mTOR pathway regulates the differentiation of peripheral blood Th2/Treg cell subsets in patients with pemphigus vulgaris

2021 ◽  
Author(s):  
Kuan Lai ◽  
Wenjing Zhang ◽  
Songshan Li ◽  
Zhiwen Zhang ◽  
Shuangde Xie ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Pemphigus Vulgaris ◽  
Treg Cells ◽  
Mtor Pathway ◽  
Cd4 T Cell ◽  
Cell Ratio ◽  
Loss Of Balance

Abstract Pemphigus vulgaris (PV) is a chronic and potentially life-threatening autoimmune blistering disease. Aberrant mTOR pathway activity is involved in many autoimmune diseases. This study investigated the correlation of mTOR pathway (PI3K/AKT/mTOR/p70S6K) activity with the loss of balance in T helper 2/regulatory T (Th2/Treg) cells in the peripheral blood of PV patients. CD4+ T cells were isolated from 15 PV patients and 15 healthy controls (HCs), the ratios of Th2/CD4+ T cells and Treg/CD4+ T cells, the activity of the mTOR pathway (PI3K/AKT/mTOR/p70S6K), the transcription factors and cytokines of Th2 and Treg cells were detected. Primary CD4+ T cells from PV patients were cultured under Th2- or Treg-polarizing conditions with or without rapamycin in vitro. We found that PV patients showed significantly elevated serum IL-4 when compared with HCs, and serum IL-4 level was positively correlated with the titer of anti-Dsg1/3 antibody and disease severity, while the serum TGF-β level was negatively correlated with the titer of anti-Dsg3 antibody and disease severity. Meanwhile, PV patients showed increased Th2/CD4+ T cell ratio; decreased Treg/CD4+ T cell ratio; elevated mRNA of PI3K, AKT, mTOR and protein of PI3K (P85), AKT, p-AKT (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), GATA3; reduced protein of forkhead box protein 3. Rapamycin inhibited Th2 cell differentiation and promoted Treg cell differentiation in vitro. These data suggest a close association between mTOR pathway activation and the loss of balance in Th2/Treg cells in peripheral blood of PV patients. Inhibiting mTORC1 can help restore the Th2/Treg balance.

scholarly journals Characterization of immunoactive and immunotolerant CD4+ T cells in breast cancer by measuring activity of signaling pathways that determine immune cell function

2020 ◽  
Author(s):  
Yvonne Wesseling-Rozendaal ◽  
Arie van Doorn ◽  
Karen Willard-Gallo ◽  
Anja van de Stolpe
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Cd4 T Cell ◽  
Cancer Tissue ◽  
Pathway Activity

AbstractCancer immunotolerance can be reversed by checkpoint blockade immunotherapy in some patients, but response prediction remains a challenge. CD4+ T cells play an important role in activating adaptive immune responses against cancer. Conversion to an immune suppressive state impairs the anti-cancer immune response and is mainly effected by CD4+ Treg cells. A number of signal transduction pathways activate and control functions of CD4+ T cell subsets. As previously described, assays have been developed which enable quantitative measurement of the activity of signal transduction pathways (e.g. TGFβ, NFκB, PI3K-FOXO, JAK-STAT1/2, JAK-STAT3, Notch) in a cell or tissue sample. Using these assays, pathway activity profiles for various CD4+ T cell subsets were defined and cellular mechanisms underlying breast cancer-induced immunotolerance investigated in vitro. Results were used to measure the immune response state in a clinical breast cancer study.MethodsSignal transduction pathway activity scores were measured on Affymetrix expression microarray data of resting, immune-activated, and immune-activated CD4+ T cells incubated with breast cancer tissue supernatants, and of CD4+ Th1, Th2, and Treg cells, and in a clinical study in which CD4+ T cells were derived from blood, lymph node and cancer tissue from primary breast cancer patients (n=10).ResultsIn vitro CD4+ T cell activation induced PI3K, NFκB, JAK-STAT1/2, and JAK-STAT3 pathway activity. Simultaneous incubation with primary cancer supernatant reduced PI3K and NFκB, and partly reduced JAK-STAT3, pathway activity, while simultaneously increasing TGFβ pathway activity; characteristic of an immune tolerant state. CD4+ Th1, Th2, and Treg cells all had a specific pathway activity profile, with activated immune suppressive Treg cells characterized by NFκB, JAK-STAT3, TGFβ, and Notch pathway activity. An immune tolerant pathway profile was identified in CD4+ T cells from tumor infiltrate of a subset of primary breast cancer patients which could be contributed to activated Treg cells. A Treg pathway profile was also identified in blood samples.ConclusionSignaling pathway assays can be used to quantitatively measure the functional immune response state of lymphocyte subsets in vitro and in vivo. Clinical results suggest that in primary breast cancer the adaptive immune response of CD4+ T cells has frequently been replaced by immunosuppressive Treg cells, potentially causing resistance to checkpoint inhibition. In vitro study results suggest that this effect is mediated by soluble factors from cancer tissue (e.g. TGFβ). Signaling pathway activity analysis on TIL and/or blood samples is expected to improve predicting and monitoring response to checkpoint inhibitor immunotherapy.

