Immune surveillance of antigen processing pathway

抗原加工途径的免疫监视

• 批准号: 9287264
• 负责人: Nilabh Shastri
• 金额: $ 53.52万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-08 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9287264
• 关键词: Abbreviations; Age; Alpha Cell; Aminopeptidase; Anatomy; Antigen Receptors; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Process; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell surface; Cells; Characteristics; Complex; Cytotoxic T-Lymphocytes; Defect; Development; Differentiation Antigens; Endoplasmic Reticulum; Ensure; Family; Generations; Genes; Genetic Polymorphism; Glycolipids; Goals; Histocompatibility; Human; I-antigen; Immune; Immune Evasion; Immune Targeting; Immune Tolerance; Immune system; Immunize; Immunologic Surveillance; In Vitro; Knockout Mice; Ligands; Link; Location; Malignant Neoplasms; Microbe; Molecular; Molecular Chaperones; Monitor; Mus; N-terminal; Obesity; Orthologous Gene; Pathway interactions; Peptide Hydrolases; Peptide/MHC Complex; Peptides; Phenotype; Protein Isoforms; Proteolysis; Qa-1 Antigen; Research; Specificity; Surface; T-Lymphocyte; T-Lymphocyte Subsets; TAP1 gene; TYRP1 gene; Testing; Thymus Gland; Tissue Grafts; Tissues; Viral; Virus; Vitamins; Wild Type Mouse; alpha-beta T-Cell Receptor; antigen processing; antigenic peptide transporter; cytokine; experience; improved; in vivo; insight; microbial; novel; pathogen; protein B; response; sensor; tumor; viral detection

Project summary The long term goal of our research is to understand and manipulate immune surveillance pathways. The antigen processing pathway yields thousands of peptide/MHC complexes (pMHC I) on the cell surface as potential ligands for CD8+ T cells to allow detection of viruses or cancer. It is now clear that generation of the normal pMHC I repertoire requires peptide trimming in the endoplasmic reticulum (ER) by ERAAP, the ER aminopeptidase associated with antigen processing. The ERAAP is targeted for immune evasion by viruses and polymorphisms in this gene are linked to many autoimmune diseases. It is therefore essential to monitor ERAAP activity to ensure effective immune surveillance by CD8+ T cells. We had discovered earlier that the unique FL9 nona peptide — derived from the Fam49a/b proteins of unknown function — was presented by the non-classical MHC Ib molecule called Qa-1b only in ERAAP- deficient cells. This FL9 peptide/Qa-1 complex, called QFL was recognized by QFL-specific CD8+ T cells which lysed target cells expressing this ligand. Thus QFL- T cells are a mechanism for detecting and eliminating cells with ERAAP-deficiency. The QFL-T cells are relatively abundant, and share key characteristics with other innate-like iNKT (invariant NK T) and MAIT (mucosal - associated invariant T) cells which are also restricted by non-classical MHC Ib molecules and respond to various microbial and self-antigens. Here we propose to fill gaps in our understanding of how the immune system monitors the fidelity of antigen processing in the ER. We hypothesize that QFL-specific CD8+ T cells and the mechanisms for generating the QFL-ligand are conserved sensors for detecting ERAAP-inhibition. Furthermore, disruption of these mechanisms in ERAAP-deficient mice may result in autoimmune obesity. We will accomplish these goals by (a) characterizing the αβ TCRs and the thymic developmental pathway for QFL-T cells to understand how these cells arise and acquire their unique functions, (b) defining the molecular steps for generating the QFL-ligand by analyzing the processing of Fam49a/b precursors into the FL9 peptide for loading the Qa-1 MHC Ib, and (c) defining the anatomical location(s) and function(s) of QFL-T cells in normal WT mice as well as their obese ERAAP-/- counterparts. Relevance Autoimmunity results when immune tolerance to self-antigens is disrupted. Understanding how self-antigens are produced by proteolytic enzymes will likely reveal potential ways to intervene in autoimmune disorders.

项目摘要 我们研究的长期目标是了解和操纵免疫监视途径。的 抗原加工途径在细胞表面产生数千种肽/MHC复合物（pMHC I）， CD 8 + T细胞的潜在配体，以允许检测病毒或癌症。现在很清楚， 正常的pMHC I谱系需要ERAAP在内质网（ER）中进行肽修剪，ER 与抗原加工相关的氨肽酶。ERAAP是病毒免疫逃避的靶点 该基因的多态性与许多自身免疫性疾病有关。因此，必须监测 ERAAP活性，以确保CD 8 + T细胞的有效免疫监视。 我们早先发现，独特的FL 9九肽-来源于Fam 49 a/B蛋白， 未知的功能-是由非经典的MHC Ib分子称为Qa-1b只在ERAAP- 缺陷细胞这种称为QFL的FL 9肽/Qa-1复合物被QFL特异性CD 8 + T细胞识别， 表达该配体的裂解的靶细胞。因此，QFL-T细胞是检测和消除细胞的机制， ERAAP缺乏症QFL-T细胞相对丰富，并且与其他细胞共享关键特征。 先天性样iNKT（不变NK T）和MAIT（粘膜相关不变T）细胞，其也受 非经典MHC Ib分子，并对各种微生物和自身抗原产生应答。 在这里，我们建议填补我们对免疫系统如何监测免疫系统的保真度的理解中的空白。 在ER中的抗原处理。我们假设QFL特异性CD 8 + T细胞和其机制可能与QFL相关。 产生QFL-配体的传感器是用于检测ERAAP-抑制的保守传感器。此外， ERAAP缺陷小鼠的这些机制可能导致自身免疫性肥胖。 我们将通过（a）描述αβ TCR和胸腺发育途径来实现这些目标 为了使QFL-T细胞了解这些细胞如何产生并获得其独特功能，（B）定义 通过分析Fam 49 a/B前体加工成 用于装载Qa-1 MHC Ib的FL 9肽，和（c）定义QFL-T的解剖学位置和功能 正常WT小鼠以及它们的肥胖ERAAP-/-对应物中的细胞。 相关性 当对自身抗原的免疫耐受被破坏时，就会产生自身免疫。了解自身抗原 由蛋白水解酶产生的蛋白质可能揭示干预自身免疫性疾病的潜在方法。