Differential mechanisms for RORgammat-regulated thymocyte development and Th17 di

描述(由申请人提供)：T细胞必须经历两个依赖于RoR？T的分化过程，然后在胸腺和外周淋巴组织中依次进行，才能成为介导实际免疫反应的合格的效应Th17细胞。ROR？T在胸腺细胞中表达上调，以提高完成胸腺T细胞成熟过程所需的存活率，而ROR？T活性的缺失严重损害胸腺细胞的发育，最终导致淋巴瘤。ROR？T在外周CD4+T细胞中再次上调，以指示Th17细胞的分化，而Th17细胞介导多种类型的自身免疫。因此，ROR？T被认为是治疗Th17依赖性自身免疫的重要药物靶点。然而，关于ROR？T用于调节这两个分化过程的共同和不同的机制，人们知之甚少。我们的目标是了解ROR？T在胸腺细胞和Th17细胞中的功能，这将有助于开发专门针对Th17依赖的自身免疫的药物，而不是干扰胸腺细胞的发育，从而导致淋巴瘤。这项应用的目的是了解胸腺细胞和外周T细胞如何不同地使用相同的转录因子ROR？T来调节它们的分化过程。

DESCRIPTION (provided by applicant): To become competent effector Th17 cells mediating the actual immune responses, T cells have to undergo two ROR?t-dependent differentiation processes sequentially carried out in thymus and peripheral lymphoid tissues. ROR?t is up-regulated in thymocyes to enhance the survival required for completion of T cell maturation process in thymus, and absence of ROR?t activity severely impairs thymocyte development that eventually leads to lymphoma. ROR?t is again up-regulated in peripheral CD4+ T cells to instruct the differentiation of Th17 cells that mediate many types of autoimmunity. ROR?t is thus considered an important drug target for treatment of Th17-dependent autoimmunity. However, little is known about the common and distinct mechanisms that ROR?t utilize to regulate these two differentiation processes. Our goal is to understand the function of ROR?t in both thymocytes and Th17 cells, which will facilitate to develop drugs specifically targeting Th17-dependent autoimmunity, but not interfering with thymocyte development that leads to lymphoma. The objective of this application is to understand how both thymocytes and peripheral T cells differentially use the same transcription factor ROR?t to regulate their differentiation processes.