demonstrated minimal to no viral sequence variation. Conclusions Collectively, these findings are consistent with FIV latency in peripheral blood CD4+ T cells isolated from chronically infected cats. The ability to isolate latently FIV-infected CD4+ T lymphocytes from FIV-infected cats provides a platform for the study of in vivo mechanisms of lentiviral latency.

  10. 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.

  11. Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells

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    Kim Julian A

    2004-11-01

    Full Text Available Abstract T cell-mediated cancer immunotherapy is dose dependent and optimally requires participation of antigen-specific CD4+ and CD8+ T cells. Here, we isolated tumor-sensitized T cells and activated them in vitro using conditions that led to greater than 108-fold numerical hyperexpansion of either the CD4+ or CD8+ subset while retaining their capacity for in vivo therapeutic efficacy. Murine tumor-draining lymph node (TDLN cells were segregated to purify the CD62Llow subset, or the CD4+ subset thereof. Cells were then propagated through multiple cycles of anti-CD3 activation with IL-2 + IL-7 for the CD8+ subset, or IL-7 + IL-23 for the CD4+ subset. A broad repertoire of TCR Vβ families was maintained throughout hyperexpansion, which was similar to the starting population. Adoptive transfer of hyper-expanded CD8+ T cells eliminated established pulmonary metastases, in an immunologically specific fashion without the requirement for adjunct IL-2. Hyper-expanded CD4+ T cells cured established tumors in intracranial or subcutaneous sites that were not susceptible to CD8+ T cells alone. Because accessibility and antigen presentation within metastases varies according to anatomic site, maintenance of a broad repertoire of both CD4+ and CD8+ T effector cells will augment the overall systemic efficacy of adoptive immunotherapy.

  12. Idiopathic CD4 lymphocytopenia with giant cell arteritis and pulmonary mucormycosis

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    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.

  13. Change of CD4+ CD25+ CD127 low regulatory T cells in peripheral blood of patients with Graves disease treated by 131 I or antithyroid drugs therapy%Graves病131I或抗甲状腺药物治疗前后外周血CD4+CD25+CD127low调节性T细胞的变化

    Institute of Scientific and Technical Information of China (English)

    杨静; 潘天荣; 杜益君; 钟兴

    2016-01-01

    目的:探讨调节性T细胞( Treg)在Graves病( GD)患者外周血中变化,以及131 I或抗甲状腺药物( ATD)治疗后其变化趋势,寻找评价131 I和ATD治疗疗效的新指标。方法健康者40例设为对照组,初诊GD患者40例设为GD组,并将GD组随机分成131 I 治疗组(20例)及 ATD 治疗组(20例)。检测131 I治疗组、ATD治疗组治疗前、治疗后及对照组CD4+CD25+CD127 low Treg 比例、白介素-10( IL-10)、转化生长因子-β1(TGF-β1)水平,通过统计学软件处理相关结果。结果①治疗前GD组Treg比例较对照组明显降低,差异有统计学意义( P<0.01);②131 I治疗组、ATD治疗组治疗后第3个月及第6个月Treg比例较治疗前均升高,差异均有统计学意义( P <0.01);③治疗后第3个月及第6个月, ATD治疗组Treg比例与131 I治疗组差异无统计学意义;④治疗前GD组IL-10、TGF-β1水平较对照组均降低,治疗后6个月,细胞因子水平较治疗前均升高,差异均有统计学意义(P<0.05),各时间点131 I治疗组与ATD治疗组之间,细胞因子差异无统计学意义。结论 GD患者Treg比例和功能显著降低,治疗后部分恢复,因此,对于甲亢患者,Treg可能是评价免疫状态及治疗后病情缓解的指标之一。%Objective To investigate the changes of regulatory T cells ( Treg) in Graves disease ( GD) before and after being treated by 131 I or antithyroid drugs( ATD) ,and to seek for new clinical indicators to evaluate the treat-ment response. Methods The study groups included 40 patients with GD ( GD group) , 20 of whom were treated by 131 I ,others were treated by ATD. Forty healthy donors without history of thyroid or autoimmune disease were en-rolled in control group. The proportions of CD4 +CD25 +CD127low Treg , IL-10 and TGF-β1 were tested before and after treatment respectively. Results ① The significant decrease in the proportion of CD4 +CD25 +CD127low Treg cells in untreated GD patients ( GD group) was

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

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    Seema M Thayil

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

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

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    Campbell James J

    2006-07-01

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

  16. 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.

  17. 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...

  18. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy.

    Science.gov (United States)

    Matsuzawa, Yu; Oshima, Shigeru; Takahara, Masahiro; Maeyashiki, Chiaki; Nemoto, Yasuhiro; Kobayashi, Masanori; Nibe, Yoichi; Nozaki, Kengo; Nagaishi, Takashi; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Ma, Averil; Watanabe, Mamoru

    2015-01-01

    Autophagy plays important roles in metabolism, differentiation, and survival in T cells. TNFAIP3/A20 is a ubiquitin-editing enzyme that is thought to be a negative regulator of autophagy in cell lines. However, the role of TNFAIP3 in autophagy remains unclear. To determine whether TNFAIP3 regulates autophagy in CD4 T cells, we first analyzed Tnfaip3-deficient naïve CD4 T cells in vitro. We demonstrated that Tnfaip3-deficient CD4 T cells exhibited reduced MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) puncta formation, increased mitochondrial content, and exaggerated reactive oxygen species (ROS) production. These results indicate that TNFAIP3 promotes autophagy after T cell receptor (TCR) stimulation in CD4 T cells. We then investigated the mechanism by which TNFAIP3 promotes autophagy signaling. We found that TNFAIP3 bound to the MTOR (mechanistic target of rapamycin) complex and that Tnfaip3-deficient cells displayed enhanced ubiquitination of the MTOR complex and MTOR activity. To confirm the effects of enhanced MTOR activity in Tnfaip3-deficient cells, we analyzed cell survival following treatment with Torin1, an MTOR inhibitor. Tnfaip3-deficient CD4 T cells exhibited fewer cell numbers than the control cells in vitro and in vivo. In addition, the impaired survival of Tnfaip3-deficient cells was ameliorated with Torin1 treatment in vitro and in vivo. The effect of Torin1 was abolished by Atg5 deficiency. Thus, enhanced MTOR activity regulates the survival of Tnfaip3-deficient CD4 T cells. Taken together, our findings illustrate that TNFAIP3 restricts MTOR signaling and promotes autophagy, providing new insight into the manner in which MTOR and autophagy regulate survival in CD4 T cells.

  19. 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...

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

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    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.

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

    Science.gov (United States)

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

    2003-07-01

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

  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. KI and WU Polyomaviruses and CD4+ Cell Counts in HIV-1–infected Patients, Italy

    Science.gov (United States)

    Babakir-Mina, Muhammed; Ciccozzi, Massimo; Farchi, Francesca; Bergallo, Massimiliano; Cavallo, Rossana; Adorno, Gaspare; Perno, Carlo Federico

    2010-01-01

    To investigate an association between KI and WU polyomavirus (KIPyV and WUPyV) infections and CD4+ cell counts, we tested HIV-1–positive patients and blood donors. No association was found between cell counts and virus infections in HIV-1–positive patients. Frequency of KIPyV infection was similar for both groups. WUPyV was more frequent in HIV-1–positive patients. PMID:20735940

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

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    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.

  5. High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer.

    Science.gov (United States)

    Péguillet, Isabelle; Milder, Maud; Louis, Delphine; Vincent-Salomon, Anne; Dorval, Thierry; Piperno-Neumann, Sophie; Scholl, Suzy M; Lantz, Olivier

    2014-04-15

    CD4(+) T cells influence tumor immunity in complex ways that are not fully understood. In this study, we characterized a population of human differentiated effector CD4(+) T cells that is defined by low levels of the interleukin (IL)-2 and IL-7 receptors (CD25(-)CD127(-)). We found that this cell population expands in patients with various types of cancer, including breast cancer, to represent 2% to 20% of total CD4(+) blood T lymphocytes as compared with only 0.2% to 2% in healthy individuals. Notably, these CD25(-)CD127(-)CD4 T cells expressed effector markers such as CD244 and CD11b with low levels of CD27, contrasting with the memory phenotype dominating this population in healthy individuals. These cells did not cycle in patients, nor did they secrete IL-10 or IL-17, but instead displayed cytotoxic features. Moreover, they encompassed oligoclonal expansions paralleling an expansion of effector CD8(+) T cells that included tumor antigen-specific T cells. During neoadjuvant chemotherapy in patients with breast cancer, we found that the increase in CD25(-)CD127(-) CD4(+) T cells correlated with tumor regression. This observation suggested that CD4(+) T cells included tumor antigen-specific cells, which may be generated by or participate in tumor regressions during chemotherapy. In summary, our results lend support to the hypothesis that CD4(+) T cells are involved in human antitumor responses.

