The role of SLP-76 phosphorylation in T cell development

描述（由申请人提供）：T细胞受体（TCR）的结合触发许多导致T细胞分化和活化的细胞内信号传导事件。几项研究表明，SLP-76在T细胞活化和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具有三个功能结构域：具有三个可磷酸化酪氨酸的酸性结构域、中央富含脯氨酸的结构域和C末端SH2结构域。在这些结构域中，三个N-末端酪氨酸的突变导致T细胞发育和功能中最深刻的缺陷。假设SLP-76的单个酪氨酸激活T细胞发育（包括胸腺细胞选择）和T细胞分化和功能所需的特异性信号传导级联。该假设将通过1）分析用在一个或多个酪氨酸磷酸化位点处携带突变的SLP-76重构的SLP-76缺陷型Jurkat细胞，2）分析在特定酪氨酸残基处表达酪氨酸突变的SLP-76敲入小鼠和3）使SLP-76敲入小鼠与T细胞受体转基因小鼠交配以评价胸腺细胞选择和T细胞耐受性机制来检验。了解T细胞如何传递信号以指导胸腺细胞发育和成熟T细胞功能对于理解驱动包括关节炎等自身免疫性疾病在内的多种疾病过程的机制至关重要。这项工作将由Martha S博士执行。约旦在宾夕法尼亚大学艾布拉姆森研究所。Jordan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处理T细胞发育的问题。该提案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，在正常和疾病状态下作为研究型大学的独立研究者。充分利用宾夕法尼亚大学提供的教师和服务，特别是艾布拉姆森研究所内的教师和服务，将确保这一提议的成功。

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.