Depletion of regulatory T cells in HIV infection is associated with immune activation

Immune activation during chronic HIV infection is a strong clinical predictor of death and may mediate CD4(+) T cell depletion. Regulatory T cells (Tregs) are CD4(+)CD25(bright)CD62L(high) cells that actively down-regulate immune responses. We asked whether loss of Tregs during HIV infection mediates immune activation in a cross-sectional study of 81 HIV-positive Ugandan volunteers. We found that Treg number is strongly correlated with both CD4(+) and CD8(+) T cell activation. In multivariate modeling, this relationship between Treg depletion and CD4(+) T cell activation was stronger than any other clinical factor examined, including viral load and absolute CD4 count. Tregs appear to decline at different rates compared with other CD4(+) T cells, resulting in an increased regulator to helper ratio in many patients with advanced disease. We hypothesize that this skewing may contribute to T cell effector dysfunction. Our findings suggest Tregs are a major contributor to the immune activation observed during chronic HIV infection.     

Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease

There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4(+), CD25(high), CD127(low), FoxP3(high) cells. A significantly increased relative frequency of Tregs within the CD4(+) compartment of HIV(+) patients compared to that of healthy controls (P < 0.0001) was observed. Additionally, the relative frequency of Tregs directly correlated with HIV viral load and inversely with CD4(+) counts. However, the absolute Treg number was reduced in HIV-infected patients versus healthy controls (P < 0.0001), with the exception of elite controllers (P > 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4(+), CD25(high), CD39(+) T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections.     

Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice

To escape expulsion by their host's immune system, pathogenic nematodes exploit regulatory pathways that are intrinsic parts of the mammalian immune system, such as regulatory T cells (Tregs). Using depletion of Treg mice, we showed that Foxp3(+) Treg numbers increased rapidly during infection with the nematode Strongyloides ratti. Transient depletion of Tregs during the first days of infection led to dramatically reduced worm burden and larval output, without aggravation of immune pathology. The transient absence of Tregs during primary infection did not interfere with the generation of protective memory. Depletion of Tregs at later time points of infection (i.e., day 4) did not improve resistance, suggesting that Tregs exert their counterregulatory function during the priming of S. ratti-specific immune responses. Improved resistance upon early Treg depletion was accompanied by accelerated and prolonged mast cell activation and increased production of types 1 and 2 cytokines. In contrast, the blockade of the regulatory receptor CTLA-4 specifically increased nematode-specific type 2 cytokine production. Despite this improved immune response, resistance to the infection was only marginally improved. Taken together, we provide evidence that Treg expansion during S. ratti infection suppresses the protective immune response to this pathogenic nematode and, thus, represents a mechanism of immune evasion.     

Modeling adaptive regulatory T-cell dynamics during early HIV infection

Regulatory T-cells (Tregs) are a subset of CD4(+) T-cells that have been found to suppress the immune response. During HIV viral infection, Treg activity has been observed to have both beneficial and deleterious effects on patient recovery; however, the extent to which this is regulated is poorly understood. We hypothesize that this dichotomy in behavior is attributed to Treg dynamics changing over the course of infection through the proliferation of an 'adaptive' Treg population which targets HIV-specific immune responses. To investigate the role Tregs play in HIV infection, a delay differatial equation model was constructed to examine (1) the possible existence of two distinct Treg populations, normal (nTregs) and adaptive (aTregs), and (2) their respective effects in limiting viral load. Sensitivity analysis was performed to test parameter regimes that show the proportionality of viral load with adaptive regulatory populations and also gave insight into the importance of downregulation of CD4(+) cells by normal Tregs on viral loads. Through the inclusion of Treg populations in the model, a diverse array of viral dynamics was found. Specifically, oscillatory and steady state behaviors were both witnessed and it was seen that the model provided a more accurate depiction of the effector cell population as compared with previous models. Through further studies of adaptive and normal Tregs, improved treatments for HIV can be constructed for patients and the viral mechanisms of infection can be further elucidated.     

Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers

Gut-associated lymphoid tissue (GALT) is a major site of HIV replication and CD4(+) T cell depletion. Furthermore, microbial translocation facilitated by mucosal damage likely contributes to the generalized immune activation observed in HIV infection. Regulatory T cells (Treg) help maintain homeostasis and suppress harmful immune activation during infection; however, in the case of persistent viral infections such as HIV, their role is less clear. Although a number of studies have examined Treg in blood during chronic infection, few have explored Treg in the gastrointestinal mucosa. For this study, paired blood and rectal biopsy samples were obtained from 12 HIV noncontrollers (viral load of >10,000 copies/ml plasma), 10 HIV controllers (viral load of <500 copies/ml plasma for more than 5 years), and 12 HIV seronegative control subjects. Noncontrollers had significantly higher percentages of Treg in rectal mononuclear cells (RMNC), but not in blood, compared to seronegative subjects (P = 0.001) or HIV controllers (P = 0.002). Mucosal Treg positively correlated with viral load (P = 0.01) and expression of immune activation markers by CD4(+) (P = 0.01) and CD8(+) (P = 0.07) T cells. Suppression assays indicated that mucosal and peripheral Treg of noncontrollers and controllers maintained their capacity to suppress non-Treg proliferation to a similar extent as Treg from seronegative subjects. Together, these findings reveal that rather than experiencing depletion, mucosal Treg frequency is enhanced during chronic HIV infection and is positively correlated with viral load and immune activation. Moreover, mucosal Treg maintain their suppressive ability during chronic HIV infection, potentially contributing to diminished HIV-specific T cell responses and viral persistence.     

Human immunodeficiency virus type 1 Nef in human monocyte-like cell line THP-1 expands treg cells via toll-like receptor 2

CD4(+) CD25(+) regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses in order to inhibit pathogenic damage resulting from over activation of the immune system. In human immunodeficiency virus-1 (HIV-1) infection, suppression of the immune response by Tregs appears to play an opposing role that promotes chronic viral infection. Treg expansion is known as a marker of the severity of HIV infection and as a potential prognostic marker of disease progression. HIV-1 Nef is one of the earliest expressed viral regulatory genes whose expression may play an important role in regulating Treg cells. We established a THP-1 cell line stably expressing HIV-1 Nef and showed that Nef protein was a potent factor for increasing Treg numbers in vitro. We further found that TLR2 plays a critical role in the increase in Treg cells induced by Nef using TLR2-specific siRNA. Our results suggest new strategies for therapeutic and preventive interventions of HIV infection.     

Frequency of circulating regulatory T cells increases during chronic HIV infection and is largely controlled by highly active antiretroviral therapy

Regulatory T cells (Tregs) act by suppressing the activation and effector functions of innate and adaptive immune responses. HIV infection impacts Treg proportion and phenotype, although discrepant results have been reported depending on the patient population and the way Tregs were characterized. The effects of highly active antiretroviral therapy (HAART) on Treg frequency have not been thoroughly documented. We performed a detailed longitudinal analysis of Treg frequency and phenotype in 11 HIV-infected individuals enrolled in a single, prospective clinical trial, in which all patients underwent the same treatment protocol and were sampled at the same time points. Tregs were characterized for their expression of molecules associated with activation, cell cycle, apoptosis, or function, and compared to circulating Tregs from a group of age-matched healthy individuals.Our results revealed increased proportions, but reduced absolute numbers of circulating CD3(+)CD4(+)FOXP3(+) Tregs in chronically infected HIV-infected patients. Treg frequency was largely normalized by HAART. Importantly, we show that similar conclusions were drawn regardless of the combination of markers used to define Tregs. Our results also showed increased expression of cell cycle markers (Ki67 and cyclin B) in Tregs from untreated infected individuals, which were decreased by HAART. However, the Treg phenotype in untreated patients was not consistent with a higher level of generalized activation, as they expressed very low levels of CD69, slightly elevated levels of HLA-DR and similar levels of GARP compared to Tregs from uninfected donors. Moreover, none of these markers was significantly changed by HAART. Treg expression of CTLA-4 and cytotoxic molecules was identical between patients and controls. The most striking difference in terms of functional molecules was the high expression of CD39 by Tregs in untreated patients, which HAART only partially controlled.     