  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. 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

  8. Expression of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+T cells of rheumatoid arthritis patients and its significance%芳香烃受体在类风湿关节炎患者外周血CCR6+CD4+T细胞的表达及意义

    Institute of Scientific and Technical Information of China (English)

    谭悦; 钱龙; 李向培; 汪国生; 厉小梅; 陶金辉; 陈本露

    2014-01-01

    目的 检测类风湿关节炎(RA)患者外周血 CCR6+CD4+T细胞芳香烃受体(AhR)水平,探讨AhR在RA发病机制中的意义.方法 采用流式细胞术测定33例RA患者及14例健康对照者外周血CCR6+CD4+T细胞中AhR阳性细胞比例,分析其与RA患者临床指标的关系.结果1)RA患者组外周血单个核细胞(PBMCs)中CCR6+CD4+T细胞占(10.75±2.92)%,高于健康对照组(4.96±2.28)%,差异有统计学意义(t=6.581,P<0.01).2)RA患者组内外周血CCR6+CD4+T细胞中AhR阳性细胞所占比例(46.02±14.68)%,高于CCR6-CD4+T细胞(21.62±6.94)%和PBMCs(34.22±10.33)%中AhR阳性细胞占比,差异均有统计学意义(z=-6.432,P<0.01;t=-3.776,P<0.01).3)RA患者组外周血CCR6+CD4+T细胞中AhR阳性细胞所占比例(46.02±14.68)%,高于健康对照组(23.18±5.62)%,差异有统计学意义(z=-4.909,P<0.01).4)相关性分析:RA患者组外周血CCR6+CD4+T细胞中AhR阳性细胞所占比例与血沉(ESR)、C反应蛋白(CRP)、抗环瓜氨酸肽(抗-CCP)抗体、DAS28评分、疾病病程均无相关性(P均>0.05).结论 AhR阳性细胞在RA患者外周血 CCR6+CD4+T细胞中比例高,可能参与了RA发病,但其水平高低不能反映RA疾病活动程度.

  9. Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia.

    Science.gov (United States)

    Matarese, Giuseppe; La Rocca, Claudia; Moon, Hyun-Seuk; Huh, Joo Young; Brinkoetter, Mary T; Chou, Sharon; Perna, Francesco; Greco, Dario; Kilim, Holly P; Gao, Chuanyun; Arampatzi, Kalliope; Wang, Zhaoxi; Mantzoros, Christos S

    2013-02-26

    Leptin is an adipocyte-derived hormone that controls food intake and reproductive and immune functions in rodents. In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T-cell counts; however, the effects of leptin replacement on the adaptive immune system have not yet been reported in the context of randomized, controlled studies and/or in conditions of chronic acquired leptin deficiency. To address these questions, we performed a randomized, double-blinded, placebo-controlled trial of recombinant methionyl-human leptin (metreleptin) administration in replacement doses in women experiencing the female triad (hypothalamic amenorrhea) with acquired chronic hypoleptinemia induced by negative energy balance. Metreleptin restored both CD4(+) T-cell counts and their in vitro proliferative responses in these women. These changes were accompanied by a transcriptional signature in which genes relevant to cell survival and hormonal response were up-regulated, and apoptosis genes were down-regulated in circulating immune cells. We also observed that signaling pathways involved in cell growth/survival/proliferation, such as the STAT3, AMPK, mTOR, ERK1/2, and Akt pathways, were activated directly by acute in vivo metreleptin administration in peripheral blood mononuclear cells and CD4(+) T-cells both from subjects with chronic hypoleptinemia and from normoleptinemic, lean female subjects. Our data show that metreleptin administration, in doses that normalize circulating leptin levels, induces transcriptional changes, activates intracellular signaling pathways, and restores CD4(+) T-cell counts. Thus, metreleptin may prove to be a safe and effective therapy for selective CD4(+) T-cell immune reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4(+) T cells are reduced. PMID:23382191

  10. 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.

  11. HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

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    Nathan Erdmann

    2015-08-01

    Full Text Available Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1 exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE or its non-adapted (NAE version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001. However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001. CD4+ T cell responses in patients with acute HIV infection (AHI demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

  12. Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis.

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    Bingfen Yang

    Full Text Available CD244 (2B4 is a member of the signaling lymphocyte activation molecule (SLAM family of immune cell receptors and it plays an important role in modulating NK cell and CD8(+ T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4(+ T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4(+ T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen-specific CD4(+ T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4(+ T cells, CD244/2B4-bright CD4(+ T cell subset had significantly reduced expression of IFN-γ, suggesting that CD244/2B4 expression may modulate IFN-γ production in M. tuberculosis antigen-responsive CD4(+ T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-γ. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-γ, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4(+ T cell function.

  13. Quorum sensing in CD4+ T cell homeostasis: a hypothesis and a model.

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    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.

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

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    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.

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

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    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.

  16. Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.

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    C Scott Mahan

    Full Text Available BACKGROUND: Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone. METHODOLOGY: This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3 and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB. RESULTS: Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period. CONCLUSION: TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.

  17. 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

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

    Science.gov (United States)

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

    2016-02-01

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

  19. 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.

  20. 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.

  1. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.

    Science.gov (United States)

    Swaims, Alison Y; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I; Devadas, Satish; Shi, Yufang; Rabson, Arnold B

    2010-10-21

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals. PMID:20634377

  2. 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 (...

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

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    Ray Krishnangshu

    2011-10-01

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real-time PCR method. CD4+ T cells were isolated from 17 paired sa...

  5. Selective Loss of Innate CD4+ Vα24 Natural Killer T Cells in Human Immunodeficiency Virus Infection

    Science.gov (United States)

    Sandberg, Johan K.; Fast, Noam M.; Palacios, Emil H.; Fennelly, Glenn; Dobroszycki, Joanna; Palumbo, Paul; Wiznia, Andrew; Grant, Robert M.; Bhardwaj, Nina; Rosenberg, Michael G.; Nixon, Douglas F.

    2002-01-01

    Vα24 natural killer T (NKT) cells are innate immune cells involved in regulation of immune tolerance, autoimmunity, and tumor immunity. However, the effect of human immunodeficiency virus type 1 (HIV-1) infection on these cells is unknown. Here, we report that the Vα24 NKT cells can be subdivided into CD4+ or CD4− subsets that differ in their expression of the homing receptors CD62L and CD11a. Furthermore, both CD4+ and CD4− NKT cells frequently express both CXCR4 and CCR5 HIV coreceptors. We find that the numbers of NKT cells are reduced in HIV-infected subjects with uncontrolled viremia and marked CD4+ T-cell depletion. The number of CD4+ NKT cells is inversely correlated with HIV load, indicating depletion of this subset. In contrast, CD4− NKT-cell numbers are unaffected in subjects with high viral loads. HIV infection experiments in vitro show preferential depletion of CD4+ NKT cells relative to regular CD4+ T cells, in particular with virus that uses the CCR5 coreceptor. Thus, HIV infection causes a selective loss of CD4+ lymph node homing (CD62L+) NKT cells, with consequent skewing of the NKT-cell compartment to a predominantly CD4− CD62L− phenotype. These data indicate that the key immunoregulatory NKT-cell compartment is compromised in HIV-1-infected patients. PMID:12097565

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

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    Adria eCarbo

    2014-07-01

    Full Text Available The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation.

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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...

  14. 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

  15. 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 ...

  16. Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype.

    Science.gov (United States)

    Kaiser, Ylva; Lepzien, Rico; Kullberg, Susanna; Eklund, Anders; Smed-Sörensen, Anna; Grunewald, Johan

    2016-08-01

    Disease phenotypes of pulmonary sarcoidosis are distinguished by clinical rather than immunological criteria. We aimed to characterise patterns of CD4(+) T-cell lineage plasticity underlying the differences in clinical presentation and disease course between the acute form, Löfgren's syndrome, and the heterogeneous, potentially progressive "non-Löfgren" form.33 pulmonary sarcoidosis patients and nine controls underwent bronchoscopy with bronchoalveolar lavage. CD4(+) T-cell transcription factor, chemokine receptor and T-cell receptor expression, proliferation and cytokine production were assessed in the lavage fluid and peripheral blood using flow cytometry and multicolour FluoroSpot.CD4(+) T-cells simultaneously expressing the T-helper cell (Th)1 and Th17 transcriptional regulators T-bet and RORγT (T-bet(+)RORγT(+)) were identified in the lavage, but not blood, of all subjects, and to a significantly higher degree in Löfgren's patients. T-bet(+)RORγT(+) cells proliferated actively, produced interferon (IFN)γ and interleukin (IL)-17A, co-expressed the chemokine receptors CXCR3 and CCR6, and correlated with nonchronic disease. T-cell receptor-restricted Vα2.3(+)Vβ22(+) T-cells strongly co-expressed T-bet/RORγT and CXCR3/CCR6. Cytokine production was more heterogeneous in Löfgren's patients, with significantly higher IL-17A, IL-10, IL-22 and IL-2, but lower IFNγ.Here we demonstrate the presence of lung T-bet(+)RORγT(+)CXCR3(+)CCR6(+) CD4(+) T-cells and Th17-associated cytokines especially in sarcoidosis patients with a favourable prognosis, suggesting a Th1/Th17-permissive environment in the lung with implications for disease resolution. PMID:27230441

  17. 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.

  18. Lack of suppressive CD4+CD25+FOXP3+ T cells in advanced stages of primary cutaneous T-cell lymphoma.

    Science.gov (United States)

    Tiemessen, Machteld M; Mitchell, Tracey J; Hendry, Lisa; Whittaker, Sean J; Taams, Leonie S; John, Susan

    2006-10-01

    Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common primary cutaneous T-cell lymphomas (CTCLs). In an ex vivo study, we investigated the percentage, phenotype, and suppressive function of CD4+CD25+ regulatory T cells (Tregs) from peripheral blood of CTCL patients. The percentage of Tregs did not differ significantly between patients and controls. Functional assays demonstrated a dichotomy in Treg function: in four out of 10 patients CD4+CD25+ T cells were incapable of suppressing autologous CD4+CD25- T-cell proliferation, whereas suppressive function was intact in the other six patients. Suppressive activity of Tregs inversely correlated with the peripheral blood tumor burden. T-plastin gene expression, used as a Sezary cell marker, confirmed that Sezary cells were heterogeneous for CD25 expression. Mixed lymphocyte reactions demonstrated that CD4+CD25- T cells from patients who lacked functional Tregs were susceptible to suppression by Tregs from healthy controls, and had not become suppressive themselves. Furthermore, we found reduced expression of Foxp3 in the CD4+CD25+ Tregs of these patients relative to the other six CTCL patients and controls. Our findings thus indicate a dysfunction of peripheral Tregs in certain CTCL patients, which correlates with tumor burden.

