Functional characterization of anergic helper T cells

对于那些缺乏足够的AIRE依赖胸腺表达的组织特异性蛋白，以确保中央 耐受性，外周耐受性机制存在，以确保健康和避免自身免疫。在……里面 除了自我同意活性高的I细胞外，克隆性无能机制 可用于限制潜在的自身反应性T细胞的增殖潜力。此外，天然的CD4+ 调节性T细胞聚集在外周，对T细胞产生逆调节作用 限制免疫病理学的反应性。在最近的赠款期间，我们发现在 严重的淋巴细胞减少(在没有调节性T细胞的情况下)克隆无能是不能诱导的，而 部分免疫重建后CD25+CD4+调节性T细胞促进小鼠诱导克隆性无能 在没有感染或佐剂的情况下识别抗原的T细胞。我们现在建议详细探讨这一问题-- CD_4~+调节性T细胞与诱导和/或逆转克隆性无能的关系 淋巴细胞减少和免疫活性免疫系统。具体地说，本申请旨在：1)定义 介导抵抗T细胞克隆性无能诱导及其逆转的细胞内信号事件 淋巴细胞减少的个体，2)早期识别促进CD4+调节性T细胞发育的分子 3)检测CD4+调节性T细胞之间的相互依赖关系 免疫活性个体T细胞克隆性无能的产生和诱导。数据生成自 这项工作将作为开发诱导移植的抗原特异性策略的基础 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.