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      Regulatory T Cells Negatively Affect IL-2 Production of Effector T Cells through CD39/Adenosine Pathway in HIV Infection

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          The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39−. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production.

          Author Summary

          Regulatory T cells (Treg) represent a subset of T lymphocytes and have a pivotal role in chronic viral infections and cancer by limiting immune activation. It has been shown that Treg are expanded in chronic HIV infected patients. However, the mechanisms of Treg immune-modulator functions are not clearly known. CD39 is an ectonucleotidase which converts the proinflammatory ATP signal into AMP and the immunosuppressive adenosine in concert with another ecto-enzyme CD73. We have previously reported that CD39/adenosine pathway is involved in AIDS progression. However, the mechanism of Treg immunosuppression through CD39 and its involvement in HIV pathogenesis remains unclear. We report here that Treg/CD39+ inhibits the production of IL-2, a cytokine that stimulates the growth of T lymphocytes, via CD39/Adenosine/cAMP enzymatic pathway. The signals induced by adenosine specific receptor A2AR, increase the intra cellular levels of cAMP. We show that cAMP inhibits CpG site demethylation of the il-2 gene promoter. We found that T cells from HIV patients have a higher expression on A2AR as well as intra-cellular cAMP and a lesser capacity to produce IL-2 upon stimulation than healthy subjects. Our results contribute to elucidate the mechanisms by which Treg suppression occurs during HIV infection.

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          Most cited references 52

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          Natural regulatory T cells in infectious disease.

          This review discusses the control exerted by natural CD4(+) CD25(+) regulatory T cells (natural T(reg) cells) during infectious processes. Natural T(reg) cells may limit the magnitude of effector responses, which may result in failure to adequately control infection. However, natural T(reg) cells also help limit collateral tissue damage caused by vigorous antimicrobial immune responses. We describe here various situations in which the balance between natural T(reg) cells and effector immune functions influences the outcome of infection and discuss how manipulating this equilibrium might be exploited therapeutically.
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            Cyclic adenosine monophosphate is a key component of regulatory T cell–mediated suppression

            Naturally occurring regulatory T cells (T reg cells) are a thymus-derived subset of T cells, which are crucial for the maintenance of peripheral tolerance by controlling potentially autoreactive T cells. However, the underlying molecular mechanisms of this strictly cell contact–dependent process are still elusive. Here we show that naturally occurring T reg cells harbor high levels of cyclic adenosine monophosphate (cAMP). This second messenger is known to be a potent inhibitor of proliferation and interleukin 2 synthesis in T cells. Upon coactivation with naturally occurring T reg cells the cAMP content of responder T cells is also strongly increased. Furthermore, we demonstrate that naturally occurring T reg cells and conventional T cells communicate via cell contact–dependent gap junction formation. The suppressive activity of naturally occurring T reg cells is abolished by a cAMP antagonist as well as by a gap junction inhibitor, which blocks the cell contact–dependent transfer of cAMP to responder T cells. Accordingly, our results suggest that cAMP is crucial for naturally occurring T reg cell–mediated suppression and traverses membranes via gap junctions. Hence, naturally occurring T reg cells unexpectedly may control the immune regulatory network by a well-known mechanism based on the intercellular transport of cAMP via gap junctions.
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              Regulatory T cells and mechanisms of immune system control.

              The immune system evolved to protect the host against the attack of foreign, potentially pathogenic, microorganisms. It does so by recognizing antigens expressed by those microorganisms and mounting an immune response against all cells expressing them, with the ultimate aim of their elimination. Various mechanisms have been reported to control and regulate the immune system to prevent or minimize reactivity to self-antigens or an overexuberant response to a pathogen, both of which can result in damage to the host. Deletion of autoreactive cells during T- and B-cell development allows the immune system to be tolerant of most self-antigens. Peripheral tolerance to self was suggested several years ago to result from the induction of anergy in peripheral self-reactive lymphocytes. More recently, however, it has become clear that avoidance of damage to the host is also achieved by active suppression mediated by regulatory T (T(reg)) cell populations. We discuss here the varied mechanisms used by T(reg) cells to suppress the immune system.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                April 2013
                April 2013
                25 April 2013
                29 April 2013
                : 9
                : 4
                [1 ]INSERM U955, Equipe 16, Créteil, France
                [2 ]Faculté de Médecine, Université Paris Est Créteil, Créteil, France
                [3 ]Vaccine Research Institute, Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) HIV Vaccine Network (AHVN), Créteil, France
                [4 ]Groupe Henri-Mondor Albert-Chènevière, Laboratory of Pharmacology and Toxicology, Créteil, France
                [5 ]Faculty of Dentistry, McGill University, Montréal, Québec, Canada
                [6 ]Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, Québec, Canada
                [7 ]Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHU de Québec, and Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec, Québec, Canada
                [8 ]Groupe Henri-Mondor Albert-Chènevière, Immunologie Clinique, Créteil, France
                National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MAJ NS YL. Performed the experiments: MAJ AY MY MC AH AK AT. Analyzed the data: MAJ NS JDL YL EG JPR JS. Contributed reagents/materials/analysis tools: JDL JPR JS. Wrote the paper: MAJ NS YL.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 11
                This work was supported by ANRS (Agence Nationale de Recherche contre le SIDA et les hépatites virales). JS receives supports from Canadian Institutes of Health Research (CIHR) and FRQ-S. JPR receives supports from AIDS and Infectious Diseases Network of FRQ-S, Canadian HIV trial network and CIHR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Immune Cells
                T Cells
                Immune Activation
                Immunity to Infections
                Infectious Diseases
                Viral Diseases
                Retrovirology and HIV immunopathogenesis

                Infectious disease & Microbiology


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