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      S1P 1 receptor overrides regulatory T cell-mediated immune suppression through Akt-mTOR

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          Abstract

          Regulatory T cells (T reg) are critically involved in maintaining immunological tolerance, but this potent suppression must be quenched to allow the generation of adaptive immune responses. Here we report that type 1 sphingosine-1-phosphate (S1P) receptor (S1P 1) delivers an intrinsic negative signal to restrain thymic generation, peripheral maintenance and suppressive activity of T reg cells. Combining loss- and gain-of-function genetic approaches, we found that S1P 1 blocked the differentiation of thymic T reg precursors and function of mature Treg cells, and affected T reg-mediated immune tolerance. S1P 1 induced the selective activation of the Akt-mTOR pathway to impede T reg development and function. Dynamic regulation of S1P 1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T reg-mediated immune suppression, the lipid-activated S1P 1-Akt-mTOR pathway orchestrates adaptive immune responses.

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          Most cited references36

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Regulatory T cell lineage specification by the forkhead transcription factor foxp3.

            Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.
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              A function for interleukin 2 in Foxp3-expressing regulatory T cells.

              Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nature immunology
                1529-2908
                1529-2916
                13 August 2009
                31 May 2009
                July 2009
                1 January 2010
                : 10
                : 7
                : 769-777
                Affiliations
                [1 ]Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105.
                [2 ]Animal Resources Center, St Jude Children’s Research Hospital, Memphis, Tennessee 38105.
                [3 ]Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
                [4 ]Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520.
                [5 ]Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
                Author notes
                Correspondence should be addressed to H.C. ( hongbo.chi@ 123456stjude.org .) Hongbo Chi, Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA. Phone: 901-595-6282; Fax: 901-595-5766

                AUTHOR CONTRIBUTIONS G.L. designed and performed the experiments with cells and mice, analyzed data, and contributed to writing the manuscript; S.B. performed retroviral transduction of BM cells and reconstitution and managed the mouse colony; G.H. and S.B. contributed to real-time PCR analysis; K.B. analyzed and scored histology data; R.L.P. and R.A.F. provided important animal models; H.C designed experiments, analyzed data, wrote the manuscript, and provided overall direction.

                Article
                nihpa112299
                10.1038/ni.1743
                2732340
                19483717
                cc7c3182-c8df-4c03-9358-a5d12544ec07
                History
                Funding
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K01 AR053573-03 ||AR
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K01 AR053573-02 ||AR
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K01 AR053573-01A1 ||AR
                Categories
                Article

                Immunology
                t cells,tolerance,signal transduction
                Immunology
                t cells, tolerance, signal transduction

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