ANTIGEN RECOGNITION BY T CELL RECEPTORS IN BASIC AND CANCER IMMUNOLOGY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 α-βT细胞受体(TCR)识别主要组织相容性复合体(MHC)蛋白结合和呈递的多肽抗原。尽管T细胞受体的交叉反应是免疫系统的一个基本特性，并与癌症和许多自身免疫疾病的免疫反应有关，但TCR识别和应答不同配体的分子机制尚不清楚。在我们NIH和ACS资助的工作中，我们正在通过研究TCR-pMHC相互作用的结构和生物物理性质来深入了解TCR的交叉反应，我们的研究涉及TCR-肽/MHC复合体以及未连接的TCR和肽/MHC分子的结构确定。结构性质与生物物理和免疫学数据有关。我们打算以更多的同步加速器时间为基础的最近的发现包括：1)观察到TCR识别可以随着界面两侧发生的协作性结构变化而进行(Gagnon等人，J Mol Biol 363 2006和未发表的结晶学数据)和2)观察到抗原肽中的微小替换可以产生复杂的结构后果，其免疫学后果很难与目前的TCR识别模型相一致(BorBulevych等人，J Mol Biol 372 2007)。后一项观察对用于癌症免疫治疗的改变肽的设计特别感兴趣(例如，BorBulevych等人。J免疫系统174,2005)。计划在不久的将来进行的实验包括与同一肽/MHC复合体结合的不同TCR的结构研究，以及旨在通过肿瘤抗原Melan-A/MART-1特异性T细胞诱导免疫反应的多肽/MHC变异体的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alpha-beta T cell receptors (TCRs) recognize peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. Although T cell receptor cross-reactivity is a fundamental property of the immune system and is implicated in the immune response to cancer and numerous autoimmune pathologies, the molecular mechanisms by which TCRs can recognize and respond to diverse ligands are poorly understood. In our NIH and ACS funded work, we are seeking insight into TCR cross-reactivity through investigations of the structural and biophysical properties of TCR-pMHC interactions, and our studies involve structural determination of TCR-peptide/MHC complexes as well as unligated TCRs and peptide/MHC molecules. Structural properties are related to biophysical and immunological data. Recent findings we aim to build on with additional synchrotron time include: 1) observations that TCR recognition can proceed with cooperative structural changes occurring on both sides of the interface (Gagnon et al., J Mol Biol 363 2006 and unpublished crystallographic data) and 2) observations that subtle substitutions in antigenic peptides can have complex structural consequences, the immunological consequences of which are difficult to reconcile with current models of TCR recognition (Borbulevych et al., J Mol Biol 372 2007). The latter observations are of particular interest in the design of altered peptides for use in cancer immunotherapy (e.g., Borbulevych et al. J Immunol 174 2005). Experiments planned for the near future include structural studies of different TCRs bound to the same peptide/MHC complex and studies of peptide/MHC variants designed to elicit improved immunological responses with T cells specific for the tumor antigen Melan-A/MART-1.