Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses.
Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses.
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DOI：
10.1084/jem.20221939
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发表时间：
2023-09-04
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影响因子：
--
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中科院分区：
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规范的MAIT TCR具有对微生物和自身抗原的双重反应能力，对MR1的混杂识别使MAIT细胞能够在没有微生物感染的情况下做出反应。粘膜相关不变T细胞(MAIT)使用典型的半不变T细胞受体(TCR)识别由抗原呈递分子MR1显示的微生物核黄素前体。MAIT TCR对生理的、微生物无关的抗原的交叉反应程度仍未得到充分研究。我们描述了在没有微生物代谢物的情况下，MAIT TCR被赋予对肿瘤和健康细胞的MR1依赖的反应性。携带与自身交叉反应的TCR的MAIT细胞很少见，但通常在健康的捐赠者中发现，并在体外显示T辅助细胞样功能。用装载了不同配体的MR1-四聚体进行的实验表明，MAIT TCR在体外和体外扩张时都具有显著的交叉反应。在极度混杂的MR1识别的基础上选择了典型的MAIT TCR。结构和分子动力学分析将性乱与独特的TCRMAIT链特征联系在一起，这些特征在健康个体的自我反应性β细胞中得到丰富。因此，对MR1的自我反应性识别代表了MAIT TCR交叉反应的功能相关指标，表明MAIT细胞在免疫稳态和疾病方面具有潜在的更广泛的作用，而不仅仅是微生物的免疫监视。
Promiscuous recognition of MR1 by canonical MAIT TCRs endowed with dual reactivity to both microbial and self-antigens enables MAIT cell responses in the absence of microbial infection. Mucosal-associated invariant T (MAIT) cells use canonical semi-invariant T cell receptors (TCR) to recognize microbial riboflavin precursors displayed by the antigen-presenting molecule MR1. The extent of MAIT TCR crossreactivity toward physiological, microbially unrelated antigens remains underexplored. We describe MAIT TCRs endowed with MR1-dependent reactivity to tumor and healthy cells in the absence of microbial metabolites. MAIT cells bearing TCRs crossreactive toward self are rare but commonly found within healthy donors and display T-helper-like functions in vitro. Experiments with MR1-tetramers loaded with distinct ligands revealed significant crossreactivity among MAIT TCRs both ex vivo and upon in vitro expansion. A canonical MAIT TCR was selected on the basis of extremely promiscuous MR1 recognition. Structural and molecular dynamic analyses associated promiscuity to unique TCRβ-chain features that were enriched within self-reactive MAIT cells of healthy individuals. Thus, self-reactive recognition of MR1 represents a functionally relevant indication of MAIT TCR crossreactivity, suggesting a potentially broader role of MAIT cells in immune homeostasis and diseases, beyond microbial immunosurveillance.
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影响因子：
4
作者：
Gherardin NA;Souter MN;Koay HF;Mangas KM;Seemann T;Stinear TP;Eckle SB;Berzins SP;d'Udekem Y;Konstantinov IE;Fairlie DP;Ritchie DS;Neeson PJ;Pellicci DG;Uldrich AP;McCluskey J;Godfrey DI
通讯作者：
Godfrey DI
影响因子：
30.5
作者：
Awad, Wael;Ler, Geraldine J. M.;Rossjohn, Jamie
通讯作者：
Rossjohn, Jamie
影响因子：
24.8
作者：
Harriff MJ;McMurtrey C;Froyd CA;Jin H;Cansler M;Null M;Worley A;Meermeier EW;Swarbrick G;Nilsen A;Lewinsohn DA;Hildebrand W;Adams EJ;Lewinsohn DM
通讯作者：
Lewinsohn DM
DOI：
10.1093/protein/gzg087
发表时间：
2003-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Boulter, JM;Glick, M;Jakobsen, BK
通讯作者：
Jakobsen, BK
影响因子：
6.3
作者：
Genheden S;Ryde U
通讯作者：
Ryde U