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

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

Title: Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells
Creator: Keller, Andrew N.; Eckle, Sidonia B. G.; Wang, Huimeng; D'Souza, Criselle; Kjer-Nielsen, Lars; Gherardin, Nicholas A.; Godfrey, Dale I.; Kostenko, Lyudmila; Corbett, Alexandra J.; Purcell, Anthony W.; Fairlie, David P.; McCluskey, James; Xu, Weijun; Rossjohn, Jamie; Liu, Ligong; Hughes, Victoria A.; Mak, Jeffrey Y. W.; Meehan, Bronwyn S.; Pediongco, Troi; Birkinshaw, Richard W.; Chen, Zhenjun
Relation: Nature Immunology Vol. 18, Issue 4, p. 402-411
Publisher Link: http://dx.doi.org/10.1038/ni.3679
Publisher: Nature Publishing Group
Resource Type: journal article
Date: 2017
Description: 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.
Subject: drugs; invariant T cells; MAIT cells; MR1 binds; drug-like molecules
Identifier: http://hdl.handle.net/1959.13/1386270
Identifier: uon:32389
Identifier: ISSN:1529-2908
Language: eng
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