Threshold control for T cell antigen receptor

描述：(改编自应聘者摘要)我的长期职业目标是 阐明免疫谱系形成的机制。这个 T细胞对抗原的识别起着决定命运的关键作用 每个T细胞克隆并最终建立免疫系统 系统。因此，我把研究重点放在T细胞抗原受体(TCR)上-- 决定T细胞命运的衍生信号。眼下的目标是确定 定义两种不同类型T细胞反应的机制。 抗原肽(激动剂)诱导成熟T细胞充分激活 产生IL-2，表达CD25(IL-2受体α)等表面蛋白 链)和CD69，并增殖。相反，部分激动肽 诱导表面抗原的表达，但不诱导其他反应。这个 这里提出的研究将确定仅涉及 激励性T细胞活化。ZAP-70，一种细胞质蛋白酪氨酸激酶 (PTK)，是TCR信号转导的重要分子。初步 结果表明，接头分子Shc是ZAP-70的底物。我的 实验室建立了一株缺失Shc表达的突变型T细胞系。研究 提示Shc对IL-2的产生是不可或缺的。 TCR刺激，但其他基因的表达不是必需的。我 假设Shc信号通路的参与是一个决定性的 刺激T细胞激活性的因素和它的缺失 Shc信号通路的一部分，将完整的T细胞反应与 部分反应。为了测试这一点，我将确定Shc 诱导IL-2基因表达的功能及生物学效应鉴定 Sc在小鼠体内的丢失。这项研究的完成将为 了解自身免疫性疾病和免疫缺陷的病因。K02 获奖将在三个标准方面帮助我的职业发展；(1) 将快速发展的基因组/蛋白质组技术纳入到 T细胞信号通路分析；(2)扩展和发展分析 方法；(3)确定信令事件的 TCR信号事件在人类免疫疾病中的意义。

DESCRIPTION: (Adapted from Applicant's Abstract) My long-term career goal is to elucidate the mechanisms of how the immunological repertoire is formed. The recognition of antigen by T cells plays a critical role to determine the fate of each T cell clone and to ultimately establish the repertoire of the immune system. Thus, I have focused my research on the T cell antigen receptor (TCR)- derived signals that determine T cell fate. The immediate goal is to identify the mechanism that defines the two different types of T cell responses. Antigenic peptides (agonist) induce full activation of mature T cells to produce IL-2, to express surface proteins such as CD25 (IL-2 receptor alpha chain) and CD69, and to proliferate. In contrast, partial agonist peptides induce expression of the surface antigens but not other responses. The research proposed here will determine the signals exclusively involved in the agonistic activation of T cells. ZAP-70, a cytoplasmic protein tyrosine kinase (PTK), is an essential molecule for TCR signal transduction. Preliminary results show that an adapter molecule Shc is a substrate of ZAP-70. My laboratory established a mutant T cell line lacking expression of Shc. Studies of this cell line revealed that Shc is indispensable for IL-2 production by TCR stimulation, but is not required for expression of other genes. I hypothesize that the involvement of the Shc signaling pathway is a determining factor to provoke agonistic activation of T cells and that it is the absence of the Shc signaling pathway that differentiates the full T cell response from the partial response. To test this, I will determine the mechanism whereby Shc functions to induce IL-2 gene expression and identify the biological effect of loss of Shc in mice. Completion of this study will provide information to understand the etiology of autoimmune diseases and immunodeficiencies. The K02 award will help the development of my career in three criteria; (1) Incorporation of rapidly developing genomic/proteomic technology into the analysis of T cell signaling pathway; (2) Extending and developing analytical methods on the signaling events at the single cell level; (3) Determining the significance of TCR signaling events in human immune disorders.