The Endogenous MHC Class I Antigen Processing Pathway

描述（由申请方提供）：本提案的长期目标是了解内源性合成或外源性蛋白质在细胞表面产生精确切割的肽/MHC I类复合物（pMHC I）的抗原加工机制。pMHC I的表达对于CD8+细胞毒性T细胞库的发展和维持以及对于自身免疫中的肿瘤、细胞内病原体、同种异体组织移植物和自身组织特异性的免疫应答是必需的。不能表达pMHC I复合物是肿瘤细胞和病毒病原体逃避免疫监视的重要机制。我们已经开发了新的细胞，生物化学和遗传技术以及模型系统，用于分析天然加工的抗原肽。这些方法允许直接分析最终加工的肽产物，并首次分析与细胞质伴侣相关的先前未知的蛋白水解中间体。在这里，我们建议测试不同的假设，如何早期抗原加工步骤形状池的自然加工的肽可用于介绍的MHC I类分子。此外，我们将确定外源性抗原如何与内源性抗原加工途径相交，并导致pMHC I在细胞表面上的展示。我们预计这些答案将填补我们对决定表位选择、免疫优势和MHC I类抗原加工途径中交叉呈递的关键因素的理解中的空白。我们预计，这项研究将提高我们对免疫系统检测感染细胞和肿瘤以及自身免疫组织的机制的理解。

DESCRIPTION (provided by applicant): The long term goal of this proposal is to understand the antigen processing mechanism by which endogenously synthesized or exogenous proteins yield precisely cleaved peptide/MHC class I complexes (pMHC I) on the cell surface. The expression of pMHC I is essential for the 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 pMHC I complexes is an important mechanism by which tumor cells and viral pathogens escape immune surveillance. We have developed novel cellular, biochemical and genetic techniques as well as model systems for analysis of naturally processed antigenic peptides. These methods allow the direct analysis of the final processed peptide products, and for the first time, their previously unknown proteolytic intermediates that are associated with cytoplasmic chaperones. Here we propose to test different hypotheses on how the early antigen processing steps shape the pool of naturally processed peptides available for presentation by MHC class I molecules. Furthermore, we will determine how exogenous antigens intersect with the endogenous antigen processing pathway and result in the display of pMHC I on the cell surface. We anticipate the answers will fill gaps in our understanding of the key factors that determine epitope selection, immunodominance and cross-presentation in the MHC class I antigen processing pathway. We anticipate that this research will improve our understanding of the mechanisms by which the immune system detects infected cells and tumors as well as self-tissues in autoimmunity.