The role of SLP-76 phosphorylation in T cell development

描述(由申请人提供)：T细胞受体(TCR)的参与触发了许多细胞内信号事件，导致T细胞的分化和激活。一些研究表明，SLP-76在T细胞激活和T细胞发育中起着核心作用，因为SLP-76缺陷的小鼠缺乏成熟的T细胞。SLP-76有三个功能结构域：一个含有三个可磷酸化酪氨酸的酸性结构域，一个中央富含脯氨酸的结构域，以及一个C末端的SH2结构域。在这些区域中，三个N末端酪氨酸的突变导致了T细胞发育和功能的最深刻的缺陷。据推测，SLP-76的单个酪氨酸激活T细胞发育所需的特定信号级联反应，包括胸腺细胞选择、T细胞分化和功能。这一假设将通过以下方式验证：1)分析SLP-76缺失的Jurkat细胞，这些细胞由SLP-76在一个或多个酪氨酸磷酸化位点突变重组；2)分析在特定酪氨酸残基上表达酪氨酸突变的SLP-76敲入鼠；以及3)将SLP-76敲入鼠与T细胞受体转基因鼠交配，以评估胸腺细胞的选择和T细胞耐受的机制。了解T细胞如何传递信号来指导胸腺细胞的发育和成熟的T细胞功能，对于了解驱动包括关节炎等自身免疫性疾病在内的几种疾病过程的机制至关重要。这项工作将由宾夕法尼亚大学艾布拉姆森研究所的玛莎·S·乔丹博士完成。乔丹博士在细胞免疫学方面的背景和目前在分子免疫学方面的培训为她提供了一个独特的角度来探讨T细胞发育问题。这项提议将为她提供在体外和体内研究T细胞功能所需的工具和试剂，无论是在正常状态下还是在疾病状态下，她都是研究型大学的独立研究员。充分利用宾夕法尼亚大学提供的教员和服务，特别是阿布拉姆森研究所内的教员和服务，将确保这项提议的成功。

DESCRIPTION (provided by applicant): Engagement of the T cell receptor (TCR) triggers a number of intracellular signaling events that lead to the differentiation and activation of T cells. Several studies have shown that SLP-76 plays a central role in T cell activation and T cell development, as mice deficient in SLP-76 lack mature T cells. SLP-76 has three functional domains: an acidic domain with three phosphorylatable tyrosines, a central proline-rich domain, and a C-terminal SH2 domain. Of these domains, mutation of the three N-terminal tyrosines results in the most profound defects in T cell development and function. It is hypothesized that the individual tyrosines of SLP-76 activate specific signaling cascades required for T cell development including thymocyte selection, and T cell differentiation and function. This hypothesis will be tested by 1) analyzing SLP-76 deficient Jurkat cells reconstituted with SLP-76 bearing mutations at one or multiple tyrosine phosphorylation sites, 2) analyzing SLP-76 knock-in mice expressing tyrosine mutations at particular tyrosine residues and 3) mating SLP-76 knock-in mice to T cell receptor transgenic mice to evaluate thymocyte selection and mechanisms of T cell tolerance. Understanding how T cells transmit signals to direct thymocyte development and mature T cell function is critical to understanding the mechanisms to drive several disease processes including autoimmune diseases such as arthritis. This work will be performed by Dr. Martha S. Jordan at the Abramson Institute at the University of Pennsylvania. Dr. Jordan's background in cellular immunology and current training in molecular immunology provides her with a distinct angle from which to approach questions of T cell development. This proposal will provide her with the tools and reagents required to study T cell function in vitro and in vivo, in normal and diseased states as an independent investigator at a research university. Full access to faculty and services provided by the University of Pennsylvania, especially those within the Abramson Institute, will ensure the success of this proposal.