  19. 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...

  20. Expression of S100 Protein in CD4-positive T-cell Lymphomas Is Often Associated With T-cell Prolymphocytic Leukemia.

    Science.gov (United States)

    Aggarwal, Nidhi; Pongpruttipan, Tawatchai; Patel, Snehal; Bayerl, Michael G; Alkan, Serhan; Nathwani, Bharat; Surti, Urvashi; Kitahara, Sumire; Chinthammitr, Yingyong; Swerdlow, Steven H

    2015-12-01

    S100 T-cell lymphomas are infrequent, and except 1 all have been CD4 negative. On the basis of an index case of CD4 S100 T-cell prolymphocytic leukemia (T-PLL), we studied S100 protein expression in 19 additional T-PLLs and 56 other T-cell lymphomas that are usually CD4, including 15 angioimmunoblastic T-cell lymphomas, 24 anaplastic large cell lymphomas (16 ALK and 8 ALK), 7 mycosis fungoides/Sézary syndrome, and 10 peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Two additional S100 CD4 PTCL, NOS cases were also reviewed. Thirty percent (6/20) of T-PLLs were S100 compared with 0/56 other T-cell lymphomas with previously unstudied S100 reactivity (40 CD4, 2 CD8, 11 CD4/CD8, 3 unknown) (P=0.0007). There were no significant differences between the S100 and S100 T-PLLs with regard to the male:female ratio (2:1 vs. 1:1), age (71.6±7.7 vs. 65.4±9.3), peripheral blood lymphocyte count (67.2±116.6 vs. 101.1±159.7×10/L), or median survival (463 vs. 578 d, where known). The 2 S100 PTCL, NOS cases occurred in a 7-year-old boy and a 45-year-old woman. Both had involvement of the bone marrow and peripheral blood but were morphologically unlike T-PLL and lacked TCL1 gene rearrangement. These results demonstrate that S100 T-cell lymphomas include a subset that are CD4 and most often, but not exclusively, are T-PLL. Although having diagnostic implications, there were no documented clinical differences between the S100 and S100 T-PLLs. PMID:26379148

  1. 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

  2. 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

  3. 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.

  4. 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

  5. Immature CD4+ dendritic cells conditioned with donor kidney antigen prolong renal allograft survival in rats

    Institute of Scientific and Technical Information of China (English)

    WANG Tao; XU Lin; LI Heng; HUANG Zheng-yu; ZHANG Sheng-ping; MIAO Bin; NA Ning

    2012-01-01

    Background AIIogeneic transplant rejection is currently a major problem encountered during organ transplantation.The dendritic cell (DC) is the most effective powerful known professional antigen-presenting cell,and recent studies have found that DCs can also induce immune tolerance,and avoid or reduce the degree of transplant rejection.The aim of this study was to evaluate the effect of transfused immature CD4+ DCs on renal allografts in the rat model.Methods In this study,we induced CD4+ immature DCs from rat bone marrow cells by a cytokine cocktail.The immature CD4+ DCs were identified by morphological analysis and then the suppressive activity of these cells conditioned with donor kidney antigen was evaluated in vitro and in vivo.Results Immature CD4+ DCs conditioned with donor kidney antigen possessed immunosuppressive activity in vitro and they were able to prolong renal transplant survival in an allograft rat model in vivo.Conclusions Our study provides new information on efficacious renal transplantation,which might be useful for understanding the function of immature CD4+ DCs in modulating renal transplant rejection and improving clinical outcome in future studies.

  6. Elevated serum IL-35 and increased expression of IL-35-p35 or -EBI3 in CD4+CD25+ T cells in patients with active tuberculosis

    Science.gov (United States)

    Kong, Bin; Liu, Gan-Bin; Zhang, Jun-Ai; Fu, Xiao-Xia; Xiang, Wen-Yu; Gao, Yu-Chi; Lu, Yuan-Bin; Wu, Xian-Jing; Qiu, Feng; Wang, Wan-Dang; Yi, Lai-Long; Zhong, Ji-Xin; Chen, Zheng W; Xu, Jun-Fa

    2016-01-01

    Despite the recent appreciation of interleukin 35 (IL-35) function in inflammatory diseases, little is known for IL-35 response in patients with active tuberculosis (ATB). In the current study, we demonstrated that ATB patients exhibited increases in serum IL-35 and in mRNA expression of both subunits of IL-35 (p35 and EBI3) in white blood cells and peripheral blood mononuclear cells. Consistently, anti-TB drug treatment led to reduction in serum IL-35 level and p35 or EBI3 expression. TB infection was associated with expression of p35 or EBI3 protein in CD4+ but not CD8+ T cells. Most p35+CD4+ T cells and EBI3+CD4+ T cells expressed Treg-associated marker CD25. Our findings may be important in understanding immune pathogenesis of TB. IL-35 in the blood may potentially serve as a biomarker for immune status and prognosis in TB. PMID:27158354

  7. Elevated serum IL-35 and increased expression of IL-35-p35 or -EBI3 in CD4(+)CD25(+) T cells in patients with active tuberculosis.

    Science.gov (United States)

    Kong, Bin; Liu, Gan-Bin; Zhang, Jun-Ai; Fu, Xiao-Xia; Xiang, Wen-Yu; Gao, Yu-Chi; Lu, Yuan-Bin; Wu, Xian-Jing; Qiu, Feng; Wang, Wan-Dang; Yi, Lai-Long; Zhong, Ji-Xin; Chen, Zheng W; Xu, Jun-Fa

    2016-01-01

    Despite the recent appreciation of interleukin 35 (IL-35) function in inflammatory diseases, little is known for IL-35 response in patients with active tuberculosis (ATB). In the current study, we demonstrated that ATB patients exhibited increases in serum IL-35 and in mRNA expression of both subunits of IL-35 (p35 and EBI3) in white blood cells and peripheral blood mononuclear cells. Consistently, anti-TB drug treatment led to reduction in serum IL-35 level and p35 or EBI3 expression. TB infection was associated with expression of p35 or EBI3 protein in CD4(+) but not CD8(+) T cells. Most p35(+)CD4(+) T cells and EBI3(+)CD4(+) T cells expressed Treg-associated marker CD25. Our findings may be important in understanding immune pathogenesis of TB. IL-35 in the blood may potentially serve as a biomarker for immune status and prognosis in TB.

  8. 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...

  9. 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...

  10. Dynamic transcription of long non-coding RNA genes during CD4+ T cell development and activation.

    Directory of Open Access Journals (Sweden)

    Fei Xia

    Full Text Available BACKGROUND: Recent evidence shows that long non-coding RNA (LncRNA play important regulatory roles in many biology process, including cell development, activation and oncogenesis. However, the roles of these LncRNAs in the development and activation of CD4+ T cells, which is an important component of immune response, remain unknown. RESULTS: To predict the function of LncRNA in the development and activation of CD4+ T cells, first, we examined the expression profiles of LncRNAs and mRNAs in CD4-CD8- (DN, CD4+CD8+ (DP, CD4+CD8-, and activated CD4+CD8- T cells in a microarray analysis and verified these results by real time PCRs (qPCR. We found that the expression of hundreds of LncRNAs significantly changed in each process of developmental transition, including DN into DP, DP into CD4+CD8-, and CD4+CD8- into activated CD4+ T cells. A Kendall distance analysis suggested that the expression of LncRNAs in DN, DP, CD4+CD8- T cells and activated CD4+ T cells were correlated with the expression of mRNAs in these T cells. The Blat algorithm and GO analysis suggested that LncRNAs may exert important roles in the development and activation of CD4+ T cells. These roles included proliferation, homeostasis, maturation, activation, migration, apoptosis and calcium ion transportation. CONCLUSION: The present study found that the expression profiles of LncRNAs in different stages of CD4+ T cells are distinguishable. LncRNAs are involved in the key biological process in CD4+ T cell development and activation.

  11. Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.

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    Michal Kuczma

    Full Text Available The presence of Foxp3(+ regulatory CD4(+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral T(reg cells represent T(reg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4(+ T cells and thus representing adaptive T(reg cells. The generation of T(reg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of T(reg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied T(reg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4(+ T cells and which preserve the heterogeneity of the T(reg population. The majority of T(reg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4(+ T cells. A small T(reg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and T(reg cells. However, the population of T(reg cells in tumors was dominated by cells expressing TCRs shared with effector CD4(+ T cells. In contrast, T(reg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all T(reg cells in tumor lesions. Our results suggest that the T(reg repertoire in tumors is generated by conversion of effector CD4(+ T cells or expansion of a minor subset of T(reg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4(+ T cells and/or selectively inhibiting the expansion of a minor T(reg subset.

  12. 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.

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

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    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.

