The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins
The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins
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DOI：
10.1073/pnas.1222678110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Adams, Erin J.
中科院分区：
文献类型：
--
作者：
Lopez-Sagaseta, Jacinto;Dulberger, Charles L.;Adams, Erin J.
粘膜相关不变T（MAIT）细胞是进化上保守的α β T细胞谱系，其表达限于MHC相关-1（MR 1）蛋白的半不变T细胞受体（TCR）。MAIT细胞的发育和刺激依赖于MR 1的表达和暴露于微生物，但这些细胞在对来自不同物种的MR 1作出反应时，可以表现出与微生物无关的刺激。我们已经使用MAIT细胞的这种不依赖微生物的跨物种反应性来定义MAIT-TCR/MR 1接合的分子基础，并在此呈现与牛MR 1结合的人MAIT-TCR的2.85埃复合物结构。MR 1结合沟的骨架结构与经典的肽呈递MHC I类分子（MHCp）相似，但部分被大的芳香残基封闭，形成适合小配体呈递的空腔。MAIT-TCR在MR 1上的对接垂直于MR 1表面并跨越MR 1 α 1和α 2螺旋，类似于经典的MHC β的α β TCR接合。然而，MAIT-TCR接触由α链主导，集中在MR 1 α 2螺旋上。TCR β链接触主要通过可变的CDR 3 β环，该可变的CDR 3 β环直接位于MR 1开放沟上方的CDR 3 α环的近端。MAIT TCR/MR 1复合物结构的阐明解释了半不变的MAIT-TCR如何与非多态性MR 1蛋白结合，并揭示了这种细胞类型的配体识别。重要的是，这种结构也为我们理解α β T细胞识别MHC和MHC样配体的进化提供了关键的联系。
Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved alpha beta T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, cross-species reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 angstrom complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 alpha 1 and alpha 2 helices, similar to classical alpha beta TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the alpha-chain, focused on the MR1 alpha 2 helix. TCR beta-chain contacts are mostly through the variable CDR3 beta loop that is positioned proximal to the CDR3 alpha loop directly over the MR1 open groove. The elucidation of the MAIT TCR/MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of alpha beta T-cell recognition of MHC and MHC-like ligands.