The Endogenous MHC Class I Antigen Processing Pathway

描述（由申请人提供）：本申请的长期目标是 了解抗原加工机制，通过该机制内源性地 合成的蛋白质产生精确切割的肽/MHC I类复合物， 细胞表面。这些肽/MHCI复合物的表达是必需的， 用于CD 8细胞毒性T细胞库的开发和维持，以及用于 对肿瘤、细胞内病原体、同种异体 组织移植物和自身组织在自身免疫中的作用肽/MHC表达失败 复合物是肿瘤细胞和病原体逃逸的重要机制 免疫监视 我们已经开发了新的细胞，生物化学和遗传技术， 天然加工抗原肽的分析。这些技术允许 直接分析最终加工的肽产品， 时间，它们的蛋白水解中间体，产生于细胞质和 急诊室在这里，我们提出测试不同的假设，（a）如何抗原 细胞质和内质网中的加工步骤形成了这种天然的 可用于由MHC I类分子呈递的加工肽，和（B） ER中的肽修剪如何导致 由细胞表面的MHC I分子精确切割的肽。 我们期望这些问题的答案将增进我们的理解 决定表位选择的关键因素，表位优势和 抗原加工途径的效率。

DESCRIPTION (provided by applicant): The long-term goal of this application is to understand the antigen processing mechanism by which endogenously synthesized proteins yield precisely cleaved peptide/MHC class I complexes on the cell surface. The expression of these peptide/MHC I complexes is essential for development and maintenance of the CD8 cytotoxic T-cell repertoire and for immune responses specific for tumors, intracellular pathogens, allogeneic tissue grafts and self-tissues in autoimmunity. Failure to express peptide/MHC complexes is an important mechanism by which tumor cells and pathogens escape immune surveillance. We have developed novel cellular, biochemical and genetic techniques for analysis of naturally processed antigenic peptides. These techniques allow the direct analysis of the final processed peptides products, and for the first time, their proteolytic intermediates that are generated in the cytosol and in the ER. Here we propose to test different hypotheses on, (a) how the antigen processing steps in the cytosol and in the ER shape this pool of naturally processed peptides available for presentation by MHC class I molecules, and (b) how peptide trimming in the ER results in the generation and display of precisely cleaved peptides by the MHC I molecules on the cell surface. We anticipate that the answer to these questions will improve our understanding of the key factors that determine epitope selection, epitope dominance and the efficiency of the antigen processing pathway.