  14. Differential role of CD4+ cells in the sensitization and effector phases of accelerated graft rejection.

    Science.gov (United States)

    Sablinski, T; Sayegh, M H; Hancock, W W; Kut, J P; Kwok, C A; Milford, E L; Tilney, N L; Kupiec-Weglinski, J W

    1991-01-01

    Although CD4-targeted therapy markedly prolongs survival of organ allografts in naive rodents, its effects in primed hosts have not been studied. In our model of accelerated rejection (ACCR) of cardiac Tx in rats, treatment with BWH-4, a CD4 mAb (IgG2a), in the sensitization (between skin and heart Tx) but not in the effector (after cardiac Tx) phase, abrogated fulminant less than 36 hr rejection response and prolonged Tx survival to ca. 11 days. This effect correlated with decreased frequency of circulating CD4+ cells, but it did not depend upon their total depletion. It was also related to BWH-4 mAb-mediated elimination/depression of strong anti-donor humoral responses and cellular responses as determined by lymphocyte-mediated cytotoxicity and mixed lymphocyte reaction and mounted otherwise at the time of engraftment by untreated sensitized hosts. Immunoperoxidase studies of cardiac Tx from BWH-4-conditioned recipients revealed reduced T and B cell activities, reflected in abolition/reduction in deposition of humoral mediators, infiltrating cells, intra-Tx elaboration of interleukin-2 and interferon-gamma, and cell activation. This first report of the successful use of CD4 mAb in sensitized recipients of vascularized organ Tx, stresses the role of CD4+ cells as potential targets for immunosuppression in the sensitization phase of accelerated Tx injury. The beneficial therapeutic effect, probably due to both depletion and functional inhibition of CD4+ T cells, has been achieved by using relatively low doses of BWH-4 mAb. PMID:1824805

  15. Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes

    Science.gov (United States)

    Pérez-Santiago, Josué; Ouchi, Dan; Urrea, Victor; Carrillo, Jorge; Cabrera, Cecilia; Villà-Freixa, Jordi; Puig, Jordi; Paredes, Roger; Negredo, Eugènia; Clotet, Bonaventura; Massanella, Marta; Blanco, Julià

    2016-01-01

    Background: The failure to increase CD4+ T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4+ T-cell homeostasis and impacts clinical evolution. Methods: We evaluated different definitions of immunodiscordance based on CD4+ T-cell counts (cutoff) or CD4+ T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals. Results: Cutoff definition of CD4+ cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4+ T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4+ T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4+ T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4+ values were maintained in these participants over time. Conclusion: A cutoff value of CD4+ T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup

  16. 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.

  17. IL-35, an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells.

    Science.gov (United States)

    Castellani, Maria Luisa; Anogeianaki, A; Felaco, P; Toniato, E; De Lutiis, M A; Shaik, B; Fulcheri, M; Vecchiet, J; Tetè, S; Salini, V; Theoharides, T C; Caraffa, A; Antinolfi, P; Frydas, I; Conti, P; Cuccurullo, C; Ciampoli, C; Cerulli, G; Kempuraj, D

    2010-01-01

    Interleukin 12 (IL 12) p35/p40 is a heterodimeric cytokine which plays a critical role in inflammation, immunity and tissue proliferation, and also plays a relevant function in T helper (Th) cell polarization and Th1 T-cell differentiation. IL-12 family members, IL-12p70, IL-23, IL-27 and IL-35, play an important role in influencing helper T-cell differentiation. EBV-induced gene 3 can be associated with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, also called IL-35. It has been shown that IL-35 has biological activity and able to expand CD4+CD25+ Treg cells, suppress the proliferation of CD4+CD25- effector cells and inhibit Th17 cell polarization. IL-35 has been shown to be constitutively expressed by regulatory T (Treg) cells CD4(+)CD25(+)Foxp3(+) and suggested to contribute to their suppressive activity. IL-35 is a crucial mediator which provokes CD4+CD25+ T cell proliferation and IL-10 generation, another well-known anti-inflammatory cytokine, along with TGFbeta cytokine. These studies suggest that IL-35, together with other successfully discovered cytokine inhibitors, represents a new potential therapeutic cytokine for chronic inflammation, autoimmunity and other immunological disorders.

  18. 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...

  19. 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...

  20. Aging disturbs the balance between effector and regulatory CD4+T cells

    NARCIS (Netherlands)

    van der Geest, Kornelis S. M.; Abdulahad, Wayel H.; Tete, Sarah M.; Lorencetti, Pedro G.; Horst, Gerda; Bos, Nicolaas A.; Kroesen, Bart-Jan; Brouwer, Elisabeth; Boots, Annemieke M. H.

    2014-01-01

    Healthy aging requires an optimal balance between pro-inflammatory and anti-inflammatory immune responses. Although CD4+ T cells play an essential role in many immune responses, few studies have directly assessed the effect of aging on the balance between effector T (Teff) cells and regulatory T (Tr

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

    DEFF Research Database (Denmark)

    Jensen, J; Langkilde, Annika Reynberg; Fenst, C;

    2004-01-01

    severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states...

  2. 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 ...

  3. 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

  4. 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...

  5. 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.

  6. Characterization of the specific CD4+ T cell response against the F protein during chronic hepatitis C virus infection.

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    De-Yong Gao

    Full Text Available BACKGROUND: The hepatitis C virus (HCV Alternate Reading Frame Protein (ARFP or F protein presents a double-frame shift product of the HCV core gene. We and others have previously reported that the specific antibodies against the F protein could be raised in the sera of HCV chronically infected patients. However, the specific CD4(+ T cell responses against the F protein during HCV infection and the pathological implications remained unclear. In the current study, we screened the MHC class II-presenting epitopes of the F protein through HLA-transgenic mouse models and eventually validated the specific CD4(+ T cell responses in HCV chronically infected patients. METHODOLOGY: DNA vaccination in HLA-DR1 and-DP4 transgenic mouse models, proliferation assay to test the F protein specific T cell response, genotyping of Chronic HCV patients and testing the F-peptide stimulated T cell response in the peripheral blood mononuclear cell (PBMC by in vitro expansion and interferon (IFN- γ intracellular staining. PRINCIPAL FINDINGS: At least three peptides within HCV F protein were identified as HLA-DR or HLA-DP4 presenting epitopes by the proliferation assays in mouse models. Further study with human PBMCs evidenced the specific CD4(+ T cell responses against HCV F protein as well in patients chronically infected with HCV. CONCLUSION: The current study provided the evidence for the first time that HCV F protein could elicit specific CD4(+ T cell response, which may provide an insight into the immunopathogenesis during HCV chronic infection.

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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...

  12. CD4+CD25+调节性T细胞在Graves眼病患者外周血中的表达%Detection of CD4+CD25+regulatory T cell in patients with Graves'ophthalmopathy

    Institute of Scientific and Technical Information of China (English)

    辛梦; 王强; 张磊; 韩兆东; 薛海波

    2013-01-01

    AIM: To observe the change law of the ratio of CD4+CD25+regulatory T cell in the peripheral blood of the patients with Graves'ophthalmopathy by detecting the ratio of this cell. METHODS: This experimental study selected 53 GO patients without exophthalmos, 51 GO patients with exophthalmos, and 51 healthy people were collected.The ratio of CD4+CD25+ T cell in peripheral blood was determined by flow cytometry. RESULTS:The ratio of CD4+CD25+T cell in GO patients without exophthalmos was lower than that in healthy group (P<0.01).The ratio of CD4+CD25+T cell in GO patients with exophthalmos was far lower than that in healthy group (P<0.01).Compared with the group of GO patients without exophthalmos, the ratio of CD4+CD25+T cell of GO patients with exophthalmos was also much lower (P<0.01). CONCLUSION:The ratio of CD4+CD25+T cell in the GO patients decreases and there is autoimmune disorder in patients of this disease. Perhaps this is an important mechanism causing immune suppression damage, which provides a new clue for immunological treatment.%目的:通过检测CD4+CD25+调节性T细胞在Graves眼病患者外周血中的表达,以观察该病患者外周血中CD4+CD25+调节性T细胞的变化规律。方法:临床实验研究。采用流式细胞术检测对Graves病不伴有眼征患者组(53例), Graves眼病患者组(51例),正常对照组(51例)的外周静脉血CD4+CD25+Treg细胞比例进行检测。结果:与正常对照组比较, Graves 病不伴有眼征患者组Treg水平下降(P<0.01);与正常对照组比较,Graves眼病患者组外周血Treg水平显著下降( P<0.01);Graves眼病患者组外周血Treg数量明显低于Graves病不伴有眼征患者组(P<0.01)。结论:Graves眼病患者外周血中CD4+CD25+Treg在淋巴细胞中所占的比例降低,存在自身免疫调节紊乱。可能是其机体细胞免疫抑制受损的重要机制,为对该疾病进行免疫学治疗提供了新线索。

  13. 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.

  14. An Imbalance between Frequency of CD4+CD25+FOXP3+ Regulatory T Cells and CCR4+ and CCR9+ Circulating Helper T Cells Is Associated with Active Perennial Allergic Conjunctivitis

    Directory of Open Access Journals (Sweden)

    J. Galicia-Carreón

    2013-01-01

    Full Text Available Allergic conjunctivitis (AC is one of the most common eye disorders in ophthalmology. In mice models, it has been suggested that control of allergic conjunctivitis is a delicate balance between Tregs and inflammatory migrating effector cells. Our aim was to evaluate the frequency of Tregs and the frequency of homing receptors expressing cells in peripheral blood mononuclear cells (PBMC from patients with perennial allergic conjunctivitis (PAC. The analyses of phenotypic markers on CD4+ T cells and both soluble or intracellular cytokines were performed by flow cytometry. CD4+CD25+ cells were 15 times more frequent in PBMC from patients than HC; the vast majority of these CD4+CD25+ cells were FOXP3−, and most of CD4+ T cells were CCR4+ and CCR9+ cells. Upon allergen-stimulation, no significant changes were observed in frequency of Treg; however, an increased frequency of CD4+CCR4+CCR9+ cells, CD4+CD103+ cells and CD4+CD108+ cells with increased IL-5, IL-6, and IL-8 production was observed. These findings suggest an immune dysregulation in PAC, characterized by diminished frequency of Tregs and increased frequency of circulating activated CD4+ T cells; upon allergen-stimulation, these cells were expressing cell-surface molecules related to mucosa homing and were able to trigger an inflammatory microenvironment.

  15. 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...

  16. 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...

  17. 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

  18. Methamphetamine decreases CD4 T cell frequency and alters pro-inflammatory cytokine production in a model of drug abuse.

