T Cell Recognition of Antigen

T细胞对抗原的识别是诱导特定免疫反应的一个重要事件。这个 TCR识别与抗原提呈细胞表面的MHC分子(p/MHC)结合的多肽。 TCR是一种高度复杂的受体，但与p/MHC配体的亲和力较低。他们的基础是 精致的TCR特异性，尽管亲和力较低，但仍不清楚。我们在认识上的一个重大进步 T细胞如何识别抗原已经直接证明了一种免疫学的形成 Synapse。免疫突触是位于T细胞和α细胞交界处的超分子结构。 可稳定运行多个小时的单个APC。免疫突触提供了分子机制 P/mhc质与量的统一。这些研究提供了一个模型，解释了TCR如何 区分密切相关的配体，但仍有许多问题存在。在这项建议中，我们的总体目标是 了解成熟T细胞和胸腺细胞如何对小的运动和结构变化做出反应 P/MHC配体。我们实验室已经开发并利用了HB/I-Ek抗原系统。我们已经产生了 并鉴定了广泛的T细胞、配体和两种T细胞3.L2和2.102的转基因小鼠 通过对3.L2和2.102 T细胞和配体的综合研究，我们建议探索几个 关键问题包括：1)不同强度配体的TCR结合特性是如何关联的 对于它们的结构和生物学效应，2)单个TCR如何识别同基因和 同种异体配体比较，3)胸腺细胞中免疫突触与成熟T细胞相比如何 以及4)CD4在免疫突触形成和TCR：P/MHC相互作用中的作用是什么？ 这些拟议的研究将提供TCR和p/MHC之间相互作用的关键分子细节。 莱兰德。这些研究可能会导致可以控制有害物质的新型药物的开发 免疫反应，如自身免疫反应。

The recognition of antigen by T cells is a seminal event in the induction of a specific immune response. The TCR recognizes a peptide bound to an MHC molecule (p/MHC) on the surface of an antigen presenting cell.! The TCR is a highly intricate receptor, but has a low affinity for the p/MHC ligand. The basis for thei exquisite TCR specificity, despite the low affinity, is still not known. A major advance in our understanding of how T cells recognize antigen has been the direct demonstration of the formation of an immunological synapse. The immunological synapse is a supramolecular structure at the interface between the T cell and a | single APC that is stable for many hours. The immunologicalsynapse provides the molecular machinery fori integration of p/MHC quality and quantity. These studies have provided a model explaining how a TCR can distinguish between closely related ligands, but many questions remain. In this proposal, our overall goal is to understand how mature T cells and thymocytes can respond to small kinetic and structural changes in the p/MHC ligands. Our laboratory has developed and utilized the Hb/I-Ek antigen system. We have generated and characterized a wide range of T cells, ligands, and transgenic mice for two T cells, 3.L2 and 2.102.i Through an integrated investigation of the 3.L2and 2.102 T cells and ligands we propose to explore several key issues including: 1) how do the TCR binding properties to a continuum of different strength ligands relate to their structure and biological effects, 2) how does the recognition by a single TCR of syngeneic and' allogeneic ligands compare, 3) how do immunological synapses in thymocytes compare to those of mature T cells, and 4) what is the role of CD4 in immunological synapse formation and TCR:p/MHC interactions? These proposed studies will provide key molecular details of the interaction between a TCR and the p/MHC ligand. These studies could lead to the development of novel pharmaceuticals which could control unwanted immune responses, such as an autoimmune response.