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

Andrew n Keller, Sidonia B G Eckle, Weijun Xu, Ligong Liu, Victoria A Hughes, Jeffrey Y W 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 & 1 others Jamie Rossjohn

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)402-411
Number of pages14
JournalNature Immunology
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2017

Keywords

  • antigen processing and presentation
  • innate immune cells

Cite this

Keller, Andrew n ; Eckle, Sidonia B G ; Xu, Weijun ; Liu, Ligong ; Hughes, Victoria A ; Mak, Jeffrey Y W ; Meehan, Bronwyn S ; Pediongco, Troi ; Birkinshaw, Richard W ; Chen, Zhenjun ; 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 ; Rossjohn, Jamie. / Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. In: Nature Immunology. 2017 ; Vol. 18, No. 4. pp. 402-411.
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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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author = "Keller, {Andrew n} and Eckle, {Sidonia B G} and Weijun Xu and Ligong Liu and Hughes, {Victoria A} and Mak, {Jeffrey Y W} and Meehan, {Bronwyn S} and Troi Pediongco and Birkinshaw, {Richard W} and Zhenjun Chen and Huimeng Wang and Criselle D'Souza and Lars Kjer-Nielsen and Gherardin, {Nicholas A} and Godfrey, {Dale I} and Lyudmila Kostenko and Corbett, {Alexandra J} and Purcell, {Anthony W} and Fairlie, {David P} and James McCluskey and Jamie Rossjohn",
year = "2017",
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doi = "10.1038/ni.3679",
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Keller, AN, Eckle, SBG, Xu, W, Liu, L, Hughes, VA, Mak, JYW, Meehan, BS, Pediongco, T, Birkinshaw, RW, Chen, Z, Wang, H, D'Souza, C, Kjer-Nielsen, L, Gherardin, NA, Godfrey, DI, Kostenko, L, Corbett, AJ, Purcell, AW, Fairlie, DP, McCluskey, J & Rossjohn, J 2017, 'Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells' Nature Immunology, vol. 18, no. 4, pp. 402-411. https://doi.org/10.1038/ni.3679

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. / Keller, Andrew n; Eckle, Sidonia B G; Xu, Weijun; Liu, Ligong; Hughes, Victoria A; Mak, Jeffrey Y W; Meehan, Bronwyn S; Pediongco, Troi; Birkinshaw, Richard W; Chen, Zhenjun; 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; Rossjohn, Jamie.

In: Nature Immunology, Vol. 18, No. 4, 04.2017, p. 402-411.

Research output: Contribution to journalArticleResearchpeer-review

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AU - D'Souza, Criselle

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