    Science.gov (United States)

    Mata, Mariana M; Napier, T Celeste; Graves, Steven M; Mahmood, Fareeha; Raeisi, Shohreh; Baum, Linda L

    2015-04-01

    The reason co-morbid methamphetamine use and HIV infection lead to more rapid progression to AIDS is unclear. We used a model of methamphetamine self-administration to measure the effect of methamphetamine on the systemic immune system to better understand the co-morbidity of methamphetamine and HIV. Catheters were implanted into the jugular veins of male, Sprague Dawley rats so they could self-administer methamphetamine (n=18) or be given saline (control; n=16) for 14 days. One day after the last operant session, blood and spleens were collected. We measured serum levels of pro-inflammatory cytokines, intracellular IFN-γ and TNF-α, and frequencies of CD4(+), CD8(+), CD200(+) and CD11b/c(+) lymphocytes in the spleen. Rats that self-administered methamphetamine had a lower frequency of CD4(+) T cells, but more of these cells produced IFN-γ. Methamphetamine did not alter the frequency of TNF-α-producing CD4(+) T cells. Methamphetamine using rats had a higher frequency of CD8(+) T cells, but fewer of them produced TNF-α. CD11b/c and CD200 expression were unchanged. Serum cytokine levels of IFN-γ, TNF-α and IL-6 in methamphetamine rats were unchanged. Methamphetamine lifetime dose inversely correlated with serum TNF-α levels. Our data suggest that methamphetamine abuse may exacerbate HIV disease progression by activating CD4 T cells, making them more susceptible to HIV infection, and contributing to their premature demise. Methamphetamine may also increase susceptibility to HIV infection, explaining why men who have sex with men (MSM) and frequently use methamphetamine are at the highest risk of HIV infection.

  19. 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

  20. 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

  1. CD4 Cell Counts at HIV Diagnosis among HIV Outpatient Study Participants, 2000–2009

    Directory of Open Access Journals (Sweden)

    Kate Buchacz

    2012-01-01

    Full Text Available Background. It is unclear if CD4 cell counts at HIV diagnosis have improved over a 10-year period of expanded HIV testing in the USA. Methods. We studied HOPS participants diagnosed with HIV infection ≤6 months prior to entry into care during 2000–2009. We assessed the correlates of CD4 count <200 cells/mm3 at HIV diagnosis (late HIV diagnosis by logistic regression. Results. Of 1,203 eligible patients, 936 (78% had a CD4 count within 3 months after HIV diagnosis. Median CD4 count at HIV diagnosis was 299 cells/mm3 and did not significantly improve over time (P=0.13. Comparing periods 2000-2001 versus 2008-2009, respectively, 39% and 35% of patients had a late HIV diagnosis (P=0.34. Independent correlates of late HIV diagnosis were having an HIV risk other than being MSM, age ≥35 years at diagnosis, and being of nonwhite race/ethnicity. Conclusions. There is need for routine universal HIV testing to reduce the frequency of late HIV diagnosis and increase opportunity for patient- and potentially population-level benefits associated with early antiretroviral treatment.

  2. CD4+ T-cell priming as biomarker to study immune response to preventive vaccines

    Directory of Open Access Journals (Sweden)

    Annalisa eCiabattini

    2013-12-01

    Full Text Available T-cell priming is a critical event in the initiation of the immune response to vaccination since it deeply influences both the magnitude and the quality of the immune response induced. CD4+ T-cell priming, required for the induction of high-affinity antibodies and immune memory, represents a key target for improving and modulating vaccine immunogenicity. A major challenge in the study of in vivo T-cell priming is due to the low frequency of antigen-specific T cells. This review discusses the current knowledge on antigen-specific CD4+ T-cell priming in the context of vaccination, as well as the most advanced tools for the characterization of the in vivo T-cell priming and the opportunities offered by the application of systems biology.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  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. 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.

  7. Screening of human tumor antigens for CD4 T cell epitopes by combination of HLA-transgenic mice, recombinant adenovirus and antigen peptide libraries.

    Directory of Open Access Journals (Sweden)

    Wolfram Osen

    Full Text Available BACKGROUND: As tumor antigen-specific CD4+ T cells can mediate strong therapeutic anti-tumor responses in melanoma patients we set out to establish a comprehensive screening strategy for the identification of tumor-specific CD4+ T cell epitopes suitable for detection, isolation and expansion of tumor-reactive T cells from patients. METHODS AND FINDINGS: To scan the human melanoma differentiation antigens TRP-1 and TRP-2 for HLA-DRB1*0301-restricted CD4+ T cell epitopes we applied the following methodology: Splenocytes of HLA-DRB1*0301-transgenic mice immunized with recombinant adenovirus encoding TRP-1 (Ad5.TRP-1 or TRP-2 (Ad5.TRP-2 were tested for their T cell reactivity against combinatorial TRP-1- and TRP-2-specific peptide libraries. CD4+ T cell epitopes thus identified were validated in the human system by stimulation of peripheral blood mononuclear cells (PBMC from healthy donors and melanoma patients. Using this strategy we observed that recombinant Ad5 induced strong CD4+ T cell responses against the heterologous tumor antigens. In Ad5.TRP-2-immunized mice CD4+ T cell reactivity was detected against the known HLA-DRB1*0301-restricted TRP-2(60-74 epitope and against the new epitope TRP-2(149-163. Importantly, human T cells specifically recognizing target cells loaded with the TRP-2(149-163-containing library peptide or infected with Ad5.TRP-2 were obtained from healthy individuals, and short term in vitro stimulation of PBMC revealed the presence of epitope-reactive CD4+ T cells in melanoma patients. Similarly, immunization of mice with Ad5.TRP-1 induced CD4+ T cell responses against TRP-1-derived peptides that turned out to be recognized also by human T cells, resulting in the identification of TRP-1(284-298 as a new HLA-DRB1*0301-restricted CD4+ T cell epitope. CONCLUSIONS: Our screening approach identified new HLA-DRB1*0301-restricted CD4+ T cell epitopes derived from melanoma antigens. This strategy is generally applicable to target

  8. 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...

  9. 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...

  10. Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults.

    Science.gov (United States)

    Leddon, Scott A; Richards, Katherine A; Treanor, John J; Sant, Andrea J

    2015-09-01

    CD4 T-cell responses are functionally complex and regulate many aspects of innate and adaptive immunity. Follicular helper (Tfh) cells are CD4 T cells specialized to support B-cell production of isotype-switched, high-affinity antibody. So far, studies of Tfh cells in humans have focused on their differentiation requirements, with little research devoted to their antigen specificity. Here, after separating circulating human memory CD4 T cells based on expression of CXCR5, a signature marker of Tfh, we have quantified and assayed the influenza protein antigen specificity of blood Tfh cells and CD4 T cells lacking this marker. Through the use of peptide pools derived from nucleoprotein (NP) or haemagglutinin (HA) and a panel of human donors, we have discovered that circulating Tfh cells preferentially recognize peptide epitopes from HA while cells lacking CXCR5 are enriched for specificity toward NP. These studies suggest that reactive CD4 T cells specific for distinct viral antigens may have generalized differences in their functional potential due to their previous stimulation history. PMID:26094691

  11. 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

  12. 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)

    Bacchus, Charline; Cheret, Antoine; 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

  13. 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.

  14. Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients

    Science.gov (United States)

    Lempicki, Richard A.; Kovacs, Joseph A.; Baseler, Michael W.; Adelsberger, Joseph W.; Dewar, Robin L.; Natarajan, Ven; Bosche, Marjorie C.; Metcalf, Julia A.; Stevens, Randy A.; Lambert, Laurie A.; Alvord, W. Gregory; Polis, Michael A.; Davey, Richard T.; Dimitrov, Dimiter S.; Lane, H. Clifford

    2000-01-01

    To evaluate the effects of HIV infection on T cell turnover, we examined levels of DNA synthesis in lymph node and peripheral blood mononuclear cell subsets by using ex vivo labeling with BrdUrd. Compared with healthy controls (n = 67), HIV-infected patients (n = 57) had significant increases in the number and fraction of dividing CD4+ and CD8+ T cells. Higher percentages of dividing CD4+ and CD8+ T cells were noted in patients with the higher viral burdens. No direct correlation was noted between rates of T cell turnover and CD4+ T cell counts. Marked reductions in CD4+ and CD8+ T cell proliferation were seen in 11/11 patients 1–12 weeks after initiation of highly active antiretroviral therapy (HAART). These reductions persisted for the length of the study (16–72 weeks). Decreases in naïve T cell proliferation correlated with increases in the levels of T cell receptor rearrangement excision circles. Division of CD4+ and CD8+ T cells increased dramatically in association with rapid increases in HIV-1 viral loads in 9/9 patients 5 weeks after termination of HAART and declined to pre-HAART-termination levels 8 weeks after reinitiation of therapy. These data are consistent with the hypothesis that HIV-1 infection induces a viral burden-related, global activation of the immune system, leading to increases in lymphocyte proliferation. PMID:11095734

  15. 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.

  16. 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 ...

  17. 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+...

  18. IL-6 Promotes Cardiac Graft Rejection Mediated by CD4+ Cells1

    OpenAIRE

    Booth, Adam Jared; Grabauskiene, Svetlana; Wood, Sherri Chan; Lu, Guanyi; Burrell, Bryna E.; Bishop, D. Keith

    2011-01-01

    IL-6 mediates numerous immunologic effects relevant to transplant rejection; however its specific contributions to these processes are not fully understood. To this end, we neutralized IL-6 in settings of acute cardiac allograft rejection associated with either CD8+ or CD4+ cell dominant responses. In a setting of CD8+ cell dominant graft rejection, IL-6 neutralization delayed the onset of acute rejection while decreasing graft infiltrate and inverting anti-graft Th1/Th2 priming dominance in ...

