The Endogenous MHC Class I Antigen Processing Pathway

描述(申请人提供)：本申请的长期目标是 了解抗原的内源性加工机制 人工合成的蛋白质产生精确切割的多肽/MHC I类复合体 细胞表面。这些多肽/MHC I复合体的表达是必不可少的 用于CD8细胞毒性T细胞谱系的开发和维护 针对肿瘤、细胞内病原体、同种异体的免疫反应 自身免疫中的组织移植和自体组织。不表达多肽/MHC 复合体是肿瘤细胞和病原体逃逸的重要机制 免疫监视。 我们开发了新的细胞、生化和遗传技术 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多肽产品，并首次 时间，它们在细胞质中产生的蛋白质分解中间产物 急诊室。在这里，我们建议测试不同的假设，关于(A)抗原如何 胞质中的处理步骤和内质网中的处理步骤自然形成这个池 可由MHC I类分子呈递的加工多肽，以及(B) 内质网中的多肽修剪如何导致产生和显示 被细胞表面的MHC I分子精确切割的多肽。 我们预计，这些问题的答案将提高我们的理解 决定表位选择、表位优势和表位优势的关键因素 抗原处理途径的效率。

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.