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Immune Surveillance of Antigen Processing Pathway

抗原加工途径的免疫监视

基本信息

批准号：
10112811
负责人：
Scheherazade Sadegh-Nasseri
金额：
$ 55.82万
依托单位：
JOHNS HOPKINS UNIVERSITY
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 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112811
关键词：
Abbreviations Age Aminopeptidase Anatomy Antigen Receptors Antigens Autoantigens Autoimmune Autoimmune Diseases 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 Mucous Membrane Mus N-terminal Obesity Orthologous Gene Pathway interactions Peptide Hydrolases Peptide/MHC Complex Peptides Phenotype Protein Isoforms Proteins Proteolysis Qa-1 Antigen Research Specificity Surface T-Lymphocyte T-Lymphocyte Subsets TAP1 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 microorganism antigen novel pathogen 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.

项目总结我们研究的长期目标是了解和操纵免疫监视途径。这个抗原处理途径在细胞表面产生数以千计的多肽/MHC复合体(PMHC I) CD8+T细胞的潜在配体，使其能够检测病毒或癌症。现在很明显，这一代正常的pMHC I谱系需要ERAAP对内质网(ER)中的多肽进行修剪与抗原加工有关的氨基肽酶。ERAAP的目标是通过病毒进行免疫逃避该基因的多态与许多自身免疫性疾病有关。因此，监测是至关重要的 ERAAP活性，以确保CD8+T细胞有效的免疫监视。我们早些时候已经发现，独一无二的Fl9 NONA多肽源自于未知功能-仅由非经典MHC Ib分子Qa-1b在ERAAP中提出- 缺乏细胞。这种被称为QFL的Fl9肽/Qa-1复合体被QFL特异性CD8+T细胞识别裂解表达该配体的靶细胞。因此，QFL-T细胞是一种检测和消除细胞的机制患有ERAAP缺乏症。QFL-T细胞相对丰富，并与其他与生俱来的iNKT(不变NK T细胞)和MAIT(粘膜相关不变T细胞)细胞也受非经典的MHC Ib分子，并对各种微生物和自身抗原产生反应。在这里，我们建议填补我们对免疫系统如何监控保真度的理解的空白急诊室的抗原处理。我们假设QFL特异性CD8+T细胞及其作用机制产生QFL配体是检测ERAAP抑制的保守传感器。此外，中断 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αβTCR和胸腺发育途径来实现这些目标为了让QFL-T细胞了解这些细胞是如何产生的并获得其独特的功能，(B)定义通过分析Fam49a/b前体进入QFL配体的过程来产生QFL配体的分子步骤 (C)确定QFL-T的解剖位置(S)和功能(S) 正常WT小鼠以及肥胖的ERAAP-/-小鼠体内的细胞。相关性当对自身抗原的免疫耐受性被破坏时，就会产生自身免疫。了解自身抗原是如何是由蛋白水解酶产生的，可能会揭示干预自身免疫性疾病的潜在方法。