Role of DM in Generation of Immunodominant Epitope(s)

描述(由申请人提供)：本申请中描述的项目解决了一项旨在了解免疫优势表位产生过程中涉及的步骤的机制研究。免疫优势是一种早已被认识到的现象，但到目前为止仍不清楚。众所周知，免疫系统关注的是极少数具有代表性的表位(称为免疫优势表位)，这些表位来自侵袭性致病物质，包括自身免疫性疾病、过敏和癌症中的抗原靶标。在所有这些情况下，免疫系统要么对MHC分子背景下的抗原肽做出积极反应，要么没有反应。最近我们对抗原呈递途径的了解进展表明，抗原处理和选择的步骤对呈递给T细胞的多肽库有重要影响。最近，我们在开发一种针对MHC II类分子的还原抗原处理系统方面取得了相当大的进展，该系统利用了II类抗原提呈途径的五个纯化蛋白成分。值得注意的是，这个系统产生了生理上相关的免疫优势表位，仅限于人类白细胞抗原-DR1。在这项提案中，我们将把这个MHC II系统扩展到另一个MHC II类分子人类白细胞抗原-DR4，并探索涉及表位捕获和抗原处理的步骤。总体而言，我们建议剖析T细胞免疫优势的潜在因素。目的1探索抗原捕获和加工之间的时间关系。在目标2中，我们将研究表位层级及其在DM中的作用，在目标3中，我们将分析HLA-DO在表位捕获和编辑中的贡献。因此，了解免疫优势表位的特性，以及清楚地了解它们是如何在细胞内产生的，可以指导有效的免疫疗法的设计。

DESCRIPTION (provided by applicant): The project described in this application addresses a mechanistic study aimed at understanding the steps involved in generation of immunodominant epitopes. Immunodominance is a phenomenon that has long been recognized but yet remains unclear to date. It is well known that the immune system focuses on and responds to very few representative epitopes (referred to as immunodominant epitopes) from invading pathogenic insults ranging from such as infectious agents and, antigenic targets in autoimmune diseases, allergy, and cancer. In each all these cases, the immune system either responds positively or fails to respond to antigenic peptides in the context of MHC molecules. Recent advances in our understanding of the antigen presentation pathway have shown that the steps of antigen processing and selection critically influence the peptide repertoire presented to T-cells. Recently, we have made considerable progress in developing a reductionist antigen processing system for MHC class II molecules that utilizes five purified protein components of the class II antigen presentation pathway. Notably, this system yielded physiologically relevant immunodominant epitopes restricted to HLA-DR1. In this proposal, we will extend this MHC II system to another MHC class II molecules HLA-DR4 and would explore steps involved in epitope capture and antigen processing. Overall, we propose to dissect underlying factors of T-cell immunodominance. Aim 1 would explore the temporal relationship between antigen capture and processing. In Aim 2, we would investigate epitope hierarchy and the role for DM, and in Aim 3, we would analyze contributions of HLA-DO to epitope capture and editing. Hence, knowledge of the identity of immunodominant epitopes, and a clear understanding of how they are generated inside cells, can guide the design of effective immunotherapeutics.