PKC-theta function in RORgammat-regulated Th17 differentiation

描述(由申请人提供)：清除某些病原体所需的强大Th17免疫反应的产生依赖于促进Th17，同时相互抑制Treg的形成。然而，有效预防Th17介导的自身免疫，如EAE，依赖于抑制致病的Th17，同时相互促进Treg的形成。然而，对Th17和Treg分化的协调机制知之甚少。我们的初步结果表明，PKC-theta是Th17和Treg相互分化的关键检查点。这些研究将探讨PKC-theta和RORyt在Th17和iTreg相互分化中的作用。基于从研究中学到的知识，我们希望开发基于PKC-8的治疗方法来预防EAE，这是一种多发性硬化症的动物模型。预计此类治疗在预防Th17介导的自身免疫方面将具有更广泛的适用性。此外，这项研究对基础T细胞生物学具有重要意义，因为它有望揭示PKC-theta介导的TCR信号在Th17和iTreg分化协调中的新的分子机制。 公共卫生相关性：这项建议是为了研究PKC-theta和RORGamma T调节Th17和Treg分化的机制。

DESCRIPTION (provided by applicant): Abstract Generation of robust Th17 immune responses required for clearance of certain pathogens depends on promoting Th17 while reciprocally inhibiting Treg formation. Whereas, effective prevention of Th17-mediated autoimmunity such as EAE depends on inhibiting pathogenic Th17 while reciprocally promoting Treg formation. However, little is known about the mechanisms responsible for coordination of Th17 and Treg differentiation. Our preliminary results demonstrated that PKC-theta is a critical checkpoint for reciprocal Th17 and Treg differentiation. The proposed studies will investigate the function of PKC- theta and RORyt in the reciprocal Th17 and iTreg differentiation. Based on the knowledge learned from the studies, we expect to develop PKC-8-based treatments for prevention of EAE, an animal model of multiple sclerosis. It is expected that such treatments will have a broader applicability in the prevention of Th17-mediated autoimmunity. In addition, the proposed research has significance to basic T cell biology, as it is expected to reveal novel molecular mechanisms for PKC- theta -mediated TCR signals in the coordination of Th17 and iTreg differentiation. PUBLIC HEALTH RELEVANCE: This proposal is to study the mechanisms responsible for PKC-theta and RORgamma T- regulated Th17 and Treg differentiation.