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 orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.

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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.).

Author information

Author notes

    • Andrew N Keller
    • , Sidonia B G Eckle
    •  & Weijun Xu

    These authors contributed equally to this work.

    • David P Fairlie
    • , James McCluskey
    •  & Jamie Rossjohn

    These authors jointly directed this work.

Affiliations

  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.

    • Andrew N Keller
    • , Victoria A Hughes
    • , Richard W Birkinshaw
    • , Anthony W Purcell
    •  & Jamie Rossjohn
  2. ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.

    • Andrew N Keller
    • , Victoria A Hughes
    •  & Jamie Rossjohn
  3. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.

    • Sidonia B G Eckle
    • , Bronwyn S Meehan
    • , Troi Pediongco
    • , Zhenjun Chen
    • , Huimeng Wang
    • , Criselle D'Souza
    • , Lars Kjer-Nielsen
    • , Nicholas A Gherardin
    • , Dale I Godfrey
    • , Lyudmila Kostenko
    • , Alexandra J Corbett
    •  & James McCluskey
  4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

    • Weijun Xu
    • , Ligong Liu
    • , Jeffrey Y W Mak
    •  & David P Fairlie
  5. ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia.

    • Weijun Xu
    • , Ligong Liu
    • , Jeffrey Y W Mak
    •  & David P Fairlie
  6. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia.

    • Nicholas A Gherardin
    •  & Dale I Godfrey
  7. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.

    • Jamie Rossjohn

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Contributions

A.N.K., S.B.G.E. and W.X. designed, performed and analyzed experiments; L.L., V.A.H., J.Y.W.M., B.S.M., T.P., R.W.B., Z.C., H.W., C.D'S., L.K.-N., N.A.G., D.I.G, L.K., A.J.C. and A.W.P. performed experiments, analyzed data and/or provided key reagents for this study; and D.P.F., J.M. and J.R. supervised experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David P Fairlie or James McCluskey or Jamie Rossjohn.

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https://doi.org/10.1038/ni.3679

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