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

1990 ◽  
Vol 171 (6) ◽  
pp. 1981-1999 ◽  
Author(s):  
S Kyoizumi ◽  
M Akiyama ◽  
Y Hirai ◽  
Y Kusunoki ◽  
K Tanabe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Receptor Expression ◽  
Inherited Disease ◽  
Variant Frequency ◽  
T Cell Dysfunction ◽  
Somatic Mutagenesis ◽  
Defective Dna Repair

The 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 the 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.

scholarly journals Upregulation of PD-1 expression on circulating CD8+ but not CD4+ T cells is associated with tuberculosis infection in health care workers

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cui-lin Shi ◽  
Jian-ping Zhang ◽  
Ping Xu ◽  
Jin Li ◽  
Jie Shen ◽  
...  
Keyword(s):  
Health Care ◽  
T Cells ◽  
T Cell ◽  
Health Care Workers ◽  
Cd4 T Cells ◽  
Receptor Expression ◽  
Effector Memory ◽  
Care Workers ◽  
Latent Tb ◽  
Latent Tb Infection

Abstract Background Health care workers (HCWs) are at risk for occupationally acquired Mycobacterium tuberculosis infection and tuberculosis (TB) disease due to repeated exposure to workplace tubercle bacilli. To determine whether continual mycobacterial stimulation correlates with increased expression of inhibitory T cell receptors, here we compared PD-1 receptor expression on surfaces of circulating T cells between naïve (uninfected) HCWs and HCWs with latent TB infection (LTBI). Result Data collected from 133 medical workers who met study selection criteria were included in the final analysis. QuantiFERON-TB Gold In-​Tube (QFT-GIT) testing yielded positive results for 32 HCWs, for an overall LTBI rate of 24.1%. Multivariate analysis identified HCW length of service > 15 years as an independent risk factor for a positive QFT-GIT result. In addition, comparisons of blood T cell subgroup profiles between QFT- and QFT+ groups indicated QFT+ subjects possessed greater proportions of mature (TM), transitional memory (TTM) and effector memory (TEM) CD4+ T cell subgroups and lower proportions of naïve T cells (TN). Moreover, the QFT+ group percentage of CD8+ T cells with detectable surface PD-1 was significantly higher than the corresponding percentage for the QFT- group. Meanwhile, no statistical intergroup difference was observed in percentages of CD4+ T cells with detectible surface PD-1. Conclusions Our data demonstrated that upregulated PD-1 expression on circulating CD8+, but not CD4+ T cells, was associated with latent TB infection of HCWs. As compared to other hospitals, occupational TB infection risk in our hospital was substantially mitigated by implementation of multitiered infection control measures.

MOG extracellular domain (p1–125) triggers elevated frequency of CXCR3+ CD4+ Th1 cells in the CNS of mice and induces greater incidence of severe EAE

2014 ◽  
Vol 20 (10) ◽  
pp. 1312-1321 ◽  
Author(s):  
Jyothi T Mony ◽  
Reza Khorooshi ◽  
Trevor Owens
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
T Cell Response ◽  
Receptor Expression ◽  
Myelin Proteins ◽  
Mhc Ii

Background: Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55). Objectives: Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55. Methods: Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry. Results: MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon-γ-producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar. Conclusions: Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-γ, identifies a pathogenic role for interferon-γ that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.

TIGIT Induces (CD3+) T Cell Dysfunction by Inhibiting Glucose Metabolism and its Reversal by TIGIT and/or PD-1 Blockade in Colorectal Cancer

2021 ◽  
Author(s):  
qi shao ◽  
Lei Wang ◽  
maoling yuan ◽  
Xiaohong Jin ◽  
changping wu
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Cancer Tissue ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Background: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear.Methods: In this study, TIGIT expression in the peripheral blood and tissue microarrays was detected flow cytometry and immunofluorescence and its relationship with prognosis was evaluated. The proliferation and cytokines of TIGIT+ T cells were measured. Glucose metabolism and key enzymes were detected by qPCR or western blot. After establishing the co-cultured system and xenotransplant models, TIGIT antibody alone or combined with PD-1 antibody was blocked to observe the tumor growth.Results: We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth.Conclusions: It is suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.

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.

