Self Antigen Specific CD4 Positive T cells

描述(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，从而使外周T细胞库中没有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方面的重要性已经得到了很好的证实，但越来越多的证据表明，许多自身抗原特异的T细胞经常逃脱缺失，并在不引起疾病的情况下聚集在外周T细胞库中。这在组织限制性自身抗原的情况下尤其可能，这些自身抗原在胸腺中表达很少。外周自身抗原特异性T细胞如何在同源抗原存在的情况下保持耐受，这是一个有趣的问题，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，有关自身抗原特异性T细胞的几个基本问题仍未得到解决。首先，目前尚不清楚克隆缺失和调节性T细胞(Treg)发育等中枢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身抗原特异性常规T细胞(Tconv)是简单地忽略了它们的抗原，功能上无能，还是受到了 树突状细胞。我们开发了强大的多肽实验系统：基于MHC四聚体的细胞浓缩技术和组织限制性抗原转基因小鼠，使我们能够直接表征自然出现在内源性谱系中的罕见的自身抗原特异性T细胞的多克隆群体。这些工具将使我们能够以前所未有的生理意义来研究这些问题。我们假设，自身抗原特异性T细胞的缺失耐受性远不如之前所认识的那样广泛，特别是在组织限制性自身抗原的情况下，因此，T细胞的外周谱系通常被许多潜在的自我反应克隆所填充。我们认为，自身抗原特异性的CD4+T细胞在发育过程中优先采用Treg血统命运，这些细胞在外围抑制其Tconv对应物，以在整个自身抗原特异性人群中建立耐受性。我们将通过追求以下最初的具体目标来验证这一假设：1)确定胸腺选择如何塑造组织限制性自身抗原特异性的外周CD4+T细胞；2)确定稳定状态耐受的程度 维持在外周人群中的自身抗原特异性的CD4+T细胞。这些目标的实现将极大地提高我们对稳定状态下自身抗原正常情况下外周T细胞耐受的非缺失机制的理解，以及我们如何利用这些信息达到治疗目的。

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.