Threshold control for T cell antigen receptor

描述：（改编自申请人摘要）我的长期职业目标是 阐明免疫系统形成的机制。的 T细胞对抗原的识别在决定T细胞的命运中起着关键作用。 每个T细胞克隆，并最终建立免疫系统的库。 系统因此，我把我的研究重点放在T细胞抗原受体（TCR）上- 决定T细胞命运的衍生信号。当前的目标是确定 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细胞的完全活化， 产生IL-2，以表达表面蛋白如CD 25（IL-2受体α 链）和CD 69，并增殖。相反，部分激动剂肽 诱导表面抗原的表达，但不诱导其它应答。的 这里提出的研究将确定专门涉及的信号， T细胞的激动性活化。ZAP-70，一种胞质蛋白酪氨酸激酶 (PTK)是TCR信号转导的必需分子。初步 结果表明，接头分子Shc是ZAP-70的底物。我 实验室建立了缺乏Shc表达的突变T细胞系。研究 结果表明，Shc对IL-2的产生是必不可少的， TCR刺激，但不需要其他基因的表达。我 假设Shc信号通路的参与是决定性的， 因子引起T细胞的激动性活化，并且缺乏 的Shc信号通路，区分完整的T细胞反应， 的部分响应。为了验证这一点，我将确定Shc 功能是诱导IL-2基因表达，并鉴定 小鼠中Shc的丢失。完成本研究将为以下人员提供信息： 了解自身免疫性疾病和免疫缺陷的病因。K02 获奖将有助于我在三个标准的职业生涯的发展;（1） 将快速发展的基因组/蛋白质组技术纳入 T细胞信号通路的分析;（2）扩展和发展分析 方法在单细胞水平上的信号事件;（3）确定 TCR信号传导事件在人类免疫疾病中的重要性。

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.