A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells.
A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells.
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DOI：
10.1084/jem.20140484
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发表时间：
2014-07-28
期刊：
影响因子：
--
通讯作者：
Rossjohn J
中科院分区：
文献类型：
--
作者：
Eckle SB;Birkinshaw RW;Kostenko L;Corbett AJ;McWilliam HE;Reantragoon R;Chen Z;Gherardin NA;Beddoe T;Liu L;Patel O;Meehan B;Fairlie DP;Villadangos JA;Godfrey DI;Kjer-Nielsen L;McCluskey J;Rossjohn J
新型MAIT细胞拮抗剂Ac-6-FP稳定MR 1并可抑制MAIT细胞活化，其中柔性TCR β链用于微调TCR对抗原-MR 1复合物的亲和力。粘膜相关不变T（MAIT）细胞表达不变T细胞受体（TCR）α链（TRAV 1 -2与人类TRAJ 33、TRAJ 20或TRAJ 12连接），与TCR β链阵列配对。MAIT TCR可以结合受主要组织相容性复合体（MHC）相关I类分子MR 1限制的基于叶酸和核黄素的代谢物。然而，MAIT TCR和MR 1-配体异质性对MAIT细胞生物学的影响尚不清楚。我们展示了一种以前未表征的MR 1配体，乙酰基-6-甲酰蝶呤（Ac-6-FP），如何显着稳定MR 1，有效地上调MR 1细胞表面表达，并抑制MAIT细胞活化。Ac-6-FP的这些增强的性质可归因于MR 1的结构改变，其随后通过互补决定区（CDR）3β环内的构象变化影响MAIT TCR识别。对7个TRBV 6 -1+ MAIT TCR的分析证明了CDR 3 β高变性如何通过改变TCR柔性以及与MR 1和Ag本身的接触来影响MAIT TCR识别。TRBV 6 -1、TRBV 6 -4和TRBV 20 + MAIT TCR与结合至有效的基于核黄素的抗原（Ag）的MR 1复合的三元结构显示了TRBV基因使用的变化如何排他性地影响共有MAIT TCR-MR 1足迹内的MR 1接触。此外，在保守的MAIT TCR-MR 1-Ag对接模式中容易容纳差异TRAJ基因使用。总的来说，MAIT TCR异质性可以以Ag依赖性方式微调MR 1识别，从而调节MAIT细胞识别。
A novel MAIT cell antagonist, Ac-6-FP, stabilizes MR1 and can inhibit MAIT cell activation with the flexible TCR β-chain serving to fine-tune the affinity of the TCR for antigen-MR1 complexes. Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) α-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR β-chains. MAIT TCRs can bind folate- and riboflavin-based metabolites restricted by the major histocompatibility complex (MHC)-related class I−like molecule, MR1. However, the impact of MAIT TCR and MR1-ligand heterogeneity on MAIT cell biology is unclear. We show how a previously uncharacterized MR1 ligand, acetyl-6-formylpterin (Ac-6-FP), markedly stabilized MR1, potently up-regulated MR1 cell surface expression, and inhibited MAIT cell activation. These enhanced properties of Ac-6-FP were attributable to structural alterations in MR1 that subsequently affected MAIT TCR recognition via conformational changes within the complementarity-determining region (CDR) 3β loop. Analysis of seven TRBV6-1+ MAIT TCRs demonstrated how CDR3β hypervariability impacted on MAIT TCR recognition by altering TCR flexibility and contacts with MR1 and the Ag itself. Ternary structures of TRBV6-1, TRBV6-4, and TRBV20+ MAIT TCRs in complex with MR1 bound to a potent riboflavin-based antigen (Ag) showed how variations in TRBV gene usage exclusively impacted on MR1 contacts within a consensus MAIT TCR-MR1 footprint. Moreover, differential TRAJ gene usage was readily accommodated within a conserved MAIT TCR-MR1-Ag docking mode. Collectively, MAIT TCR heterogeneity can fine-tune MR1 recognition in an Ag-dependent manner, thereby modulating MAIT cell recognition.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16.8
作者：
Dushek O;van der Merwe PA
通讯作者：
van der Merwe PA
影响因子：
9.8
作者：
Gold MC;Cerri S;Smyk-Pearson S;Cansler ME;Vogt TM;Delepine J;Winata E;Swarbrick GM;Chua WJ;Yu YY;Lantz O;Cook MS;Null MD;Jacoby DB;Harriff MJ;Lewinsohn DA;Hansen TH;Lewinsohn DM
通讯作者：
Lewinsohn DM
影响因子：
64.8
作者：
Corbett, Alexandra J.;Eckle, Sidonia B. G.;McCluskey, James
通讯作者：
McCluskey, James
影响因子：
32.4
作者：
Degano, M;Garcia, KC;Wilson, IA
通讯作者：
Wilson, IA