In Vitro HIV Infection Impairs the Capacity of Myeloid Dendritic Cells to Induce Regulatory T Cells

Myeloid dendritic cells (mDCs) are the antigen-presenting cells best capable of promoting peripheral induction of regulatory T cells (Tregs), and are among the first targets of HIV. It is thus important to understand whether HIV alters their capacity to promote Treg conversion. Monocyte-derived DCs (moDCs) from uninfected donors induced a Treg phenotype (CD25(+)FOXP3(+)) in autologous conventional T cells. These converted FOXP3(+) cells suppressed the proliferation of responder T cells similarly to circulating Tregs. In contrast, the capacity of moDCs to induce CD25 or FOXP3 was severely impaired by their in vitro infection with CCR5-utilizing virus. MoDC exposure to inactivated HIV was sufficient to impair FOXP3 induction. This DC defect was not dependent on IL-10, TGF-β or other soluble factors, but was due to preferential killing of Tregs by HIV-exposed/infected moDCs, through a caspase-dependent pathway. Importantly, similar results were obtained with circulating primary myeloid DCs. Upon infection in vitro, these mDCs also killed Treg through mechanisms at least partially caspase-dependent, leading to a significantly lower proportion of induced Tregs. Taken together, our data suggest that Treg induction may be defective when DCs are exposed to high levels of virus, such as during the acute phase of infection or in AIDS patients.     

FoxP3+ Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies

Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.     

New Tools to Expand Regulatory T Cells from HIV-1-infected Individuals

CD4+ Regulatory T cells (Tregs) are potent immune modulators and serve an important function in human immune homeostasis. Depletion of Tregs has led to measurable increases in antigen-specific T cell responses in vaccine settings for cancer and infectious pathogens. However, their role in HIV-1 immuno-pathogenesis remains controversial, as they could either serve to suppress deleterious HIV-1-associated immune activation and thus slow HIV-1 disease progression or alternatively suppress HIV-1-specific immunity and thereby promote virus spread. Understanding and modulating Treg function in the context of HIV-1 could lead to potential new strategies for immunotherapy or HIV vaccines. However, important open questions remain on their role in the context of HIV-1 infection, which needs to be carefully studied.Representing roughly 5% of human CD4+ T cells in the peripheral blood, studying the Treg population has proven to be difficult, especially in HIV-1 infected individuals where HIV-1-associated CD4 T cell and with that Treg depletion occurs. The characterization of regulatory T cells in individuals with advanced HIV-1 disease or tissue samples, for which only very small biological samples can be obtained, is therefore extremely challenging. We propose a technical solution to overcome these limitations using isolation and expansion of Tregs from HIV-1-positive individuals.Here we describe an easy and robust method to successfully expand Tregs isolated from HIV-1-infected individuals in vitro. Flow-sorted CD3⁺CD4⁺CD25⁺CD127^low Tregs were stimulated with anti-CD3/anti-CD28 coated beads and cultured in the presence of IL-2. The expanded Tregs expressed high levels of FOXP3, CTLA4 and HELIOS compared to conventional T cells and were shown to be highly suppressive. Easier access to large numbers of Tregs will allow researchers to address important questions concerning their role in HIV-1 immunopathogenesis. We believe answering these questions may provide useful insight for the development of an effective HIV-1 vaccine.     

