Immune surveillance via non-classical MHC class Ib molecules

描述(由申请者提供)：我们研究的长期目标是了解和操纵免疫监视途径。MHC-I类抗原处理途径产生大量的多肽，作为CD8T细胞的pMHC-I配体。这些pMHC I配体通知CD8 T细胞细胞内蛋白质环境的变化，这些变化是由病毒感染或致瘤转化引起的。不足为奇的是，该途径的关键步骤，如肽转运体TAP，经常被病毒阻断并在肿瘤中突变。免疫系统也进化出了对抗策略，使用NK细胞来检测和消除由于抗原处理途径缺陷而导致pMHC谱系发生剧烈变化的细胞。ERAAP(或ERAP1)是与抗原处理相关的ER氨基肽酶，对于生成pMHC I谱系是必不可少的。最近对人类自身免疫性疾病、巨细胞病毒感染和肿瘤细胞的研究表明，ERAAP的表达在这些条件下也会改变。然而，免疫系统检测ERAAP功能障碍的机制尚不清楚。在这里，我们将测试一个新的CD8T细胞亚群，称为QFL，具有先天类似功能的假设，检测并消除ERAAP缺陷的细胞。QFL CD8 T细胞是Qa-1b的特异性T细胞，非经典的MHC Ib分子仅在ERAAP缺陷细胞中呈现不变的Fl9肽。QFL CD8 T细胞可用QA1/FL9四聚体试剂检测、鉴定和分离。在定义明确的小鼠模型中，我们将表征CD8T细胞QFL亚群的TCRs、功能和发育途径，以建立一个潜在的新的免疫监测范式，用于抗原处理和提呈途径的缺陷的免疫监测。 公共卫生相关性：我们预计这项研究将提高我们对用于检测病原体免疫逃避的免疫机制的理解。

DESCRIPTION (provided by applicant): The long term goal of our research is to understand and manipulate immune surveillance pathways. The MHC class I antigen processing pathway generates a vast repertoire of peptides as pMHC I ligands for the CD8 T cells. These pMHC I ligands inform the CD8 T cells of intracellular changes in the protein milieu caused by a virus infection or tumorigenic transformation. Not surprisingly, key steps of this pathway, such as the peptide transporter TAP, is frequently blocked by viruses and mutated in tumors. The immune system has also evolved counter strategies using NK cells to detect and eliminate cells with drastic changes in the pMHC repertoire due to defects in the antigen processing pathway. The ERAAP (or ERAP1), the ER aminopeptidase associated with antigen processing, is essential for generating the pMHC I repertoire. Recent studies with human autoimmune disorders, cytomegalovirus infected, and tumor cells have revealed that ERAAP expression is also altered in these conditions. However, the mechanism by which the immune system detects ERAAP dysfunction is not known. Here, we will test the hypothesis that a novel subpopulation of CD8 T cells, termed Qfl, with innate-like functions detects and eliminates cells with ERAAP deficiency. The Qfl CD8 T cells are specific for Qa-1b, non- classical MHC Ib molecule presenting the invariant FL9 peptide exclusively in ERAAP-deficient cells. The Qfl CD8 T cells can be detected, characterized and isolated using the Qa1/FL9 tetramer reagent. In well defined mouse models we will characterize the TCRs, function and developmental pathway of the Qfl subset of CD8 T cells to establish a potentially new paradigm for immune surveillance for defects in the antigen processing and presentation pathway. PUBLIC HEALTH RELEVANCE: We anticipate that this research will improve our understanding of the immune mechanisms used to detect immune evasion by pathogens.