Journal article

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells

Andrew N Keller, Sidonia BG Eckle, Weijun Xu, Ligong Liu, Victoria A Hughes, Jeffrey YW Mak, Bronwyn S Meehan, Troi Pediongco, Richard W Birkinshaw, Zhenjun Chen, Huimeng Wang, Criselle D'Souza, Lars Kjer-Nielsen, Nicholas A Gherardin, Dale I Godfrey, Lyudmila Kostenko, Alexandra J Corbett, Anthony W Purcell, David P Fairlie, James McCluskey Show all

NATURE IMMUNOLOGY | NATURE PUBLISHING GROUP | Published : 2017

Abstract

The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand or..

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Grants

Awarded by Australian National Health and Medical Research Council


Awarded by Australian Research Council


Funding Acknowledgements

We thank the staff at the Australian Synchrotron for assistance with data collection; the staff at the Monash Macromolecular crystallization facility; and T. Hansen (University of Washington) and W.J. Yankelevich (US Food and Drug Administration) for the 26.5 hybridoma. Supported by The University of Melbourne (S.E.), the Australian National Health and Medical Research Council (1020770 and 1027369 to D.I.G and D.P.F.; 1044215 to A.W.P.; 1113293 to J.M.; and 1125493 to J.R.), the Australian Research Council (CE140100011 and DE170100407 to S.E.; FT160100083 to A.J.C.; and FL160100049 to J.R.), the Leukaemia Foundation of Australia (N.A.G.) and Cancer Council Victoria (N.A.G.).