Functional characterization of anergic helper T cells

对于那些缺乏足够的AIRE依赖性胸腺表达以确保中枢免疫的组织特异性蛋白质， 耐受性，外周耐受机制的存在，以确保健康和避免自身免疫。在 除了外周缺失具有高自噬活性的I细胞外，克隆性无能的机制是 可用于限制潜在自身反应性T细胞的增殖潜力。天然CD 4 + 调节性T细胞在外周聚集，并对T细胞产生反调节作用。 限制免疫病理学反应。在最近的赠款期间，我们发现， 不能诱导严重的淋巴细胞减少症（并且在缺乏调节性T细胞的情况下）克隆性无反应性，而 在部分免疫重建后，CD 25 + CD 4+调节性T细胞促进诱导克隆性无反应性， 在没有感染或佐剂的情况下识别Ag的T细胞。我们现在就来详细探讨一下这个问题-- CD 4+调节性T细胞与克隆性无反应性的诱导和/或逆转之间的关系， 淋巴细胞减少和免疫活性免疫系统。具体地，本申请寻求：1）定义 介导对T细胞克隆无反应性诱导的抗性及其在细胞内的逆转的细胞内信号传导事件 淋巴细胞减少的个体，2）鉴定促进CD 4+调节性T细胞早期发育的分子 在淋巴细胞减少症的恢复过程中，以及3）检查CD 4+调节性T细胞的相互依赖性 免疫活性个体中T细胞克隆无反应性的产生和诱导。数据生成自 这项工作将作为开发Ag特异性策略以诱导移植的基础 耐受或治愈临床自身免疫性疾病。

For those tissue-specific proteins that lack sufficient AIRE-dependent thymic expression to ensure central tolerance, peripheral tolerance mechanisms exist to ensure health and the avoidance of autoimmunity. In addition totheperipheral deletion ofI cells with high self Agreactivity, the clonal anergy mechanismis available to limit the proliferative potential of potentially autoreactive T cells. Furthermore, natural CD4+ regulatory T cells accumulate in the periphery and exert a counter-regulatory influence on T cell responsiveness to limit immunopathology. In the most recent grant period, we discovered that in the setting of profound lymphopenia (and in the absence of regulatory T cells) clonal anergy cannot be induced, whereas following partial immune reconstitution CD25+ CD4+ regulatory T cells facilitate the induction clonal anergy in T cells that recognize Ag in absence of infection or adjuvant. We now propose to explore in detail this inter- relationship between CD4+ regulatory T cells and the induction and/or reversal of clonal anergy in both the lymphopenic and immunocompetent immune system. Specifically, this application seeks to: 1) define intracellular signaling events that mediate a resistance to T cell clonal anergy induction and its reversal within lymphopenic individuals, 2) identify molecules that promote the development CD4+ regulatory T cells early during the recovery from lymphopenia, and 3) examine the inter-dependence of CD4+ regulatory T cell generation and the induction of T cell clonal anergy in immunocompetent individuals. Data generatedfrom this work will serve as the basis for the development of Ag-specific strategies to induce transplantation tolerance or cure clinical autoimmune disease.