Self Antigen Specific CD4 Positive T cells

描述（由申请人提供）：在中枢耐受的经典范例中，具有自身抗原特异性的胸腺细胞在发育过程中被删除，从而使周围T细胞库缺乏任何能够对自身组织产生反应的细胞。虽然这种机制在预防自身免疫中的重要性已经得到了很好的确立，但越来越多的证据表明，许多自身抗原特异性T细胞通常会逃避缺失，并填充外周T细胞库，而不会引起疾病。这尤其可能发生在组织限制性自身抗原在胸腺中表达不良的情况下。外周自身抗原特异性T细胞如何在同源抗原存在下保持耐受性是一个有趣的问题，因为这些细胞可能参与自身免疫和抗肿瘤免疫。由于单克隆TCR转基因T细胞系统在准确模拟复杂的抗原特异性T细胞多克隆群体方面的严重局限性，关于自身抗原特异性T细胞的几个基本问题仍未解决。首先，目前尚不清楚克隆缺失和调节性T细胞（Treg）发育等中心耐受机制在多大程度上调节T细胞对组织限制性自身抗原的反应性。此外，目前尚不清楚存在于外周的自体抗原特异性常规T细胞（Tconv）是否对其抗原一无所知，功能上无能，还是受到免疫系统的积极抑制

DESCRIPTION (provided by applicant): In the classic paradigm of central tolerance, thymocytes with specificity for self-antigens are deleted during development, thereby leaving the peripheral T cell repertoire devoid of any cells capable of reacting to self-tissues. While the significance of this mechanism in preventing autoimmunity is well established, growing evidence indicates that many self-antigen specific T cells routinely escape deletion and populate the peripheral T cell repertoire without causing disease. This is especially likely in the case of tissue-restricted self-antigens that are poorly expressed in the thymus. How peripheral self-antigen specific T cells remain tolerant in the presence of their cognate antigen poses an intriguing question as these cells are likely involved in autoimmunity as well as anti-tumor immunity. Due to the severe limitations of monoclonal TCR transgenic T cell systems to accurately model complex polyclonal populations of antigen-specific T cells, several fundamental questions about self-antigen specific T cells remain unresolved. First, it is unclear to what extent central tolerance mechanisms such as clonal deletion and regulatory T cell (Treg) development play in the regulation of T cell reactivity to tissue-restricted self-antigens. Furthermore, it is unclear whether self-antigen specific conventional T cells (Tconv) present in the periphery are simply ignorant of their antigen, functionally anergic, or actively suppressed by Treg cells. We have developed powerful experimental systems involving peptide:MHC tetramer-based cell enrichment techniques and tissue-restricted antigen transgenic mice that allow us to directly characterize rare polyclonal populations of self-antigen specific T cells that naturally arise in endogenous repertoires. These tools will enable us to investigate these issues at an unprecedented level of physiological significance. We hypothesize that deletional tolerance of self-antigen specific T cells is far less extensive than previously appreciated, particularly in th case of tissue-restricted self-antigens, and accordingly, the peripheral repertoire of T cells is normally populated with numerous potentially self-reactive clones. We believe that self-antigen specific CD4+ T cells preferentially adopt a Treg lineage fate during development, and these cells suppress their Tconv counterparts in the periphery to establish tolerance within the overall self-antigen specific population. We will test this hypothesis by pursuing the following initial specific aims: 1) Determine how thymic selection shapes the peripheral repertoire of CD4+ T cells specific for tissue- restricted self-antigens, and 2) Determine how steady state tolerance is maintained in peripheral populations of self-antigen specific CD4+ T cells. The achievement of these aims will greatly improve our understanding of how non-deletional mechanisms of peripheral T cell tolerance are normally established for self-antigens in the steady state, and how we may exploit this information for therapeutic purposes.