Investigating the basis of MAIT cell antigen potency

研究 MAIT 细胞抗原效力的基础

• 批准号: 10405515
• 负责人: James McCluskey
• 金额: $ 53.92万
• 依托单位: UNIVERSITY OF MELBOURNE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405515
• 关键词: Address; Agonist; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Ants; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Cell Antigen Receptor; Binding; Biochemical; CD4 Positive T Lymphocytes; CD69 antigen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cell surface; Cells; Chemicals; Complex; Detection; Disease; Environment; Evolution; Folic Acid; Francisella; Future; Health; Homeostasis; Human; Immune; Immune response; Immunity; Immunologic Surveillance; Immunotherapeutic agent; Infection; Inflammatory; Inflammatory Bowel Diseases; Legionella longbeachae; Ligand Binding; Ligands; Lipids; Liver; Lung; MHC Class I Genes; Major Histocompatibility Complex; Malignant Neoplasms; Mammals; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microbe; Mucous Membrane; Mycobacterium tuberculosis; Nature; Outcome; Pathogen detection; Peptic Ulcer; Peptides; Periodontal Diseases; Pharmaceutical Preparations; Phenotype; Population; Proteins; Pterins; Reaction; Recurrence; Regulation; Riboflavin; Role; System; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Tuberculosis; Tumor Antigens; Uracil; Virus Diseases; Work; adaptive immunity; base; cell type; chronic inflammatory disease; detection platform; effector T cell; gastrointestinal; immunopathology; in vivo; insight; lumazine; microbial; novel; nutrition; pathogen; peripheral blood; prevent; repaired; tumor

SUMMARY Mucosal Associated Invariant T (MAIT) cells comprise up to 10% of human peripheral blood T cells, and are enriched in the liver, lungs and gastrointestinal mucosa. This indicates that MAIT cells are key players in immunity. However, their roles in immune protection, and in immunopathology are yet to be fully established. Nevertheless, MAIT cells are implicated in chronic inflammatory diseases including tuberculosis, peptic ulceration, periodontal disease and inflammatory bowel disease. Central to the function of MAIT cells is the MAIT T cell antigen receptor (TCR). Consistent with their innate-like phenotype, MAIT cells express a very restricted T cell repertoire. Namely, human MAIT cells are characterized by an invariant TCR a-chain (TRAV1-2-TRAJ33) paired with a limited array of TCR b-chains (TRBV6 or TRBV20). The MAIT TCR is restricted to the monomorphic Major Histocompatibility Complex class I related protein, MR1. A very high level of conservation of MR1 in mammals and the restricted MAIT TCR usage strongly indicate an important and evolutionarily conserved function for the MAIT TCR-MR1 axis in immunity. Based on our previous work and preliminary findings, we aim to: (i) Investigate novel MAIT cell antigens and their impact on MAIT TCR diversity; (ii) Define the cellular machinery involved in acquisition and presentation of MR1 antigens; (iii) Investigate the structural basis of MAIT cell antigen potency and selectivity. Our proposed studies will advance our understanding of MR1 presentation and subsequent recognition by the MAIT TCR, which is a fundamental precursor for harnessing MAIT cells for future immunotherapeutics.

总结 粘液相关不变T（MAIT）细胞包含高达10%的人外周血T细胞，并且是 在肝、肺和胃肠道粘膜中富集。这表明MAIT细胞是参与 免疫力然而，它们在免疫保护和免疫病理学中的作用尚未完全确定。 然而，MAIT细胞与慢性炎性疾病包括结核病、消化性溃疡、结肠炎和结肠炎有关。 溃疡、牙周病和炎性肠病。MAIT细胞功能的核心是MAIT T细胞抗原受体（TCR）。与它们的先天样表型一致，MAIT细胞表达非常有限的 T细胞库。即，人MAIT细胞的特征在于不变的TCR α链（TRAV 1 -2-TRAJ 33）。 与有限的TCR b链阵列（TRBV 6或TRBV 20）配对。MAIT TCR仅限于单晶型 主要组织相容性复合物I类相关蛋白，MR 1。MR 1基因的高度保守性， 哺乳动物和有限的MAIT TCR使用强烈表明一个重要的和进化上保守的 MAIT TCR-MR 1轴在免疫中的作用。基于我们以前的工作和初步的发现，我们的目标是 目的：（i）研究新的MAIT细胞抗原及其对MAIT TCR多样性的影响;（ii）确定细胞免疫应答的分子机制; 参与MR 1抗原获得和呈递的机制;（iii）研究MAIT的结构基础 细胞抗原效力和选择性。我们提出的研究将促进我们对MR 1表达的理解 以及随后被MAIT TCR识别，这是利用MAIT细胞进行 未来的免疫疗法