scholarly journals CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

2021 ◽  
Vol 22 (2) ◽  
pp. 912
Author(s):  
Nabila Seddiki ◽  
John Zaunders ◽  
Chan Phetsouphanh ◽  
Vedran Brezar ◽  
Yin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Significant Proportion ◽  
Long Term Memory ◽  
Ki 67 ◽  
Memory Cd4 T Cells ◽  
Hiv 1

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.

scholarly journals Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

2019 ◽  
Vol 11 (2) ◽  
pp. 108-123
Author(s):  
Dan Tong ◽  
Li Zhang ◽  
Fei Ning ◽  
Ying Xu ◽  
Xiaoyu Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

scholarly journals African Green Monkey TRIM5α Restriction in Simian Immunodeficiency Virus-Specific Rhesus Macaque Effector CD4 T Cells Enhances Their Survival and Antiviral Function

2015 ◽  
Vol 89 (8) ◽  
pp. 4449-4456 ◽  
Author(s):  
Sumiti Jain ◽  
Matthew T. Trivett ◽  
Victor I. Ayala ◽  
Claes Ohlen ◽  
David E. Ott
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rhesus Macaque ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
T Cell Clones ◽  
Cell Clones ◽  
Immunodeficiency Virus ◽  
Antiviral Function

ABSTRACTThe expression of xenogeneic TRIM5α proteins can restrict infection in various retrovirus/host cell pairings. Previously, we have shown that African green monkey TRIM5α (AgmTRIM5α) potently restricts both human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus mac239 (SIVmac239) replication in a transformed human T-cell line (L. V. Coren, et al., Retrovirology 12:11, 2015,http://dx.doi.org/10.1186/s12977-015-0137-9). To assess AgmTRIM5α restriction in primary cells, we transduced AgmTRIM5α into primary rhesus macaque CD4 T cells and infected them with SIVmac239. Experiments with T-cell clones revealed that AgmTRIM5α could reproducibly restrict SIVmac239replication, and that this restriction synergizes with an intrinsic resistance to infection present in some CD4 T-cell clones. AgmTRIM5α transduction of virus-specific CD4 T-cell clones increased and prolonged their ability to suppress SIV spread in CD4 target cells. This increased antiviral function was strongly linked to decreased viral replication in the AgmTRIM5α-expressing effectors, consistent with restriction preventing the virus-induced cytopathogenicity that disables effector function. Taken together, our data show that AgmTRIM5α restriction, although not absolute, reduces SIV replication in primary rhesus CD4 T cells which, in turn, increases their antiviral function. These results support priorin vivodata indicating that the contribution of virus-specific CD4 T-cell effectors to viral control is limited due to infection.IMPORTANCEThe potential of effector CD4 T cells to immunologically modulate SIV/HIV infection likely is limited by their susceptibility to infection and subsequent inactivation or elimination. Here, we show that AgmTRIM5α expression inhibits SIV spread in primary effector CD4 T cellsin vitro. Importantly, protection of effector CD4 T cells by AgmTRIM5α markedly enhanced their antiviral function by delaying SIV infection, thereby extending their viability despite the presence of virus. Ourin vitrodata support priorin vivoHIV-1 studies suggesting that the antiviral CD4 effector response is impaired due to infection and subsequent cytopathogenicity. The ability of AgmTRIM5α expression to restrict SIV infection in primary rhesus effector CD4 T cells now opens an opportunity to use the SIV/rhesus macaque model to further elucidate the potential and scope of anti-AIDS virus effector CD4 T-cell function.

scholarly journals Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract

2004 ◽  
Vol 200 (6) ◽  
pp. 761-770 ◽  
Author(s):  
Saurabh Mehandru ◽  
Michael A. Poles ◽  
Klara Tenner-Racz ◽  
Amir Horowitz ◽  
Arlene Hurley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Cell Loss ◽  
Cd4 T Cell ◽  
Suppressive Therapy ◽  
Hiv 1 ◽  
Gi Mucosa

Given its population of CCR5-expressing, immunologically activated CD4+ T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4+ T cells would be observed in HIV-1–infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4+ T cells compared with peripheral blood CD4+ T cells is seen during primary HIV-1 infection. CD4+ T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4+ T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.

