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      Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection

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          Abstract

          Autoimmunity occurs because central and peripheral tolerance mechanisms fail to tolerize T cells with weak self-reactivity to tissue-restricted antigen.

          Abstract

          Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8 + T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity.

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          Most cited references34

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          Projection of an immunological self shadow within the thymus by the aire protein.

          Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
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            Positive and negative selection of T cells.

            A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.
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              Complete but curtailed T cell response to very low affinity antigen

              Following an infection, CD8+ T cells are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells1–3. The pool of naïve T cell clones is diverse and contains cells bearing T cell antigen receptors (TCR) that differ in their affinity for the same antigen4,5. How these differences in affinity impact the function and the response kinetics of individual T cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR-ligand interactions are sufficient to activate naïve T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically impacts when expansion stops, when the cells exit lymphoid organs and when contraction begins, i.e. strongly stimulated T cells contract and exit lymphoid organs later than do weakly stimulated cells. Our data challenges the prevailing view that strong TCR ligation is a prerequisite for CD8+ T cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T cell expansion. We propose that in response to microbial challenge, T cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity due to the more prolonged expansion of high affinity T cell clones.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                24 September 2012
                : 209
                : 10
                : 1769-1779
                Affiliations
                [1 ]Swiss Vaccine Research Institute and Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
                [2 ]Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospital, 1211 Geneva, Switzerland
                [3 ]Department of Neuropathology, University Medical Center, Georg August University, 37099 Göttingen, Germany
                [4 ]Department of Immunology, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195
                Author notes
                CORRESPONDENCE Dietmar Zehn: dietmar.zehn@ 123456chuv.ch
                Article
                20120905
                10.1084/jem.20120905
                3457731
                22987800
                36321125-cbe2-4af6-9f45-78cfad68cb37
                © 2012 Enouz et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 30 April 2012
                : 20 August 2012
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                Medicine
                Medicine

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