Self Peptides Bound to MHC Class II In T Cell Selection

描述(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)在抑制自身反应性T细胞逃避胸腺负选择和外周耐受诱导方面发挥关键作用。在之前的资助期间，我们发现保护性Tr细胞本身利用TCR，对自肽MHC II类复合体具有高度的反应性。亲和力增强的TCR信号与其他鲜为人知的信号一起，可能是Tr细胞分化所必需的。然而，Tr介导的自身免疫保护的TCR特异性要求、不同APC类型对胸腺Tr生成的贡献以及它们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群体保护不同组织和器官中自身免疫性炎症的能力是由表达APC的特定类型的胸腺和外周MHC II类不同所决定的。在目前的提案中，我们将使用一套独特的遗传工具来验证这些假设，通过研究胸腺皮质上皮细胞单独或与胸腺髓质上皮细胞或树突状细胞一起选择的Tr细胞的抑制潜力，以防止各种器官中的自身免疫性损害。我们还将研究Tr细胞显示的TCR谱系是如何由不同类型的APC显示的MHC II类分子形成的。最后，我们将测试不同类型的APC对胸腺分化和Tr细胞外周维持的需求，表达单一的TCR，并检查这些细胞防止自身免疫的能力。总之，本申请中描述的研究将为涉及调节T细胞的功能保护库的分化和维持的细胞机制提供新的见解。

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.