Self Peptides Bound to MHC Class II In T Cell Selection

描述（由申请人提供）：最近的研究表明，表达转录因子Foxp3的调节性T细胞（Tr）在控制胸腺自身反应性T细胞逃避负选择和外周耐受诱导中起关键作用。在之前的资助期间，我们发现保护性Tr细胞本身利用TCR对MHC II类自肽复合物具有更高的反应性。亲和性增加的TCR信号以及其他鲜为人知的信号可能是Tr细胞分化所必需的。然而，TCR对Tr介导的自身免疫保护的特异性要求以及不同APC类型对胸腺Tr生成的贡献及其在外周的维持和功能仍不清楚。几种类型的胸腺APC可以促进Tr细胞的分化，我们假设Tr群体在不同组织和器官中保护自身免疫性炎症的能力是由特定类型的胸腺和外周MHC II类APC表达的差异而形成的。在目前的建议中，我们将采用一套独特的遗传工具来测试这些假设，通过研究胸腺皮质上皮细胞单独或与胸腺髓上皮细胞或树突状细胞一起选择的Tr细胞的抑制潜力，以防止各种器官的自身免疫性病变。我们还将研究Tr细胞显示的TCR库如何被不同类型APC显示的MHC II类分子塑造。最后，我们将测试不同类型的APC对胸腺分化和Tr细胞外周维持的要求，表达单个TCR，并检查这些细胞防止自身免疫的能力。总之，当前应用中描述的研究将为涉及调节性T细胞分化和维持功能保护库的细胞机制提供新的见解。公共卫生相关性：

DESCRIPTION (provided by applicant): Recent studies suggested that regulatory T cells (Tr) expressing transcription factor Foxp3 play a key role in keeping in check autoreactive T cells escaping negative selection in the thymus and peripheral tolerance induction. During previous funding period, we found protective Tr cells themselves utilize TCR with a heightened reactivity towards self-peptide MHC class II complexes. The increased affinity TCR signals together with additional poorly understood signals are likely essential for the differentiation of Tr cells. Nevertheless, TCR specificity requirement for Tr mediated protection against autoimmunity and the contribution of distinct APC types to Tr generation in the thymus and their maintenance and function in the periphery remain unknown. Several types of thymic APC can contribute to differentiation of Tr cells and we hypothesize that the ability of the Tr population to protect against autoimmune inflammation in distinct tissues and organs is differentially shaped by particular types of thymic and peripheral MHC class II expressing APC. In the current proposal we will employ a unique set of genetic tools to test these hypotheses by investigating the suppressive potential of Tr cells selected by the thymic cortical epithelial cells alone or together with the thymic medullary epithelial cells or dendritic cells to prevent autoimmune lesions in various organs. We will also examine how the repertoire of TCR displayed by Tr cells is shaped by MHC class II molecules displayed by distinct types of APC. Finally, we will test a requirement for distinct types of APC for thymic differentiation and peripheral maintenance of Tr cells, expressing a single TCR, and examine the ability of these cells to prevent autoimmunity. Together, the studies described in the current application will provide novel insights into cellular mechanisms involved in differentiation and maintenance of a functional protective repertoire of regulatory T cells. PUBLIC HEALTH RELEVANCE: Regulatory T cells recently emerged as a key mechanism preventing autoimmunity and excessive tissue damage in the course of the immune response to viral, bacterial, and parasitic infections. Furthermore, these cells greatly diminish anti-tumor immunity. In studies described in this application, we will investigate the ways a functional protective repertoire of regulatory T cells is shaped during their differentiation. This work will lead to a better understanding of powerful protection against immune-inflicted damage of specific organs and tissues afforded by regulatory T cells and facilitate development of novel therapeutic approaches to treatment of autoimmune diseases.