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

Eckle, Sidonia B.G., Birkinshaw, Richard W., Kostenko, Lyudmila, Corbett, Alexandra J., McWilliam, Hamish E. G., Reantragoon, Rangsima, Chen, Zhenjun, Gherardin, Nicholas A., Beddoe, Travis, Liu, Ligong, Patel, Onisha, Meehan, Bronwyn, Fairlie, David P., Villadangos, Jose A., Godfrey, Dale I., Kjer-Nielsen, Lars, McCluskey, James and Rossjohn, Jamie (2014) A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. Journal of Experimental Medicine, 211 8: 1585-1600. doi:10.1084/jem.20140484

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Author Eckle, Sidonia B.G.
Birkinshaw, Richard W.
Kostenko, Lyudmila
Corbett, Alexandra J.
McWilliam, Hamish E. G.
Reantragoon, Rangsima
Chen, Zhenjun
Gherardin, Nicholas A.
Beddoe, Travis
Liu, Ligong
Patel, Onisha
Meehan, Bronwyn
Fairlie, David P.
Villadangos, Jose A.
Godfrey, Dale I.
Kjer-Nielsen, Lars
McCluskey, James
Rossjohn, Jamie
Title A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells
Journal name Journal of Experimental Medicine   Check publisher's open access policy
ISSN 1540-9538
Publication date 2014-07-28
Year available 2014
Sub-type Article (original research)
DOI 10.1084/jem.20140484
Open Access Status File (Publisher version)
Volume 211
Issue 8
Start page 1585
End page 1600
Total pages 16
Place of publication New York, NY United States
Publisher Rockefeller University Press
Collection year 2015
Language eng
Formatted abstract
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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Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
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Citation counts: TR Web of Science Citation Count  Cited 39 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 42 times in Scopus Article | Citations
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