工程化调节性T细胞调控机体免疫耐受及其生物医学应用

调节性T细胞（Tregs）是一类机体发挥免疫调节功能的T淋巴细胞亚群，能够高效、安全、可控地调节机体免疫，在自身免疫疾病及器官移植术后免疫排斥等炎症疾病的治疗应用中发挥关键作用。然而，治疗脱靶和功能表型不稳定给Tregs的临床应用带来巨大挑战。生物医学工程改造策略不仅能够促进Tregs主动靶向与炎症趋化，还可维持Tregs叉头盒蛋白p3 (Foxp3)在炎症环境中的表达稳定性，持续发挥机体免疫调节功能。本文详述Tregs的免疫调节机制，并对生物医学工程化改造的Tregs在自身免疫疾病、器官移植等炎症疾病中的应用进行展望，旨在启发和促进Tregs免疫过继疗法的临床应用研究。     

Increased Presence of FOXP3+ Regulatory T Cells in Inflamed Muscle of Patients with Active Juvenile Dermatomyositis Compared to Peripheral Blood

Juvenile dermatomyositis (JDM) is an immune-mediated inflammatory disease affecting the microvasculature of skin and muscle. CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs) are key regulators of immune homeostasis. A role for Tregs in JDM pathogenesis has not yet been established. Here, we explored Treg presence and function in peripheral blood and muscle of JDM patients. We analyzed number, phenotype and function of Tregs in blood from JDM patients by flow cytometry and in vitro suppression assays, in comparison to healthy controls and disease controls (Duchenne’s Muscular Dystrophy). Presence of Tregs in muscle was analyzed by immunohistochemistry. Overall, Treg percentages in peripheral blood of JDM patients were similar compared to both control groups. Muscle biopsies of new onset JDM patients showed increased infiltration of numbers of T cells compared to Duchenne’s muscular dystrophy. Both in JDM and Duchenne’s muscular dystrophy the proportion of FOXP3⁺ T cells in muscles were increased compared to JDM peripheral blood. Interestingly, JDM is not a self-remitting disease, suggesting that the high proportion of Tregs in inflamed muscle do not suppress inflammation. In line with this, peripheral blood Tregs of active JDM patients were less capable of suppressing effector T cell activation in vitro, compared to Tregs of JDM in clinical remission. These data show a functional impairment of Tregs in a proportion of patients with active disease, and suggest a regulatory role for Tregs in JDM inflammation.     

The phenotype and activation status of regulatory T cells during Friend retrovirus infection

The suppressive capacity of regulatory T cells (Tregs) has been extensively studied and is well established for many diseases. The expansion, accumulation, and activation of Tregs in viral infections are of major interest in order to find ways to alter Treg functions for therapeutic benefit. Tregs are able to dampen effector T cell responses to viral infections and thereby contribute to the establishment of a chronic infection. In the Friend retrovirus (FV) mouse model, Tregs are known to expand in all infected organs. To better understand the characteristics of these Treg populations, their phenotype was analyzed in detail. During acute FV-infection, Tregs became activated in the spleen and bone marrow, as indicated by various T cell activation markers, such as CD43 and CD103. Interestingly, Tregs in the bone marrow, which contains the highest viral loads during acute infection, displayed greater levels of activation than Tregs from the spleen. Treg expansion was driven by proliferation but no FV-specific Tregs could be detected. Activated Tregs in FV-infection did not produce Granzyme B (GzmB) or tumor necrosis factor α (TNFα), which are thought to be a potential mechanism for their suppressive activity. Furthermore, Tregs expressed inhibitory markers, such as TIM3, PD-1 and PD-L1. Blocking TIM3 and PD-L1 with antibodies during chronic FV-infection increased the numbers of activated Tregs. These data may have important implications for the understanding of Treg functions during chronic viral infections.     

