MECHANISM OF MCMV's INHIBITION OF ANTIGEN PRESENTATION

描述(由申请人提供)：许多疱疹病毒编码的蛋白质扰乱了MHC I类抗原处理途径；这些基因提供了对基本免疫学和细胞生物学过程的洞察，并为免疫学研究和潜在的治疗提供了新的工具。小鼠巨细胞病毒(MCMV)为了解这些基因的功能及其对宿主免疫系统的影响提供了一个独特的机会，这些基因与宿主共同进化了数千万年。两个MCMV基因(M6和ML52)已被证明干扰抗原加工。有证据表明，第三个基因M4也干扰抗原提呈。M4在病毒免疫逃避基因中是独一无二的，因为它不会改变I类分子的运输模式。它的产物m4gp34主要存在于内质网中，在那里它与I类分子广泛相互作用。一小部分m4gp34与I类分子形成不同的洗涤剂稳定复合体，并与其一起进入细胞表面，在那里它们仍然紧密结合。本项目的目标是确定m4gp34抑制抗原提呈的分子机制。将建立表达OVA的重组MCMV，以跟踪m4gp34对负载特异性抗原肽的I类的影响。这些将被用来确定，首先，m4gp34是否作用于细胞表面，抑制1类多肽复合体与其受体或辅助受体结合并向CTL传递激活信号的能力；其次，内质网中的m4gp34是否干扰KB分子获得抗原肽的能力。

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.