  19. 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...... in humans, and that the balance between subsets of parasite-specific T cells may play an important regulatory role in determining the outcome of the infections....

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

    Science.gov (United States)

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

    2016-01-15

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

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

    Science.gov (United States)

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

    2013-01-01

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

  2. 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

    Many novel vaccine strategies rely on recombinant viral vectors for antigen delivery, and adenovirus vectors have emerged among the most potent of these. In this report, we have compared the immune response induced through priming with adenovirus vector-encoded full-length viral protein...... to that elicited with an adenovirus-encoded minimal epitope covalently linked to beta(2)-microglobulin. We demonstrate that the beta(2)-microglobulin-linked epitope induced an accelerated and augmented CD8(+) T-cell response. Furthermore, the immunity conferred by vaccination with beta(2)-microglobulin...... in the absence of CD4(+) T-cell help were sustained in the long term and able to expand and control a secondary challenge with LCMV. Our results demonstrate that modifications to the antigen used in adenovirus vaccines may be used to improve the induced T-cell response. Such a strategy for CD4(+) T...

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

    Science.gov (United States)

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

    2002-08-15

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

  4. 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

  5. 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...

  6. 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

  7. Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema.

    Science.gov (United States)

    Ogata, Fusa; Fujiu, Katsuhito; Matsumoto, Sahohime; Nakayama, Yukiteru; Shibata, Munehiko; Oike, Yuichi; Koshima, Isao; Watabe, Tetsuro; Nagai, Ryozo; Manabe, Ichiro

    2016-03-01

    Lymphedema is a debilitating progressive condition that severely restricts quality of life and is frequently observed after cancer surgery. The mechanism underlying lymphedema development remains poorly understood, and no effective pharmacological means to prevent or alleviate the ailment is currently available. Using a mouse model of lymphedema, we show here that excessive generation of immature lymphatic vessels is essential for initial edema development and that this early process is also important for later development of lymphedema pathology. We found that CD4(+) T cells interact with macrophages to promote lymphangiogenesis, and that both lymphangiogenesis and edema were greatly reduced in macrophage-depleted mice, lymphocyte-deficient Rag2(?/?) mice or CD4(+) T-cell-deficient mice. Mechanistically, T helper type 1 and T helper type 17 cells activate lesional macrophages to produce vascular endothelial growth factor-C, which promotes lymphangiogenesis, and inhibition of this mechanism suppressed not only early lymphangiogenesis, but also later development of lymphedema. Finally, we show that atorvastatin suppresses excessive lymphangiogenesis and lymphedema by inhibiting T helper type 1 and T helper type 17 cell activation. These results demonstrate that the interaction between CD4(+) T cells and macrophages is a potential therapeutic target for prevention of lymphedema after surgery.

  8. 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.

  9. CD4 on CD8+ T cells directly enhances effector function and is a target for HIV infection

    Science.gov (United States)

    Kitchen, Scott G.; Jones, Nicole R.; Laforge, Stuart; Whitmire, Jason K.; Vu, Bien-Aimee; Galic, Zoran; Brooks, David G.; Brown, Stephen J.; Kitchen, Christina M. R.; Zack, Jerome A.

    2004-06-01

    Costimulation of purified CD8+ T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8+ T cell function by modulating expression of IFN- and Fas ligand, two important CD8+ T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-, Fas ligand, and the cytotoxic responses of activated CD8+ T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease.

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

    NARCIS (Netherlands)

    A. Mocroft; A.N. Phillips; B. Ledergerber; C. Smith; J.R. Bogner; K. Lacombe; A. Wiercinska-Drapalo; P. Reiss; O. Kirk; J.D. Lundgren

    2010-01-01

    Background: Patients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4(+) T-cell count according to levels of viraemia in patients on cART. Methods: A total of 111,371 CD4(+) T-cell counts and

  11. 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...

  12. 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...

  13. CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder.

    Science.gov (United States)

    Lefèvre, Guillaume; Copin, Marie-Christine; Roumier, Christophe; Aubert, Hélène; Avenel-Audran, Martine; Grardel, Nathalie; Poulain, Stéphanie; Staumont-Sallé, Delphine; Seneschal, Julien; Salles, Gilles; Ghomari, Kamel; Terriou, Louis; Leclech, Christian; Morati-Hafsaoui, Chafika; Morschhauser, Franck; Lambotte, Olivier; Ackerman, Félix; Trauet, Jacques; Geffroy, Sandrine; Dumezy, Florent; Capron, Monique; Roche-Lestienne, Catherine; Taieb, Alain; Hatron, Pierre-Yves; Dubucquoi, Sylvain; Hachulla, Eric; Prin, Lionel; Labalette, Myriam; Launay, David; Preudhomme, Claude; Kahn, Jean-Emmanuel

    2015-08-01

    The CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3(-)CD4(+) T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome. Atypical CD4(+) T cells lymphoid infiltrates were found in 10 of 12 CD3(-)CD4(+) L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3(-)CD4(+) T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3(-)CD4(+) T cells were CD2(hi) (n=9 of 14), CD5(hi) (n=12 of 14), and CD7(-)(n=4 of 14) or CD7(low) (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3(-)CD4(+) T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative

  14. The CD4+CD26-T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile

    NARCIS (Netherlands)

    Ma, Yue; Visser, Lydia; Blokzijl, Tjasso; Harms, Geert; Atayar, Cigdem; Poppema, Sibrand; van den Berg, Anke

    2008-01-01

    Little is known about the gene expression profile and significance of the rosetting CD4+CD26- T cells in classical Hodgkin's lymphoma (cHL). To characterize these T cells, CD4+CD26- and CD4+CD26+ T-cell populations were sorted from lymph node (LN) cell suspensions from nodular sclerosis HL (NSHL) an

  15. Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver.

    Directory of Open Access Journals (Sweden)

    Katrin Neumann

    Full Text Available Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4(+ T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4(+ T cells expressing the CXC chemokine receptor (CXCR3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC which represent the first contact site for T-cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin-coated vesicles to CD4(+ T cells leading to enhanced transmigration of CXCR4(+ total CD4(+ T cells and CXCR3(+ effector/memory CD4(+ T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4(+ T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4(+ T-cell transmigration in vitro as well as migration of CD4(+ T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3(+ CD4(+ T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4- and clathrin-dependent intracellular

  16. In vivo safety and persistence of endoribonuclease gene-transduced CD4+ T cells in cynomolgus macaques for HIV-1 gene therapy model.

    Directory of Open Access Journals (Sweden)

    Hideto Chono

    Full Text Available BACKGROUND: MazF is an endoribonuclease encoded by Escherichia coli that specifically cleaves the ACA sequence of mRNA. In our previous report, conditional expression of MazF in the HIV-1 LTR rendered CD4+ T lymphocytes resistant to HIV-1 replication. In this study, we examined the in vivo safety and persistence of MazF-transduced cynomolgus macaque CD4+ T cells infused into autologous monkeys. METHODOLOGY/PRINCIPAL FINDINGS: The in vivo persistence of the gene-modified CD4+ T cells in the peripheral blood was monitored for more than half a year using quantitative real-time PCR and flow cytometry, followed by experimental autopsy in order to examine the safety and distribution pattern of the infused cells in several organs. Although the levels of the MazF-transduced CD4+ T cells gradually decreased in the peripheral blood, they were clearly detected throughout the experimental period. Moreover, the infused cells were detected in the distal lymphoid tissues, such as several lymph nodes and the spleen. Histopathological analyses of tissues revealed that there were no lesions related to the infused gene modified cells. Antibodies against MazF were not detected. These data suggest the safety and the low immunogenicity of MazF-transduced CD4+ T cells. Finally, gene modified cells harvested from the monkey more than half a year post-infusion suppressed the replication of SHIV 89.6P. CONCLUSIONS/SIGNIFICANCE: The long-term persistence, safety and continuous HIV replication resistance of the mazF gene-modified CD4+ T cells in the non-human primate model suggests that autologous transplantation of mazF gene-modified cells is an attractive strategy for HIV gene therapy.

  17. Association Between Circulating Early Endothelial Progenitors and CD4+CD25+ Regulatory T Cells: A Possible Cross-talk between Immunity and Angiogenesis?

    Directory of Open Access Journals (Sweden)

    Shmuel Schwartzenberg

    2005-01-01

    Full Text Available Regulatory T-cells (Treg are a recently defined subset of CD4+ cells that can suppress inflammation and induce tolerance. Phenotypically, T-regs are characterized by a high level of expression of the IL-2 receptor alpha chain, CD25. Endothelial progenitor cells (EPCs can transform into mature endothelial cells and promote vessel formation by inducing postnatal angiogenesis and vasculogenesis. Herein, we tested the hypothesis that an association exists between circulating EPC and Tregs that could potentially allude to cross talk between immunity and angiogenesis. Peripheral blood mononuclear cells were isolated by Ficoll density-gradient centrifugation from 28 subjects. Circulating number of EPCs at various developmental stages (CD133+CD34+, CD133+VEGFR2+, CD34+VEGFR2+, total CD4+ and Treg CD4+CD25high numbers were determined by FACS analysis. We found a positive correlation between early progenitor cell (CD133+CD34+ number and Tregs, but no correlation between differentiated EPCs and Tregs, or between CD4+ and any of the EPCs sampled. Early EPCs (CD133+CD34+ did not correlate with CD34+/KDR or with CD133/KDR cells. Circulating numbers of early but not ‘mature’ EPC correlate with Tregs but not CD4 numbers. This finding may suggest a novel role for Tregs in promoting EPC recruitment or delaying EPC maturation.

