Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells.
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.
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.
Andrew N
AN
Keller
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Sidonia B G
0000-0003-0766-171X
SB
Eckle
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia.
Weijun
W
Xu
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia.
Ligong
0000-0002-2693-1896
L
Liu
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.
Victoria A
VA
Hughes
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia.
Jeffrey Y W
JY
Mak
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Bronwyn S
BS
Meehan
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Troi
T
Pediongco
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
Richard W
RW
Birkinshaw
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Zhenjun
Z
Chen
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Huimeng
H
Wang
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Criselle
C
D'Souza
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Lars
L
Kjer-Nielsen
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia.
Nicholas A
NA
Gherardin
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia.
Dale I
0000-0002-3009-5472
DI
Godfrey
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Lyudmila
L
Kostenko
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
Alexandra J
0000-0003-1618-4337
AJ
Corbett
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
Anthony W
0000-0003-0532-8331
AW
Purcell
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia.
David P
DP
Fairlie
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
James
J
McCluskey
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.|ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.|Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Jamie
J
Rossjohn
D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D015778:Minor Histocompatibility Antigens / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D000072336:Mucosal-Associated Invariant T Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D015395:Histocompatibility Antigens Class I; D008024:Ligands; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell