Mechanisms and consequences of CD3 rearrangement during TCR triggering

描述（由申请人提供）：我们对“T细胞佐剂”的开发非常感兴趣，这是一种能够增强T细胞免疫反应对抗肿瘤或慢性感染的生物化合物。为了靶向病变组织进行清除，T细胞必须通过T细胞抗原受体（TCR）识别抗原，并诱导TCR相关CD3复合物的构象变化(v)。然而，发生这种情况的机制，以及这种情况对T细胞免疫的确切作用，尚不完全清楚。在这个项目中，我们打算阐明控制CD3？c在实验中，旨在为关于T细胞活化的结构方面的新概念模型提供信息。我们将重点关注TCR/CD3亚基、结构域和cd3c中涉及的氨基酸序列。以这种方式发现的相关序列将被突变和表达，以确定它们对T细胞发育和激活的功能贡献。我们还将确定外源性提供CD3的贡献？c赋予T细胞功能，通过使用我们生成的新试剂。该试剂可诱导CD3？c不诱导其他T细胞信号传导，因此它对非抗原接合的T细胞是惰性的。然而，该试剂似乎可以增强弱抗原对T细胞的激活，因此可能代表了一类新的“T细胞佐剂”。我们将研究该试剂降低T细胞激活信号阈值的能力，并增强小鼠T细胞介导的肿瘤排斥反应。从这些研究中获得的信息将促进我们对T细胞抗原识别的理解，并指向CD3？C作为具有治疗潜力的分子靶点。

DESCRIPTION (provided by applicant): There is significant interest in the development of 'T cell adjuvants', biocompounds capable of enhancing T cell immune responses against tumors or chronic infections. In order to target diseased tissue for elimination, T cells must recognize antigens via the T cell antigen receptor (TCR), and induce a conformational change in the TCR-associated CD3 complex (v). However, the mechanism(s) by which this occurs, and the precise contribution this makes to T cell immunity, are not completely understood. In this project, we propose to elucidate the protein sequences controlling CD3?c in experiments designed to inform new conceptual models regarding the structural aspects of T cell activation. We will focus on the TCR/CD3 subunits, domains, and amino acid sequences involved in CD3?c. Relevant sequences that are discovered in this manner will be mutated and expressed to ascertain their functional contribution to T cell development and activation. We will also determine the contribution that exogenous provision of CD3?c imparts to T cell function, via the use of a new reagent we have generated. This reagent can induce CD3?c without inducing other T cell signaling, and therefore it is inert to non-antigen-engaged T cells. However, the reagent appears to enhance T cell activation by weak antigens, and thus may represent a novel class of 'T cell adjuvant'. We will examine the ability of this reagent to lower the T cell activation signaling threshold, and to enhance T cell-mediated tumor rejection in mice. The information obtained from these studies will advance our comprehension of antigen recognition by T cells, and point toward CD3?c as molecular target with therapeutic potential.