B-Cell Control of Regulatory T Cells in Friend Virus Infection

B lymphocytes have well-established effector roles during viral infections, including production of antibodies and functioning as antigen-presenting cells for CD4 + and CD8 + T cells. B cells have also been shown to regulate immune responses and induce regulatory T cells (Tregs). In the Friend virus (FV) model, Tregs are known to inhibit effector CD8 + T-cell responses and contribute to virus persistence. Recent work has uncovered a role for B cells in the induction and activation of Tregs during FV infection. In addition to inducing Tregs, B cell antibody production and antigen-presenting cell activity is a target of Treg suppression. This review focuses on the dynamic interactions between B cells and Tregs during FV infection.     

Characterization of the Treg Response in the Hepatitis B Virus Hydrodynamic Injection Mouse Model

Regulatory T cells (Tregs) play an important role in counter-regulating effector T cell responses in many infectious diseases. However, they can also contribute to the development of T cell dysfunction and pathogen persistence in chronic infections. Tregs have been reported to suppress virus-specific T cell responses in hepatitis B virus (HBV) infection of human patients as well as in HBV animal models. However, the phenotype and expansion of Tregs has so far only been investigated in other infections, but not in HBV. We therefore performed hydrodynamic injections of HBV plasmids into mice and analyzed the Treg response in the spleen and liver. Absolute Treg numbers significantly increased in the liver but not the spleen after HBV injection. The cells were natural Tregs that surprisingly did not show any activation or proliferation in response to the infection. However, they were able to suppress effector T cell responses, as selective depletion of Tregs significantly increased HBV-specific CD8+ T cell responses and accelerated viral antigen clearance. The data implies that natural Tregs infiltrate the liver in HBV infection without further activation or expansion but are still able to interfere with T cell mediated viral clearance.     

Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals

Increased numbers of T regulatory cells (Tregs), key mediators of immune homeostasis, were reported in human and murine malaria and it is current opinion that these cells play a role in balancing protective immunity and pathogenesis during infection. However, the mechanisms governing their expansion during malaria infection are not completely defined. In this article we show that soluble extracts of Plasmodium falciparum (PfSEs), but not equivalent preparation of uninfected erythrocytes, induce the differentiation of polyclonally activated CD4(+) cells in Tregs endowed with strong suppressive activity. PfSEs activate latent TGFβ bound on the membrane of Treg cells, thus allowing the cytokine interaction with TGFβ receptor, and inducing Foxp3 gene expression and TGFβ production. The activation of membrane-bound latent TGFβ by PfSEs is significantly reduced by a broad-spectrum metalloproteinases inhibitor with Zn(++) -chelating activity, and completely inhibited by the combined action of such inhibitor and antibodies to a P. falciparum thrombospondin-related adhesive protein (PfTRAP). We conclude that Pf-Zn(++) -dependent proteinases and, to a lesser extent, PfTRAP molecules are involved in the activation of latent TGFβ bound on the membrane of activated Treg cells and suggest that, in malaria infection, this mechanism could contribute to the expansion of Tregs with different antigen specificity.     

Cyclophosphamide-induced type-1 diabetes in the NOD mouse is associated with a reduction of CD4+CD25+Foxp3+ regulatory T cells

Regulatory T cells (Tregs) have been implicated as key players in immune tolerance as well as suppression of antitumor responses. The chemotherapeutic alkylating agent cyclophosphamide (CY) is widely used in the treatment of tumors and some autoimmune conditions. Although previous data has demonstrated that Tregs may be preferentially affected by CY, its relevance in promoting autoimmune conditions has not been addressed. The nonobese diabetic mouse spontaneously develops type-1 diabetes (T1D). We demonstrate in this study that CY targets CD4+CD25+Foxp3+ Tregs in vivo. CD4+CD25+ T cells isolated from CY-treated mice display reduced suppressive activity in vitro and increased expression of apoptotic markers. Although Treg numbers rapidly recovered to pretreatment levels in the peripheral lymphoid tissues, Tregs failed to recover proportionally within pancreatic infiltrates. T1D progression was effectively prevented by adoptive transfer of a small number of islet Ag-specific CD4+CD25+ Tregs to CY-treated recipients. Prevention of T1D was associated with reduced T cell activation and higher Treg proportions in the pancreas. We conclude that acceleration of T1D by CY is associated with a reduction in CD4+CD25+Foxp3+ Tregs and can be prevented by transfer of CD4+CD25+ Tregs.     

