Molecular Recognition of Ligand by the gamma delta T cell Receptor

描述（由申请人提供）：？d T细胞构成了针对感染因子和癌性转化的免疫应答的重要组成部分，但它们通过其体细胞重组T细胞受体（TCR）检测抗原的生化机制仍不清楚。与TCR不同，TCR仅限于识别主要组织相容性复合物（MHC）分子中的抗原，？d TCR可以识别多种配体，从自身MHC到完整的、未加工的病毒糖蛋白。当？d TCR在结构上与a <$TCR相似，两者都使用CD 3信号复合物的成分进行信号转导，清楚吗？dTCR以不同和不同的方式结合抗原。缺乏具体的生物化学表征这些受体及其与配体的相互作用阻碍了真正了解这些受体的作用？d T细胞活化。因此，本提案的长期目标是了解的生化和结构机制？d TCR接合以及这种结合事件如何区分健康和不健康的组织以启动T细胞活化。我们计划使用两种直接互补但又独特的平行策略来研究这些问题。第一个是结构/功能为基础的方法结合生物化学，结构生物学和细胞为基础的功能测定，以确定具体的分子细节，管理？d确定的配体的TCR识别。我们将集中我们的生物化学，生物物理和结构研究两个受体/配体相互作用：？d特异于1）鼠MHC T107 T22分子和2）人MHC CD 1c分子的TCR。第二种方法涉及使用跨物种的序列为基础的分析，以了解选择性，进化机制，塑造？d TCR V、D和J基因库。这种方法将定义什么类型的选择压力（多样化，中性或纯化）控制了人类和非人类灵长类动物中这些基因的进化，表明它们所结合的配体的性质。这些方法，一起，将有助于阐明分子识别的原则？d TCR相互作用，并确定是否？d TCR以收敛的方式识别配体，例如在TCR/MHCp相互作用中看到的，或者是否存在多种识别解决方案，每个都是独特的？d T细胞群体和特定配体。

DESCRIPTION (provided by applicant): ?d T cells constitute an important component of the immune response against infectious agents and cancerous transformations, yet the biochemical mechanisms by which they detect antigen through their somatically recombined T cell receptor (TCR) remain unclear. Unlike a¿TCRs, which are restricted to recognizing antigens in the context of Major Histocompatibility Complex (MHC) molecules, ?d TCRs can recognize a diversity of ligands ranging from self MHC to intact, unprocessed, viral glycoproteins. While the ?d TCR is structurally similar to the a¿TCR, and both use components of the CD3 signaling complex for signal transduction, it is clear ?d TCRs bind antigen in a distinct and divergent way. The lack of concrete biochemical characterization of these receptors and their interactions with ligands has hindered a true understanding of the role of these receptors in ?d T cell activation. Thus, the long-term goal of this proposal is to understand the biochemical and structural mechanisms of ?d TCR engagement and how this binding event discriminates between healthy and unhealthy tissue to initiate T cell activation. We plan to study these questions using two parallel strategies that are directly complementary, yet unique. The first is a structure/function-based approach combining biochemistry, structural biology and cell-based functional assays to determine the specific molecular details that govern ?d TCR recognition of defined ligands. We will focus our biochemical, biophysical and structural studies on two receptor/ligand interactions: ?d TCRs specific for 1) the murine MHC T107T22 molecules and 2) the human MHC CD1c molecules. The second approach involves using a cross-species sequence-based analysis to understand the selective, evolutionary mechanisms that shape the ?d TCR V, D and J gene repertoire. This approach will define what types of selective pressures (diversifying, neutral or purifying) have governed the evolution of these genes in humans and non-human primates, indicating the nature of the ligands to which they bind. These approaches, together, will help to elucidate the molecular recognition principles of ?d TCR interactions, and determine if ?d TCRs recognize ligands in a convergent manner, such as seen in a¿ TCR/MHCp interactions, or whether there are a diversity of recognition solutions, unique to each ?d T cell population and particular ligand.