A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells

被引：240

作者：

Eckle, Sidonia B. G. ^{[1
]}

Birkinshaw, Richard W. ^{[2
]}

Kostenko, Lyudmila ^{[1
]}

Corbett, Alexandra J. ^{[1
]}

McWilliam, Hamish E. G. ^{[1
]}

Reantragoon, Rangsima ^{[1
]}

Chen, Zhenjun ^{[1
]}

Gherardin, Nicholas A. ^{[1
]}

Beddoe, Travis ^{[2
]}

Liu, Ligong ^{[3
]}

Patel, Onisha ^{[2
]}

Meehan, Bronwyn ^{[1
]}

Fairlie, David P. ^{[3
,4
]}

Villadangos, Jose A. ^{[1
]}

Godfrey, Dale I. ^{[1
,5
]}

Kjer-Nielsen, Lars ^{[1
]}

McCluskey, James ^{[1
]}

Rossjohn, Jamie ^{[2
,6
,7
]}

机构：

[1] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia

[2] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia

[3] Univ Queensland, Inst Mol Biosci, Div Chem & Struct Biol, Brisbane, Qld 4072, Australia

[4] Univ Queensland, ARC Ctr Excellence Adv Mol Imaging, Brisbane, Qld 4072, Australia

[5] Univ Melbourne, ARC Ctr Excellence Adv Mol Imaging, Parkville, Vic 3010, Australia

[6] Monash Univ, ARC Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia

[7] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2014年 / 211卷 / 08期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 澳大利亚研究理事会;

关键词：

VITAMIN-B METABOLITES; MR1 ANTIGEN PRESENTATION; MAIT CELLS; BACTERIAL-INFECTION; ALPHA-CHAIN; RECOGNITION; MHC; TCR; GLYCOLIPIDS; ACTIVATION;

D O I：

10.1084/jem.20140484

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) alpha-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR beta-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) 3 beta loop. Analysis of seven TRBV6-1(+) MAIT TCRs demonstrated how CDR3 beta 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.

引用

页码：1585 / 1600

页数：16

共 60 条

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