MECHANISM OF MCMV's INHIBITION OF ANTIGEN PRESENTATION

MCMV抑制抗原呈递的机制

• 批准号: 7027644
• 负责人: Ann B Hill
• 金额: $ 25.8万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027644
• 关键词: MHC class I antigen; antigen presentation; cytomegalovirus; cytotoxic T lymphocyte; endoplasmic reticulum; gene targeting; host organism interaction; microorganism immunology; ovalbumin; protein protein interaction; recombinant virus; tissue /cell culture; virus protein

DESCRIPTION (provided by the applicant): Many herpes viruses encode proteins that disrupt the MHC class I pathway of antigen processing; these genes offer insights into basic immunological and cell biological processes, and provide new tools for immunological investigation and potentially therapeutics. Murine cytomegalovirus (MCMV) offers a unique opportunity to understand how these genes function and their impact on the immune system in the host with which they have co-evolved for tens of millions of years. Two MCMV genes (m6 and ml 52) have been shown to interfere with antigen processing. Evidence is presented that a third gene, m4, also interferes with antigen presentation. m4 is unique amongst viral immune evasion genes in that it does not alter the trafficking pattern of class I molecules. Its product, m4gp34, is primarily found in the ER, where it interacts extensively with class I. A small portion of m4gp34 forms a different, detergent stable complex with class I and travels with it to the cell surface where they remain tightly associated. The goal of this project is to identify the molecular mechanism whereby m4gp34 inhibits antigen presentation. Recombinant MCMV expressing ova wilt be established to enable the effect of m4gp34 on class I loaded with specific antigenic peptide to be followed. These will be used to determine, firstly, whether m4gp34 acts at the cell surface to inhibit the ability of the class 1-peptide complex to engage its receptor or co-receptor and transmit an activating signal to CTL; and secondly, whether m4gp34 in the ER interferes with the ability of Kb molecules to acquire antigenic peptide.

描述（由申请方提供）：许多疱疹病毒编码破坏抗原加工的MHC I类途径的蛋白质;这些基因提供了对基本免疫学和细胞生物学过程的见解，并为免疫学研究和潜在治疗提供了新工具。小鼠巨细胞病毒（MCMV）提供了一个独特的机会，以了解这些基因如何发挥作用，以及它们对宿主免疫系统的影响，这些基因与宿主共同进化了数千万年。两个MCMV基因（m6和m152）已被证明干扰抗原加工。有证据表明，第三个基因，M4，也干扰抗原呈递。M4在病毒免疫逃避基因中是独特的，因为它不改变I类分子的运输模式。它的产物m4 gp 34主要存在于ER中，在那里它与I类广泛相互作用。一小部分m4 gp 34与I类形成不同的去污剂稳定的复合物，并与其一起移动到细胞表面，在那里它们保持紧密结合。本项目的目标是确定m4 gp 34抑制抗原呈递的分子机制。将建立表达卵的重组MCMV，以便能够跟踪m4 gp 34对负载特异性抗原肽的I类细胞的作用。这些将用于确定，首先，m4 gp 34是否在细胞表面起作用以抑制1类肽复合物与其受体或共受体接合并将激活信号传递给CTL的能力;其次，ER中的m4 gp 34是否干扰Kb分子获得抗原肽的能力。