The Endogenous MHC Class I Antigen Processing Pathway

内源性 MHC I 类抗原加工途径

• 批准号: 7007308
• 负责人: Nilabh Shastri
• 金额: $ 29.02万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007308
• 关键词: MHC class I antigen; antigen presentation; cytotoxic T lymphocyte; endoplasmic reticulum; genetic regulation; genetically modified animals; intracellular; laboratory mouse; proteolysis; tissue /cell culture

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.

描述（由申请人提供）：本申请的长期目标是 了解内源性抗原加工机制 合成的蛋白质在其上产生精确切割的肽/MHC I 类复合物 细胞表面。这些肽/MHC I 复合物的表达至关重要 用于开发和维持 CD8 细胞毒性 T 细胞库以及 针对肿瘤、细胞内病原体、同种异体的特异性免疫反应 自身免疫中的组织移植和自体组织。无法表达肽/MHC 复合物是肿瘤细胞和病原体逃逸的重要机制 免疫监视。 我们开发了新颖的细胞、生化和遗传技术 天然加工的抗原肽的分析。这些技术允许 直接分析最终加工的肽产品，并首次 随着时间的推移，它们在细胞质和细胞质中产生的蛋白水解中间体 急诊室。在这里，我们建议测试不同的假设，（a）抗原如何 细胞质和内质网中的加工步骤塑造了这个自然池 可通过 MHC I 类分子呈递的加工肽，以及 (b) ER 中的肽修剪如何导致生成和展示 通过细胞表面的 MHC I 分子精确切割肽。 我们预计这些问题的答案将增进我们的理解 决定表位选择、表位优势和表位优势的关键因素 抗原加工途径的效率。