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      Thymus-derived regulatory T cells control tolerance to commensal microbiota

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          Abstract

          Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4 +Foxp3 + regulatory T cells 1, 2 generated in the thymus (tTregs) or extrathymically by induction of naive CD4 +Foxp3 T cells (iTregs). Prior studies suggested that the T cell receptor (TCR) repertoires of tTregs and iTregs are biased towards self and non-self antigens, respectively 36 but their relative contribution in controlling immunopathology, e.g. colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved 7 . The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota- and food-derived antigens to which Tregs and other T cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage 8, 9 and favor tolerogenic presentation of antigens to naive CD4 + T cells 10, 11 , suggesting that intestinal homeostasis depends on microbiota-specific iTregs 1215 . Here, to identify the origin and antigen-specificity of intestinal Tregs, we performed single cell as well as high-throughput (HT) sequencing of the TCR repertoires of CD4 +Foxp3 + and CD4 +Foxp3 T cells and analyzed their reactivity against specific commensal species. We show that tTregs constitute the majority of Tregs in all lymphoid and intestinal organs, including colon, where their repertoire is heavily influenced by the composition of the microbiota. Our results suggest that tTregs, and not iTregs, dominantly mediate tolerance to antigens produced by intestinal commensals.

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          Most cited references22

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          Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.

          Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR) to undergo selection to become CD4+CD25+ regulatory T cells. Selection of CD4+CD25+ thymocytes appears to require a TCR with high affinity for a self peptide because thymocytes that bear TCRs with low affinity do not undergo selection into this pathway. Our findings indicate that specificity for self-peptides directs the selection of CD4+CD25+ regulatory thymocytes by a process that is distinct from positive selection and deletion.
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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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              Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors.

              Naturally arising CD25+ CD4+ regulatory T cells (TR) play an important role in the prevention of autoimmunity. TCR specificity is thought to play a critical role in TR development and function, but the repertoire and specificity of TR TCRs remain largely unknown. We find by sequencing of TRAV14 (Valpha2) TCRalpha chains associated with a transgenic TCRbeta chain that the TRand CD25- CD4+ TCR repertoires are similarly diverse, yet only partially overlapping. Retroviral expression of TCRalpha genes in TCR transgenic RAG-deficient T cells revealed that a high frequency of TCRs derived from CD25+ but not CD25- CD4+ T cells confers the ability to rapidly expand upon transfer into a lymphopenic host. Thus, these data show that a large proportion of naturally arising TR have substantially more efficient interactions with MHC class II bound peptides from the peripheral self than CD25- T cells.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                8 May 2013
                28 April 2013
                9 May 2013
                09 November 2013
                : 497
                : 7448
                : 258-262
                Affiliations
                [1 ]Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA, 30912, USA
                [2 ]Mathematical Biosciences Institute, College of Public Health, Ohio State University, Columbus, OH,43210, USA
                [3 ]Department of Pediatrics, Emory University, Atlanta, GA, 30329, USA
                [4 ]Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
                [5 ]Faculty of Mathematics and Computer Science, University of Lodz, 90-238 Lodz, Poland
                [6 ]Department of Tumor Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, 53-114 Wroclaw, Poland
                Author notes
                Correspondence should be addressed to: Leszek Ignatowicz, Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia 30912-2400, USA. Phone (706)721-7323; Fax (706)721-3482; lignatowicz@ 123456gru.edu

                Author Information Reprints and permission information is available at www.nature.com/reprints.

                Article
                NIHMS457569
                10.1038/nature12079
                3711137
                23624374
                d8d54efc-2cc9-431e-8b27-35b6b46909f7

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R01 HD061916 || HD
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: P30 DK034854 || DK
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