Decrease in CD4+ T Cells in Multiple Myeloma Patients Receiving Bortezomib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3865-3865
Author(s):  
Ulrike Heider ◽  
Jessica Rademacher ◽  
Martin Kaiser ◽  
Ivana von Metzler ◽  
Karin Marquardt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Herpes Zoster ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Proteasome Inhibitor ◽  
Median Number ◽  
Cell Subpopulation ◽  
Cd4 Lymphocytes

Abstract Abstract 3865 Poster Board III-801 The proteasome inhibitor bortezomib is highly effective in multiple myeloma and widely used in this disease. Recently, an increased incidence of opportunistic infections, particularly varicella zoster virus (VZV) reactivation (herpes zoster), was reported in myeloma patients undergoing treatment with bortezomib. We therefore analyzed the influence of bortezomib on lymphocyte subsets, particularly T-cell subpopulations, in the peripheral blood of myeloma patients before initiation and during the treatment. In addition, the results were correlated with the incidence of VZV reactivation. Peripheral blood samples from 53 multiple myeloma patients treated with bortezomib were collected. Eight of the patients were previously untreated and received bortezomib as front-line therapy, whereas 45 patients were treated in the relapse setting. Different subsets of lymphocytes in the peripheral blood were analyzed by four-color flow cytometry. A decrease of CD4+ T-cells was seen in 42/53 patients (77%). The median numbers of CD4+ T-cells decreased by 45% from 494/μl (range 130-2187) to 274/μl (range 41-1404) during therapy with the proteasome inhibitor (p < 0.001). In the majority of the patients (76%), CD4+ lymphocytes dropped to < 400/μl during bortezomib treatment, and in 18/53 patients (33.9%) the CD4+ T cells fell below 200/μl. The minimum CD4+ cell count was seen at a medium of 6 weeks (range 2-22) after the initiation of treatment, but recovered within a few weeks. The median number of circulating CD3+/CD8+ T-cells decreased by 33.6% from 420/μl (range 48-1518) to 279/μl (range 19-1693) during bortezomib therapy (p < 0.001). This was accompanied by a slight decrease of the median CD4/CD8 ratio from 1.17 (range 0.23-6.0) to 1.0 (range 0.15-4.18). Importantly, all of the patients receiving bortezomib as first-line treatment had a normal CD4+ lymphocyte count before initiation of treatment, and all of them showed a decrease of CD3+/ CD4+ cells during the therapy. The median number of circulating CD4+ T-cells in this subgroup decreased by 70% from 924/μl (range 479-1579) to 276/μl (range 80-626) (p < 0.01). The incidence of herpes zoster reactivation was 5.3% in the whole population of myeloma patients receiving bortezomib. 19/53 patients received acyclovir at a dose of 400mg daily as prophylaxis against VZV reactivation. In this group, none of the patients developed herpes zoster. The incidence of VZV reactivation in patients not receiving acyclovir was 3/34 (8.8%). Importantly, occurrence of herpes zoster was associated with reduced CD4+ T cell subpopulation: all patients who developed herpes zoster had CD4+ lymphocytes < 400/μl. In conclusion, our results show that bortezomib leads to a transient decrease in CD4+ lymphocytes, accompanied by an increased incidence of VZV infections. The antiviral prophylaxis with acyclovir is effective in myeloma patients treated with bortezomib. Disclosures: No relevant conflicts of interest to declare.

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 Kinetics of Regulatory T Cells Predict the Recurrence of CML after Stopping Imatinib in Japanese CML Patiens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4240-4240
Author(s):  
Yuki Fujioka ◽  
Hiroyoshi Nishikawa ◽  
Naoto Takahashi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Research Funding ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Molecular Responses ◽  
Treg Population ◽  
Kinetics Of