Local and Systemic Induction of an Abundant CD4+CD25+ Regulatory T Cell Population by Non-Hodgkin’s Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 357-357
Author(s):  
S. Mittal ◽  
N.A. Marshall ◽  
L. Duncan ◽  
D.J. Culligan ◽  
R.N. Barker ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Cell Contact ◽  
Healthy Controls ◽  
Soluble Factors ◽  
Tissue Samples ◽  
Ann Arbor

Abstract Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin’s lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMC) and involved tissues from 30 newly diagnosed patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMC (median=20.4% CD4 T cells, n=20) versus healthy controls (median=3.2%, n=13; p<0. 001, rank sum test) and correlated with serum lactate dehydrogenase (n=14; Rs=0.79, p <0.0001) and disease stage. The median Treg percentage of CD4 T cells from early stages (Ann Arbor stage I and II, n=4) was 12.2%, whereas it was 25.4% in advanced disease (Ann Arbor stages III, IV or bulky stage II, ≥5cm, n=10; p =0.013). We also enumerated Tr1 cells, both in peripheral blood and involved tissue samples, and again compared with healthy controls but no significant differences were noted. We documented poor proliferation of T cells with mitogen ConA and almost none with recall antigens PPD and DPT in both PBMC and involved tissue samples (n=9). T cell hyporesponsiveness was reversed by depleting CD25+ cells (n=4), or by adding anti-CTLA-4 (n=3), supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median=38.8% CD4 T cells, n=15) versus reactive nodes (median=11.6%, n=2, p=0.02). Therefore, we tested the hypothesis that a regulatory phenotype is induced from conventional T cells within the tumor microenvironment. When autologous CD25- PBMC fractions were incubated with tumor cells from patients (n=6) in vitro, there was consistent strong induction and then expansion of cells with the CD4+CD25+FoxP3+ phenotype of classic ‘natural’ Treg cells as indicated by CFSE dilution. This induction was dependent on tumor dose and was seen when we depleted lymphoid dendritic cells from the involved tissue cell suspension using anti-CD304, or enriched the tumor cells by positive selection of CD20+ cells. This population was confirmed to be suppressive in function (n=3). We also investigated the mechanisms of this induction. Both cell-cell contact and soluble factors appeared important. In two of four cases, some induction was also noted with transwell experiments or with tumor cell conditioned supernatant, indicating that in these cases soluble factors are also involved apart from direct cell-cell contact mechanism. Reports elsewhere suggest roles for prostaglandin E2, tryptophan catabolism, IL-9 and PD-1 interaction with its ligands in inducing a Treg phenotype. Thus, we used cyclooxygenase inhibitors aspirin and sulindac, the indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl tryptophan (1MT), anti-IL-9 receptor antibody and blocking anti-PDL-1 or anti-PDL-2 antibodies in four samples. None of these reagents inhibited Treg induction apart from one case where both anti-PDL-1 and anti-PDL-2 blocking antibodies inhibited Treg induction. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.

Preliminary Study on the Abnormal DNA Methylation in T Cells from the Patients with Immune Related Pancytopenia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5156-5156
Author(s):  
Zonghong Shao ◽  
Yue Ren ◽  
Rong Fu
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Mrna Expression ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Mrna Level ◽  
Cd4 T Cell ◽  
Global Dna Methylation ◽  
Normal Controls

Abstract Objective To explore the global DNA methylation and the expression of regulatory genes for methylation in CD4 + T cells of the patients with immune related pancytopenia (IRP) and explore the role of methylation in pathogenesis of IRP. Methods Thirty IRP patients (untreated, n=15; remission, n=15) and 15 healthy donors as controls were enrolled from December 2012 to December 2013. CD4+ T cells were sorted by immunomagnetic separation. The global DNA methylation was tested with enzyme-linked immunosorbent assay (ELISA). The mRNA levels of DNA methylation-related regulating genes, DNA methyltransferases (DNMTs) and methylated CpG binding proteins (MBDs), were measured by real-time quantitative polymerase chain reaction (RT-PCR). Results The level of global DNA methylation in peripheral blood CD4+ T cells of untreated IRP patients (3.525%±2.046%)and remission patients (4.790%±1.471%) were significantly lower than that of normal controls (10.101%±3.449%) respectively (both P<0.05). DNMT3b mRNA level of untreated IRP patients (1.332±0.785) was significantly lower than that of normal controls (2.077±1.059) in CD4+T cells (P<0.05). The mRNA expression of MBD2 was significantly higher in CD4+ T cells from untreated and remission IRP patients (2.999±1.601, 2.055±1.576) than that in controls (0.581±0.247) (both P<0.05). The MBD4 mRNA level was significantly higher in CD4+ T cells from untreated IRP patients (2.736±2.719) compared to that in normal controls (1.167±1.006) (p<0.05). DNMT3b mRNA expression and CD4+ T cell DNA methylation to be positive correlated within IRP patients (r=0.569, p<0.01). The MBD2 mRNA expression negatively correlated with CD4+ T cell DNA methylation and the ratio of Th1/Th2 (r=-0.763, p<0.001; r = -0.652, p<0.05). The global methylation of CD4+ T cells negatively related to the ratio of CD5+ B cells (r= -0.439, p<0.05). Conclusions The globe DNA hypomethylation and abnormal expression of DNA methylation-related enzymes in peripheral blood CD4+ T cells may be related with the pathogenesis of IRP. Disclosures No relevant conflicts of interest to declare.

