Investigating the basis of MAIT cell antigen potency

摘要 粘膜相关不变T细胞(MAIT)占人外周血T细胞的10%，并且 富含于肝、肺和胃肠粘膜。这表明MAIT细胞是其中的关键角色 豁免权。然而，它们在免疫保护和免疫病理中的作用尚未完全确定。 然而，MAIT细胞与包括结核病、消化炎在内的慢性炎症性疾病有关 溃疡、牙周病和炎症性肠病。MAIT细胞的核心功能是MAIT T细胞抗原受体(TCR)。与其与生俱来的表型一致，MAIT细胞表达一个非常有限的 T细胞谱系。也就是说，人类MAIT细胞的特征是一个不变的TCR a链(TRAV1-2-TRAJ33) 与TCRb链(TRBV6或TRBV20)的有限阵列配对。MAIT TCR仅限于单态 主要组织相容性复合体I类相关蛋白，MR1。MR1的高度保守性 哺乳动物和MAIT TCR的有限使用强烈表明了一种重要的和进化上保守的 MAIT TCR-MR1轴在免疫中的作用。基于我们以前的工作和初步发现，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 参与获得和呈递MR1抗原的机制；(3)调查MAIT的结构基础 细胞抗原效价和选择性。我们建议的研究将增进我们对MR1演示文稿的理解 并随后被MAIT TCR识别，这是利用MAIT细胞进行 未来的免疫疗法。

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.