  18. 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

  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

    2011-06-01

    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

  20. 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

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

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    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.

  2. 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...

  3. 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

  4. 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.

  5. 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...

  6. 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.

  7. 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 ...

  8. 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...

  9. 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...

  10. 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

  11. 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

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

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    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.

  13. 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

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

    DEFF Research Database (Denmark)

    Jensen, Helle; Folkersen, Lasse; Skov, Søren

    2012-01-01

    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......NKG2D is a stimulatory receptor expressed by natural killer (NK) cells, CD8(+) T-cells, and ¿d 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...

  15. HIV-1 Trans Infection of CD4+ T Cells by Professional Antigen Presenting Cells

    Directory of Open Access Journals (Sweden)

    Charles R. Rinaldo

    2013-01-01

    Full Text Available Since the 1990s we have known of the fascinating ability of a complex set of professional antigen presenting cells (APCs; dendritic cells, monocytes/macrophages, and B lymphocytes to mediate HIV-1 trans infection of CD4+ T cells. This results in a burst of virus replication in the T cells that is much greater than that resulting from direct, cis infection of either APC or T cells, or trans infection between T cells. Such APC-to-T cell trans infection first involves a complex set of virus subtype, attachment, entry, and replication patterns that have many similarities among APC, as well as distinct differences related to virus receptors, intracellular trafficking, and productive and nonproductive replication pathways. The end result is that HIV-1 can sequester within the APC for several days and be transmitted via membrane extensions intracellularly and extracellularly to T cells across the virologic synapse. Virus replication requires activated T cells that can develop concurrently with the events of virus transmission. Further research is essential to fill the many gaps in our understanding of these trans infection processes and their role in natural HIV-1 infection.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. Targeted infection of HIV-1 Env expressing cells by HIV(CD4/CXCR4 vectors reveals a potential new rationale for HIV-1 mediated down-modulation of CD4

    Directory of Open Access Journals (Sweden)

    Harmison George G

    2005-12-01

    Full Text Available Abstract Background Efficient targeted gene transfer and cell type specific transgene expression are important for the safe and effective expression of transgenes in vivo. Enveloped viral vectors allow insertion of exogenous membrane proteins into their envelopes, which could potentially aid in the targeted transduction of specific cell types. Our goal was to specifically target cells that express the T cell tropic HIV-1 envelope protein (Env using the highly specific interaction of Env with its cellular receptor (CD4 inserted into the envelope of an HIV-1-based viral vector. Results To generate HIV-1-based vectors carrying the CD4 molecule in their envelope, the CD4 ectodomain was fused to diverse membrane anchors and inserted together with the HIV-1 coreceptor CXCR4 into the envelopes of HIV-1 vector particles. Independent of the type of CD4 anchor, all chimeric CD4 proteins inserted into HIV-1 vector envelopes and the resultant HIV(CD4/CXCR4 particles were able to selectively confer neomycin resistance to cells expressing the fusogenic T cell tropic HIV-1 Env protein. Unexpectedly, in the absence of Env on the target cells, all vector particles carrying the CD4 ectodomain anchored in their envelope adhered to various cell types without infecting these cells. This cell adhesion was very avid. It was independent of the presence of Env on the target cell, the type of CD4 anchor or the presence of CXCR4 on the particle. In mixed cell populations with defined ratios of Env+/Env- cells, the targeted transduction of Env+ cells by HIV(CD4/CXCR4 particles was diminished in proportion to the number of Env- cells. Conclusion Vector diversion caused by a strong, non-selective cell binding of CD4+-vector particles effectively prevents the targeted transduction of HIV-1 Env expressing cells in mixed cell populations. This Env-independent cell adhesion severely limits the effective use of targeted HIV(CD4/CXCR4 vectors designed to interfere with HIV-1

  1. 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

  2. CD4(+)B220(+)TCRγδ(+) T cells produce IL-17 in lupus-prone MRL/lpr mice.

    Science.gov (United States)

    Qiu, Feng; Li, Tingting; Zhang, Kui; Wan, Jun; Qi, Xiaokun

    2016-09-01

    Systemic lupus erythematosus is an autoimmune disease with comprehensive immune cell disorders. Recent studies suggested that pro-inflammatory cytokine IL-17 plays important role in lupus, leaving the cellular sources and their pathogenic and physiologic characters largely unknown. In the current study, by using lupus-prone MRL/lpr mice, we demonstrated that Th17 response prevails in lupus disease regarding significantly accumulated serum IL-17, increased IL-17-producing splenocytes, and elevated phospho-STAT3 in CD4(+) T cells. Intracellular staining revealed that unusual CD4(+)B220(+) T cells are major IL-17-producing cells, whereas conventional CD4(+)B220(-) T cells are major IFN-γ-producing cells. Subsequent studies showed that CD4(+)B220(+) cells contains both αβ and γδ T cells in the spleen and thymus of MRL/lpr mice. Further study showed that around 60% of γδ T cells in MRL/lpr mice co-express both B220 and CD4 on their surface, and are the major RORγt(+) cells in MRL/lpr mice. Finally, CD4(+)B220(+) T cells alone do not proliferate, but could enhance the proliferation and IFN-γ-production of conventional CD4(+)B220(-) T cells. Our findings suggest the pathogenic role of unusual CD4(+)B220(+) T cells in lupus disease in MRL/lpr mice according to their IL-17-producing ability and stimulatory function for conventional CD4(+)B220(-) T cells. PMID:27235595

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

    DEFF Research Database (Denmark)

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

    2001-01-01

    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...

  4. Docosahexaenoic acid reduces suppressive and migratory functions of CD4CD25 regulatory T-cells

    Science.gov (United States)

    Yessoufou, Akadiri; Plé, Aude; Moutairou, Kabirou; Hichami, Aziz; Khan, Naim Akhtar

    2009-01-01

    Immunological tolerance is one of the fundamental aspects of the immune system. The CD4+CD25+ regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4+CD25− effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-β, and IL-10; nonetheless, this fatty acid increased the expression of p27KIP1 mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease. PMID:19561360

  5. 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.

  6. 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

  7. 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...

  8. 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".

  9. 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.

  10. 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.

  11. 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.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    and viral load measurements in 8,227 patients were analysed. Annual change in CD4(+) T-cell numbers was estimated using mixed models. RESULTS: After adjustment, the estimated average annual change in CD4(+) T-cell count significantly increased when viral load was ... was >/=10,000 copies/ml (-44.4 cells/mm(3), 95% CI -62.0--26.9; P=0.0012, test for interaction). CONCLUSIONS: On average, CD4(+) T-cell counts did not significantly decrease until the viral load exceeded 10,000 copies/ml in patients treated with a boosted PI-containing cART regimen, but decreased...

  13. 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

  14. 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

  15. 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.

  16. 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

  17. Cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies.

    Directory of Open Access Journals (Sweden)

    Irene A Abela

    Full Text Available HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo.

  18. Cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies.

    Science.gov (United States)

    Abela, Irene A; Berlinger, Livia; Schanz, Merle; Reynell, Lucy; Günthard, Huldrych F; Rusert, Peter; Trkola, Alexandra

    2012-01-01

    HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo. PMID:22496655

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

    Directory of Open Access Journals (Sweden)

    Charlotte eMariani

    2014-06-01

    Full Text Available HIV-1 is an RNA enveloped virus that preferentiallyinfects CD4+ T lymphocytes andalso macrophages. In CD4+ T cells, HIV-1mainly buds from the host cell plasma membrane.The viral Gag polyprotein targets theplasma membrane and is the orchestrator ofthe HIV assembly as its expression is sufficientto promote the formation of virus-likeparticles particles carrying a lipidic envelopederiving from the host cell membrane. Certainlipids are enriched in the viral membraneand are thought to play a key role in theassembly process and the envelop composition.A large body of work performed oninfected CD4+ T cells has provided importantknowledge about the assembly process andthe membrane virus lipid composition. WhileHIV assembly and budding in macrophages isthought to follow the same general Gag-drivenmechanism as in T-lymphocytes, the HIV cyclein macrophage exhibits specific features.In these cells, new virions bud from the limitingmembrane of seemingly intracellular compartments,where they accumulate while remaininginfectious. These structures are now oftenreferred to as Virus Containing Compartments(VCCs. Recent studies suggest that VCCsrepresent intracellularly sequestered regionsof the plasma membrane, but their precisenature remains elusive. The proteomic andlipidomic characterization of virions producedby T cells or macrophages has highlightedthe similarity between their composition andthat of the plasma membrane of producercells, as well as their enrichment in acidiclipids, some components of raft lipids andin tetraspanin-enriched microdomains. Greatchances are that Gag promotes the coalescenceof these components into an assemblyplatform from which viral budding takesplace. How Gag exactly interacts with membranelipids and what are the mechanisms involvedin the interaction between the differentmembrane nanodomains within the assemblyplatform remains unclear. Here we review recentliterature regarding the role of Gag andlipids

  20. 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

  1. 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.

  2. Decrease in immune activation in HIV-infected patients treated with highly active antiretroviral therapy correlates with the function of hematopoietic progenitor cells and the number of naive CD4+ cells

    DEFF Research Database (Denmark)

    Nielsen, S D; Sørensen, T U; Ersbøll, A K;

    2000-01-01

    This study was conducted to determine the impact of immune activation, cytokine production and apoptosis on the naive CD4+ cell count and the function of hematopoietic progenitor cells during the initial phase of highly active antiretroviral therapy (HAART). Blood samples from 11 HIV......-infected patients were collected prior to HAART and after 4 and 12 weeks of therapy. Flow cytometry was used to determine the naive CD4+ count and activated T cells. The cloning efficiency of progenitor cells was determined using a colony-forming cells assay. Finally, apoptosis and cytokine production were...... cells. A negative correlation was found between apoptosis and the naive CD4+ count. Alterations in cytokine production during HAART or correlation between cytokine production and the naive CD4+ count or the cloning efficiency of progenitor cells were not detected. In conclusion, immune activation in HIV...

