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      Definition of target antigens for naturally occurring CD4 + CD25 + regulatory T cells


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          The antigenic targets recognized by naturally occurring CD4 + CD25 + regulatory T cells (T reg cells) have been elusive. We have serologically defined a series of broadly expressed self-antigens derived from chemically induced mouse sarcomas by serological identification of antigens by recombinant expression cloning (SEREX). CD4 + CD25 + T cells from mice immunized with SEREX-defined self-antigens had strong suppressive activity on peptide-specific proliferation of CD4 + CD25 T cells and CD8 + T cells. The suppressive effect was observed without in vitro T cell stimulation. Foxp3 expression in these CD4 + CD25 + T cells from immunized mice was 5–10 times greater than CD4 + CD25 + T cells derived from naive mice. The suppressive effect required cellular contact and was blocked by anti-glucocorticoid–induced tumor necrosis factor receptor family–related gene antibody. In vitro suppressive activity essentially disappeared 8 wk after the last immunization. However, it was regained by in vitro restimulation with cognate self-antigen protein but not with control protein. We propose that SEREX-defined self-antigens such as those used in this study represent self-antigens that elicit naturally occurring CD4 + CD25 + T reg cells.

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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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            Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.

            CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.
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              Natural versus adaptive regulatory T cells.

              The regulation of immune responses to self-antigens is a complex process that involves maintaining self-tolerance while retaining the capacity to mount robust immune responses against invading microorganisms. Over the past few years, many new insights into this process have been gained, leading to the re-emergence of the idea that regulatory T (T(Reg)) cells are a central mechanism of immune regulation. These insights have raised fundamental questions concerning what constitutes a T(Reg) cell, where they develop and what signals maintain T(Reg)-cell populations in a functional state. Here, we propose the existence of two subsets of CD4+ T(Reg) cells--natural and adaptive--that differ in terms of their development, specificity, mechanism of action and dependence on T-cell receptor and co-stimulatory signalling.

                Author and article information

                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                7 March 2005
                : 201
                : 5
                : 681-686
                [1 ]Second Department of Internal Medicine, Mie University School of Medicine, Mie 514-8507, Japan
                [2 ]Department of Bioregulation, Mie University School of Medicine, Mie 514-8507, Japan
                [3 ]Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110
                [4 ]Department of Experimental Pathology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan
                [5 ]Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
                Author notes

                CORRESPONDENCE Hiroshi Shiku: shiku@ 123456clin.medic.mie-u.ac.jp

                Copyright © 2005, The Rockefeller University Press
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