scholarly journals Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Sushant Khanal ◽  
Qiyuan Tang ◽  
Dechao Cao ◽  
Juan Zhao ◽  
Lam Nhat Nguyen ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Apoptosis ◽  
Cd4 T Cells ◽  
Molecular Mechanisms ◽  
Cd4 T Cell ◽  
Cell Aging

ABSTRACT CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in vitro in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an in vitro HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection in vivo. We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This in vitro model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection. IMPORTANCE The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.

Relation of CD4+CD25+ Regulatory T Cells to Immune Status in Patients with HIV Infection.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3106-3106
Author(s):  
Sachi Tsunemi ◽  
Tsuyoshi Iwasaki ◽  
Takehito Imado ◽  
Satoshi Higasa ◽  
Eizo Kakishita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Hiv Infection ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Healthy Controls ◽  
Cell Counts ◽  
Hiv 1

Abstract Human immunodeficiency virus (HIV) infection is characterized by marked defects in CD4+ helper T cell (Th) functions that commonly progress to a substantial decline in peripheral CD4+ T cell counts. However, the mechanisms responsible for the loss of Th functions in HIV-infected patients independent of CD4+ T cell counts remains unclear. CD4+CD25+ regulatory T cells (T Reg) are essential for down-regulation of both autoreactive and alloreactive T cells. Therefore, we decided to investigate the role of T Reg in immune status of HIV-infected patients. We examined the expression of cell surface CD25, cytoplasmic IL-4 and cytoplasmic IFN-gamma in peripheral blood CD4+ T cells from both healthy controls (n=9) and HIV-infected patients (n=43). We also compared T Reg functions between the 2 groups. CD4+CD25+ T Reg isolated from both HIV-infected patients and healthy controls strongly expressed CD45RO, HLA-DR, and FoxP3, and suppressed the proliferation of CD4+CD25− T cells, suggesting that CD4+CD25+ T cells from both healthy controls and HIV-infected patients possess phenotypic and functional characteristics of Treg. CD4+CD25high T cells are a subset of circulating CD4+CD25+ T cells in normal humans and exhibit strong in vitro regulatory functions similar to those reported for murine CD4+CD25+ T Reg. We measured the frequency of CD4+CD25high T Reg by analysis of surface CD25 on CD4+ T cells in peripheral blood samples. We also examined Th1 and Th2 frequencies by analysis of cytoplasmic IFN-gamma and IL-4 levels in CD4+ T cells. T Reg from HIV-infected patients with detectable plasma HIV-1 RNA showed a statistically significant increase in CD4+CD25high cell frequency (p<0.05) compared to healthy controls, with T Reg frequencies inversely proportional to CD4+ T cell numbers (p<0.01). However, in HIV-infected patients with undetectable plasma HIV-RNA, frequencies of CD4+CD25high T Reg were not increased and not related to CD4+ T cell numbers. In both HIV-infected patient groups, T Reg frequency was inversely related to Th1 frequency (detectable: p<0.05, undetectable: p<0.001), but positively related to Th2 frequency (detectable: p<0.01, undetectable: p<0.001). Our results indicate that increased frequencies of peripheral blood T Reg were related to disease progression as measured by detectable plasma HIV-1 RNA, decreased peripheral blood CD4+ T cell counts, and polarization toward Th2 immune responses in HIV-infected patients. HIV infection may lead to induction of T reg that inhibit antiviral immune responses, resulting in the progression of the disease. Manipulation of T Reg could help restore antiviral immune responses in HIV infection, and prevent the progression of HIV infection.

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