Molecular Mechanisms of HLA-DO in Antigen Processing

描述（由申请人提供）：本申请中描述的项目涉及一项机制研究，旨在了解MHC II类辅助蛋白HLA-DO的作用机制及其在免疫显性表位产生中的作用。免疫优势是一种早已被认识到但至今仍不清楚的现象。众所周知，免疫系统关注并响应入侵致病性损伤的极少数具有代表性的表位（称为免疫显性表位），包括感染性病原体和自身免疫性疾病、过敏和癌症中的抗原靶点。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有积极反应，要么没有反应。抗原递呈途径的最新进展表明，抗原加工和选择的步骤对递呈给t细胞的肽库有重要影响。最近，我们在开发MHC II类分子的还原剂抗原处理系统方面取得了相当大的进展，该系统利用了II类抗原递呈途径的五种纯化蛋白组分。值得注意的是，该系统产生了限制于HLA-DR1的生理相关免疫显性表位。在本提案中，我们将扩展MHC II系统，包括另一种MHC II类分子HLA-DO，并将探索其对表位捕获和加工的贡献。Aim 1将探索HLA-DO如何与MHC II和HLA-DM相互作用的机制方面，从而导致肽结合的调节，在Aim 2中，我们将研究HLA-DO对全长蛋白抗原的表位捕获和编辑以及免疫优势的贡献。清楚地了解HLA-DO功能及其在抗原加工中的作用和免疫显性表位的选择，可以指导设计有效的免疫治疗药物。

DESCRIPTION (provided by applicant): The project described in this application addresses a mechanistic study aimed at understanding the mechanism of action of MHC class II accessory protein, HLA-DO and its role 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 include another MHC class II molecules HLA-DO and would explore its contribution to epitope capture and processing. Aim 1 would explore mechanistic aspects of how HLA-DO interacts with MHC II and HLA-DM, leading to regulation of peptide binding, and in Aim 2 we would investigate contributions of HLA-DO to epitope capture and editing from full length protein antigens and immunodominance. A clear understanding of HLA-DO function and its role in antigen processing and the selection of immunodominant epitopes, can guide the design of effective immunotherapeutics.