Abstract Introduction: Imatinib have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. Recently, treatment free remission (TFR) is proposed as one of the goals in CML treatment, and some prospective trials suggest that imatinib therapy may be safely stopped in CML patients with deep and sustained molecular responses (Lancet Oncol 2010, Blood 2013, JCO 2014). We have previously show that approximately 70% patients with deep and sustained molecular responses could stop imatinib (ASH 2015). On the other hands, the frequency of regulatory T (Treg) cells in imatinib-treated CML patients with complete molecular response (CMR) exhibited significantly lower compared with that in non-CMR (Haematologica, 2013), indicating the important roles of Tregs in CML treatment. Here, we analyzed T-cell profile in Japanese CML patients to identify biomarkers predicting patients that can successfully stop tyrosine kinase inhibitors (TKI) treatment. Methods: Japanese CML patients treated with imatinib for at least three years and confirmed in deeper molecular response (DMR) for at least two years (>4 log reduction of CML cells by four consecutive PCR tests with imatinib therapy for >24 months) were eligible. Patients who received other TKI or stem cell transplantations were excluded. MR4.5 was tested at the beginning of this study using Ipsogen BCR-ABL1 M-BCR IS-PCR kit in a central laboratory (Sysmex, Kobe, Japan). The patientfs peripheral blood was collected at pre- and 1, 3 months after stopping imatinb. Peripheral blood mononuclear cells (PBMCs) ware subjected to direct staining with T-cell markers and analyzed by flowcytometer. Results: Samples of 68 CML patients (77 patients ware enrolled and nine ware excluded due to consent withdrawal or ineligible) were analyzed. We classified these CML patients into three groups (TFR, Fluctuated and Retreatment groups) by clinical courses after stopping imatinib; TFR group (n=33) maintained MR4.5 without further treatment for 2years, Fluctuated group (n=12) moved below and above MR4.5, Retreatment group (n=23) lost MR4.5 and was re-started TKI retreatment. Frequency of CD4+ T cells and CD8+ T cells in CD3+ T cells ware approximately 60% and 25% in all patients at pre-stopping. FoxP3+ T cells are reportedly classified as three fractions with FoxP3 and CD45RA ; FoxP3loCD45+ naïve Treg (nTreg), FoxP3hiCD45- effector Treg (eTreg) which have highly suppressive function and FoxP3loCD45- effector non-Treg which do not possess suppressive activity (figure 1). Average of the frequency of nTreg, eTreg, and non-Treg fractions in CD4+ T cells were 0.6%, 2.9%, and 3.6% (pre-stopping), 0.7%, 3.5%, and 3.9% (On month after stopping) 0.6%, 2.5%, and 3.4% (3 month after stopping), respectively. The frequency of the each fractions (nTreg, eTreg, non-Treg) and total Foxp3+CD4+ T cells (nTreg+eTreg+non-Treg) elevated 1 month after stopping imatinib, but the frequency of Tregs were suddenly dropped to the basal level at 3 months after stopping imatinib. When the kinetics of T cells were evaluated based on three clinical courses, it is noteworthy that Treg elevation after stopping imatinib was not detected in Retreatment group, indicating that Treg repression by imatinib was not observed in this group (figure 2). Conclusion: Treg population in PBMCs elevated transiently after stopping TKI in CML patients with DMR after long-term TKI therapy. This may due to the release of imatinib suppression to Tregs. However, this transient increase of Tregs was not observed in patients who relapsed after stopping imatinib and received TKI retreatment. Together with our previous reports, it is proposed that activation of anti-CML immune responses by decreasing Tregs by imatinib is an important factor for long duration of anti-CML effect by imatinib. Disclosures Takahashi: Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding.

CD8+CD28− T cells: key cytotoxic players impacting disease pathogenesis in chronic HBV infection

2019 ◽  
Vol 133 (17) ◽  
pp. 1917-1934
Author(s):  
Madhuparna Nandi ◽  
Sourina Pal ◽  
Sumantra Ghosh ◽  
Bidhan Chandra Chakraborty ◽  
Debangana Dey ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Hepatitis B E Antigen ◽  
Tnf Α ◽  
Ifn Γ

Abstract During chronic hepatitis B (CHB), CD8+ T cells down-regulate CD28, the primary co-stimulation molecule for T-cell activation. Diverse functional attributes of CD8+CD28− T cells are suggested in various disease contexts. The present study aimed to characterize CD8+CD28− T cells in different phases of chronic Hepatitis B virus (HBV) infection (CHI)- Immune-tolerance (IT), Hepatitis B e-antigen-positive CHB (EP-CHB), Inactive carriers (IC) and Hepatitis B e-antigen-negative CHB (EN-CHB), to appraise their contribution in HBV-related disease pathophysiology. Flow cytometry analysis of T cells in peripheral blood of study subjects revealed enhanced CD8+CD28− T-cell accumulation in EP-/EN-CHB, compared with IT/IC and they expanded equivalently in HBV-specific and non-specific CD8+ T-cell compartments. Profound increase in CD8+CD28− T cells expressing perforin/granzyme-B/CD57/IFN-γ/TNF-α and markers of terminal differentiation were observed exclusively in EP-/EN-CHB. Further, activation with anti-NKG2D resulted in heightened IFN-γ/TNF-α production selectively from CD8+CD28− T cells, suggesting NKG2D-mediated alternative co-stimulation. CD8+CD28− T cells sorted from CHB patients induced enhanced apoptosis of peripheral blood mononuclear cells (PBMC), including CD4+ T cells. However, NKG2D-ligand (major histocompatibility complex class I chain-related molecule A/B (MICA/B)) was preferentially expressed by HBV-specific CD4+ T cells of CHB patients, making these cells a potential target to NKG2D-dependent CD8+CD28− T-cell killing. Both CD28+ and CD28− T cells in CHB expressed CXCR3 at similar levels and thus capable of homing to the liver. A positive correlation was seen between CD8+CD28− T-cell frequency and serum-alanine transaminase (ALT) levels and CHB-derived CD8+CD28− T cells caused pronounced cell death in HBV-transfected Huh7 cells. Immunofluorescence staining identified greater intrahepatic incidence of CD8+CD28− T cells but decline in CD4+ T cells in CHB than IC. Collectively, CD8+CD28− T cells demonstrated differential distribution and phenotypic/functional skewing in different CHI phases and contribute to disease progression by Perforin-Granzyme- or IFN-γ-TNF-α-mediated cytotoxicity while restraining antiviral immunity through NKG2D-dependent HBV-specific CD4+ T-cell depletion.

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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