  3. 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

  4. Functional signatures of human CD4 and CD8 T cell responses to Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Teresa ePrezzemolo

    2014-04-01

    Full Text Available With 1.4 million deaths and 8.7 million new cases in 2011, tuberculosis (TB remains a global health care problem and together with HIV and Malaria represents the one of the three infectious diseases world-wild. Control of the global TB epidemic has been impaired by the lack of an effective vaccine, by the emergence of drug-resistant forms of Mycobacterium tuberculosis (Mtb and by the lack of sensitive and rapid diagnostics. It is estimated, by epidemiological reports, that one third of the world’s population is latently infected with Mtb, but the majority of infected individuals develops long-lived protective immunity, which controls and contains Mtb in a T cell-dependent manner. Development of TB disease results from interactions among the environment, the host, and the pathogen, and known risk factors include HIV coinfection, immunodeficiency, diabetes mellitus, overcrowding, malnutrition, and general poverty; therefore an effective T cell response determines whether the infection resolves or develops into clinically evident disease. Consequently, there is great interest in determining which T cells subsets mediate anti-mycobacterial immunity, delineating their effector functions. On the other hand, many aspects remain unsolved in understanding why some individuals are protected from Mtb infection while others go on to develop disease.Several studies have demonstrated that CD4+ T cells are involved in protection against Mtb, as supported by the evidence that CD4+ T cell depletion is responsible for Mtb reactivation in HIV-infected individuals. There are many subsets of CD4+ T cells, such as T-helper 1 (Th1, Th2, Th17, and regulatory T cells (Tregs, and all these subsets cooperate or interfere with each other to control infection; the dominant subset may differ between active and latent Mtb infection cases. Mtb-specific CD4+ Th1 cell response is considered to have a protective role for the ability to produce cytokines such as IFN- or TNF

  5. 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...

  6. Functional maturation of mouse CD4~+CD8~- thymocytes induced by medullary-type thymus epithelial cells

    Institute of Scientific and Technical Information of China (English)

    路力生; 陈慰峰

    1996-01-01

    Murine CD4+CD8- (CD4SP) thymocyte subset is a heterogeneous population, in which the Qa-2- cells are less functional, whereas the Qa-2+ cells are fully functional. Evidence is provided here that the transition from Qa-2- to Qa-2+ CD4SP thymocytes is an intrathymic process of differentiation induced by thymic medullary-type epithelial cells. The separated Qa-2-CD4SP could be induced to express Qa-2 molecules up to 84%- 89% of the total viable celb after cocultured for 3d with MTEC1 cells, a murine thymic medullary type epithelial cell line established in our laboratory. Kinetic study showed that both the percentage of Qa-2+ cells and the density of the expressed Qa-2 molecules on CD4SP thymocytes induced by MTEC1 were progressively increasing in 72-h cultures. The MTECl-induced Qa-2+CD4SP thymocytes were fully functional, which exhibited capabilities of proliferation and cytokine secretion in response to Con A stimulation as high as those of freshly isolated Qa-2+CD4SP thymocytes. The profile of cytokine

  7. An increased frequency of autoantibody-inducing CD4+ T cells in pre-diseased lupus-prone mice.

    Science.gov (United States)

    Busser, Brian W; Cancro, Michael P; Laufer, Terri M

    2004-07-01

    Pathogenic autoantibody production in murine models of lupus is dependent on autoreactive CD4+ helper T cells. However, the mechanisms which permit the selection and maintenance of this autoantibody-inducing CD4+ T-cell repertoire are currently unknown. We hypothesized that the peripheral CD4+ T-cell repertoire of lupus-prone mice was enriched with autoantibody-inducing specificities. To test this, we utilized the splenic focus assay to determine if pre-diseased lupus-prone (NZB x NZW)F(1) mice have an elevated frequency of autoreactive CD4+ T lymphocytes capable of supporting autoantibody production. The splenic focus limiting dilution assay permits anti-nuclear antibodies to be generated from contact-dependent T-B interactions in vitro. We show that young, pre-diseased lupus-prone mice have an elevated frequency of autoantibody-inducing CD4+ T cells. Interestingly, these autoantibody-inducing CD4+ T-cell responses are also present in the thymus. Therefore, an elevated frequency of autoantibody-inducing CD4+ T cells predisposes lupus-prone mice to the development of autoantibodies.

  8. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up

    DEFF Research Database (Denmark)

    Lundgren, Jens; Babiker, Abdel; El-Sadr, Wafaa;

    2008-01-01

    BACKGROUND AND METHODS: The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease...... or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported. RESULTS: During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count ...%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Fengliang Liu

    2016-06-01

    Full Text Available 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.

  11. 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...

  12. 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...

  13. Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys1

    OpenAIRE

    Gordon, Shari N.; Klatt, Nichole R.; Bosinger, Steven E; Brenchley, Jason M.; Milush, Jeffrey M.; Engram, Jessica C.; Dunham, Richard M.; Paiardini, Mirko; Klucking, Sara; Danesh, Ali; Strobert, Elizabeth A.; Apetrei, Cristian; Pandrea, Ivona V.; Kelvin, David; Douek, Daniel C.

    2007-01-01

    HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs i...

  14. TLR2 engagement on CD4(+) T cells enhances effector functions and protective responses to Mycobacterium tuberculosis.

    Science.gov (United States)

    Reba, Scott M; Li, Qing; Onwuzulike, Sophia; Ding, Xuedong; Karim, Ahmad F; Hernandez, Yeritza; Fulton, Scott A; Harding, Clifford V; Lancioni, Christina L; Nagy, Nancy; Rodriguez, Myriam E; Wearsch, Pamela A; Rojas, Roxana E

    2014-05-01

    We have previously demonstrated that mycobacterial lipoproteins engage TLR2 on human CD4(+) T cells and upregulate TCR-triggered IFN-γ secretion and cell proliferation in vitro. Here we examined the role of CD4(+) T-cell-expressed TLR2 in Mycobacterium tuberculosis (MTB) Ag-specific T-cell priming and in protection against MTB infection in vivo. Like their human counterparts, mouse CD4(+) T cells express TLR2 and respond to TLR2 costimulation in vitro. This Th1-like response was observed in the context of both polyclonal and Ag-specific TCR stimulation. To evaluate the role of T-cell TLR2 in priming of CD4(+) T cells in vivo, naive MTB Ag85B-specific TCR transgenic CD4(+) T cells (P25 TCR-Tg) were adoptively transferred into Tlr2(-/-) recipient C57BL/6 mice that were then immunized with Ag85B and with or without TLR2 ligand Pam3 Cys-SKKKK. TLR2 engagement during priming resulted in increased numbers of IFN-γ-secreting P25 TCR-Tg T cells 1 week after immunization. P25 TCR-Tg T cells stimulated in vitro via TCR and TLR2 conferred more protection than T cells stimulated via TCR alone when adoptively transferred before MTB infection. Our findings indicate that TLR2 engagement on CD4(+) T cells increases MTB Ag-specific responses and may contribute to protection against MTB infection.

  15. 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.

  16. CD4+CD25+CD127low regulatory T cells play predominant anti-tumor suppressive role in hepatitis B virus associated hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Shreya eSharma

    2015-02-01

    Full Text Available Background:Hepatocellular carcinoma (HCC is the second leading cause of cancer death worldwide and hepatitis B is one of the commonest causes. T regulatory cells (Tregs are strong immunomodulators and are likely to play a major role in HCC development. HBV infection is reported to induce expansion of Tregs. We investigated the CD4+CD25+CD127-veFoxP3+ Tregs in HBV related HCC as compared to non-HBV-HCC. Patients and Methods: Whole blood Immunophenotyping was analysed by multicolor flow cytometry in patients with HBV related HCC (HBV-HCC, n=17, non-HBV-HCC (n=22; NASH =16, alcohol related=6 and chronic hepatitis B infection (CHBV; n=10.T regulatory cells and functionality was checked by in vitro suppression assays using CD4+ CD25+ CD127low T regulatory cells. Levels of serum alpha fetoprotein(AFP,expression of FoxP3, IL-10, PD-1, TGF-β and Notch in Tregs and liver explants was analyzed by flow cytometry, immuno-histochemistry and quantitative RT-PCR.Results:CD4+CD25+hi and Foxp3 expression in CD4+CD25+hiCD127low was significantly increased (P=0.04, P=0.007 in HBVHCC compared to non-HBVHCC and CHBV patients. HBVHCC also showed high IL-10and TGF-β secreting CD4+CD25+hiTregs.The PD1 expression in CD4+CD25+hi was significantly decreased in the HBVHCC than non-HBVHCC. In HBVHCC, AFP levels were significantly high (median 941, range 2-727940 than non-HBVHCC (median 13.5, range 2-18,900. In HBVHCC,patients with high AFP (range;3982-727940 ng/ml showed positive correlation with Foxp3 expression in CD4+CD25+hi CD127low(r=0.857,p=0.014. Reduced PD1 expression in HBVHCC also had negative correlation with FOXP3 in CD4+CD25+hi CD127low(r=-0.78, p=0.04. However, AFP levels in non-HBVHCC showed negative correlation with (R=-0.67, p=0.005 with CD4+CD25+hi Tregs. Conclusions:Our results demonstrates that CD4+ CD25+hi Tregs from HBVHCC patients have decreased expression of PD-1, resulting in higher IL-10 and TGF-β secretion. Increased suppressive ability of

  17. 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

  18. 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