The molecular basis underpinning the potency and specificity of MAIT cell antigens
The molecular basis underpinning the potency and specificity of MAIT cell antigens
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DOI：
10.1038/s41590-020-0616-6
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发表时间：
2020-03-02
影响因子：
30.5
通讯作者：
Rossjohn, Jamie
中科院分区：
文献类型：
--
作者：
Awad, Wael;Ler, Geraldine J. M.;Rossjohn, Jamie
粘膜相关的不变T（MAIT）细胞被激活的微生物核黄素为基础的代谢物抗原时，提出的MR 1。对有效抗原5-OP-RU的修饰如何影响MR 1的呈递和MAIT细胞活化仍不清楚。在这里，我们设计了20个衍生物，称为改变代谢物配体（AML），解剖不同抗原成分对人MAIT-MR 1轴的影响。对MAIT T细胞抗原受体（TCR）-MR 1-AML三元复合物的11种晶体结构的分析，沿着生物化学和功能测定，表明MR 1细胞表面上调受配体的核糖基和非核糖基组分以及MR 1-AML界面的疏水性的影响。AML的极性核糖基链通过MAIT TCR-MR 1-AML相互作用三元组内的动态补偿相互作用强烈影响MAIT细胞活化效力。我们定义了MAIT TCR可以区别识别AML的基础，从而提供了对MAIT细胞抗原特异性和效力的深入了解。粘膜相关不变T（MAIT）细胞识别由分子MR 1呈递的维生素B代谢物。Rossjohn及其同事产生了多种改变的代谢物配体，并在MR 1和TCR的背景下确定了它们的结构，以开发MAIT细胞抗原识别的通用框架。
Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT-MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)-MR1-AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1-AML interface. The polar ribityl chain of the AML strongly influences MAIT cell activation potency through dynamic compensatory interactions within a MAIT TCR-MR1-AML interaction triad. We define the basis by which the MAIT TCR can differentially recognize AMLs, thereby providing insight into MAIT cell antigen specificity and potency.Mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites presented by the molecule MR1. Rossjohn and colleagues generate multiple altered metabolite ligands and determine their structures in the context of MR1 and the TCR to develop a generalized framework for MAIT cell antigen recognition.