Immune surveillance via non-classical MHC class Ib molecules

通过非经典 MHC Ib 类分子进行免疫监视

• 批准号: 8358263
• 负责人: Nilabh Shastri
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-03 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358263
• 关键词: Abbreviations; Activated Natural Killer Cell; Aminopeptidase; Antigen Presentation Pathway; Antigen Receptors; Antigens; Autoimmune Diseases; Bone Marrow; CD44 gene; CD8B1 gene; Cell surface; Cells; Chimera organism; Code; Complex; Cytomegalovirus; Cytoplasm; Defect; Detection; Development; Differentiation Antigens; Endoplasmic Reticulum; Functional disorder; Gene Expression; Genes; Goals; Histocompatibility Antigens Class I; Human; IL2RB gene; Immune; Immune Targeting; Immune system; Immunologic Surveillance; Individual; Ligands; MHC Class I Genes; Molecular Profiling; Mucous Membrane; Mus; Mutant Strains Mice; Mutate; Natural Killer Cells; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Population; Proteins; Qa-1 Antigen; Reagent; Research; Surveys; T-Cell Receptor; T-Cell Receptors alpha-Chain; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transcript; Ursidae Family; Variant; Virus; Virus Diseases; Wild Type Mouse; antigen processing; base; experience; improved; killer T cell; mouse model; neoplastic cell; novel; pathogen; tumor; tumorigenic

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.

描述（由申请人提供）：我们研究的长期目标是理解和操纵免疫监视途径。MHC I类抗原加工途径产生大量的肽库，作为CD8 T细胞的MHC I配体。这些pMHC I配体通知CD8 T细胞由病毒感染或致瘤转化引起的细胞内蛋白质环境的变化。不足为奇的是，这一途径的关键步骤，如肽转运体TAP，经常被病毒阻断并在肿瘤中发生突变。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加工途径中的缺陷而导致pMHC库发生剧烈变化的细胞。ERAAP（或ERAP1）是与抗原加工相关的内质网氨基肽酶，对于生成pMHC I库至关重要。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，在这些疾病中，ERAAP的表达也发生了改变。然而，免疫系统检测ERAAP功能障碍的机制尚不清楚。在这里，我们将验证一种新的CD8 T细胞亚群，称为Qfl，具有先天功能，可以检测并消除具有ERAAP缺陷的细胞。Qfl CD8 T细胞特异性针对Qa-1b，非经典MHC Ib分子，仅在eraap缺陷细胞中呈现不变的FL9肽。Qfl CD8 T细胞可通过Qa1/FL9四聚体试剂进行检测、表征和分离。在定义良好的小鼠模型中，我们将表征CD8 T细胞Qfl亚群的tcr、功能和发育途径，为抗原加工和递呈途径缺陷的免疫监测建立一个潜在的新范式。