Immune surveillance of antigen processing pathway

抗原加工途径的免疫监视

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我们研究的长期目标是了解和操纵免疫监视途径。抗原加工途径在细胞表面产生数千个肽/MHC 复合物 (pMHC I) CD8+ T 细胞的潜在配体可以检测病毒或癌症。正常的 pMHC I 库需要通过 ERAAP（ER）在内质网 (ER) 中进行肽修剪与抗原加工相关的氨肽酶是病毒免疫逃避的目标。该基因的多态性与许多自身免疫性疾病有关，因此有必要进行监测。 ERAAP 活性可确保 CD8+ T 细胞进行有效的免疫监视。我们之前发现独特的 FL9 nona 肽 — 源自 Fam49a/b 蛋白未知功能 — 仅在 ERAAP 中由称为 Qa-1b 的非经典 MHC Ib 分子呈现这种 FL9 肽/Qa-1 复合物（称为 QFL）被 QFL 特异性 CD8+ T 细胞识别。因此，QFL-T 细胞是检测和消除细胞的机制。具有 ERAAP 缺陷的 QFL-T 细胞相对丰富，并且与其他细胞具有相同的关键特征。先天性 iNKT（不变 NK T）和 MAIT（粘膜相关不变 T）细胞也受到非经典 MHC Ib 分子并对各种微生物和自身抗原做出反应。在这里，我们建议填补我们对免疫系统如何监控免疫系统保真度的理解空白。我们对 QFL 特异性 CD8+ T 细胞及其机制进行了研究。生成 QFL 配体是用于检测 ERAAP 抑制的保守传感器。 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) 表征 αβ TCR 和胸腺发育途径来实现这些目标让 QFL-T 细胞了解这些细胞如何产生并获得其独特的功能，(b) 定义通过分析 Fam49a/b 前体加工成 QFL 配体的分子步骤用于加载 Qa-1 MHC Ib 的 FL9 肽，以及 (c) 定义 QFL-T 的解剖位置和功能正常 WT 小鼠的细胞及其肥胖 ERAAP-/- 积分。关联当对自身抗原的免疫耐受被破坏时，就会产生自身免疫。由蛋白水解酶产生的这些物质可能会揭示干预自身免疫性疾病的潜在方法。