Self Antigen Specific CD4 Positive T cells

项目总结 在中枢耐受的经典范例中，对自身抗原具有特异性的胸腺细胞在 发育，从而使外周T细胞谱系中没有任何能够对自身... 纸巾。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，但仍在增长 有证据表明，许多自身抗原特异的T细胞例行公事地逃避缺失并聚集在外周 不会导致疾病的T细胞谱系。这在组织限制性自身抗原的情况下尤其可能发生。 在胸腺中表达很差的基因。外周血中自身抗原特异性T细胞如何保持耐受 它们的同源抗原的存在提出了一个有趣的问题，因为这些细胞可能参与了 自身免疫和抗肿瘤免疫。由于单抗TCR转基因T细胞的严重局限性 精确模拟抗原特异性T细胞的复杂多克隆群体的细胞系统，几个 关于自身抗原特异性T细胞的基本问题仍然没有解决。首先，目前还不清楚在多大程度上 中枢耐受机制，如克隆性缺失和调节性T细胞(Treg)发育在 调节T细胞对组织限制性自身抗原的反应性。此外，目前还不清楚自身抗原是否 存在于外周的特定常规T细胞(Tconv)在功能上完全忽略了它们的抗原 无能，或被Treg细胞主动抑制。我们开发了强大的实验系统，包括 肽：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罕见的自身抗原特异性T细胞的多克隆群体，这种T细胞自然出现在 内生曲目。这些工具将使我们能够以前所未有的水平调查这些问题 生理意义。我们假设自身抗原特异性T细胞的缺失耐受性要小得多 比以前认识到的更广泛，特别是在组织限制性自身抗原的情况下，以及 因此，T细胞的外周谱系通常被许多潜在的自我反应所填充 克隆人。我们认为，自身抗原特异性的CD4+T细胞优先采用Treg血统命运 发育，这些细胞抑制它们在外围的Tconv对应物，以建立耐受性 总的自身抗原特异群。我们将通过追求以下最初的具体情况来检验这一假设 目的：1)确定胸腺选择如何塑造组织特异性的外周CD4+T细胞- 限制性自身抗原，以及2)决定如何在外周人群中维持稳定的耐受性 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 外周T细胞耐受的非缺失机制通常是如何为自身抗原建立的 稳定状态，以及我们如何将这些信息用于治疗目的。

PROJECT SUMMARY 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 the 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.