CD4^＋CD25^＋调节性T细胞与人类获得性免疫缺陷病毒感染

CD4^＋CD25^＋是调节性T细胞中功能最重要的一类。它是一类具有特殊免疫调节功能的T细胞亚群。它能够抑制自身免疫病的发生和发展,参与肿瘤免疫的调节,同时在感染和移植免疫中也发挥着极其重要的作用。T细胞的这一亚群具有免疫调节和免疫抑制的特性,新近发现它亦与爱滋病的发生、发展关系密切。HIV进入人体后,CD4^＋CD25^＋调节性T细胞抑制了机体的免疫效应但它也同时被感染,最终由于细胞毒的作用而死亡。由于调节性T细胞数量的减少不能有效的发挥其抑制作用,HIV持续的过度活化使得T细胞逐渐耗竭说明在HIV发生、发展的不同阶段Treg细胞可能都发挥了免疫抑制作用,但是却对HIV感染与爱滋病发病的进程产生了不同的效应。此外,CD4^＋CD25^＋调节性T细胞还与HIV病毒的持续存在密切相关。本文就CD4^＋CD25^＋调节性T细胞与人类获得性免疫缺陷病毒（HIV）感染之间关系进行初步的探讨。     

CD4+CD25+调节性T细胞与人类获得性免疫缺陷病毒感染

CD4 CD25 是调节性T细胞中功能最重要的一类.它是一类具有特殊免疫调节功能的T细胞亚群.它能够抑制自身免疫病的发生和发展,参与肿瘤免疫的调节,同时在感染和移植免疫中也发挥着极其重要的作用.T细胞的这一亚群具有免疫调节和免疫抑制的特性,新近发现它亦与爱滋病的发生、发展关系密切.HIV进入人体后,CD4 CD25 调节性T细胞抑制了机体的免疫效应但它也同时被感染,最终由于细胞毒的作用而死亡.由于调节性T细胞数量的减少不能有效的发挥其抑制作用,HIV持续的过度活化使得T细胞逐渐耗竭说明在HIV发生、发展的不同阶段Treg细胞可能都发挥了免疫抑制作用,但是却对HIV感染与爱滋病发病的进程产生了不同的效应.此外,CD4 CD25 调节性T细胞还与HIV病毒的持续存在密切相关.本文就CD4 CD25 调节性T细胞与人类获得性免疫缺陷病毒(HIV)感染之间关系进行初步的探讨.     

In vitro suppression of CD8+ T cell function by Friend virus-induced regulatory T cells

Regulatory T cell (Treg)-mediated suppression of CD8+ T cells has been implicated in the establishment and maintenance of chronic viral infections, but little is known about the mechanism of suppression. In this study an in vitro assay was developed to investigate the suppression of CD8+ T cells by Friend retrovirus (FV)-induced Tregs. CD4+CD25+ T cells isolated from mice chronically infected with the FV suppressed the development of effector function in naive CD8+ T cells without affecting their ability to proliferate or up-regulate activation markers. In vitro restimulation was not required for suppression by FV-induced Tregs, correlating with their high activation state in vivo. Suppression was mediated by direct T cell-T cell interactions and occurred in the absence of APCs. Furthermore, suppression occurred irrespective of the TCR specificity of the CD8+ T cells. Most interestingly, FV-induced Tregs were able to suppress the function of CD8+ effector T cells that had been physiologically activated during acute FV infection. The ability to suppress the effector function of activated CTLs is likely a requisite role for Tregs in limiting immunopathology by CD8+ T cells during antiviral immune responses. Such activity may also have adverse consequences by allowing viruses to establish and maintain chronic infections if suppression of antiviral immune responses occurs before virus eradication.