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

Nature Immunology volume 18, pages 402–411 (2017)Cite this article

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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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Figure 1: In silico virtual screening for putative MR1 ligands.
Figure 2: Drugs and drug-related molecules cause upregulation of the cell-surface expression of MR1 and inhibition of MAIT cells.
Figure 3: DCF metabolites activate MAIT cell lines in an MR1-dependent manner.
Figure 4: Drugs and drug-related molecules inhibit the activation of MAIT cells ex vivo and in vivo.
Figure 5: MR1 structures with drugs and drug-related molecules.
Figure 6: Inhibitors bound within the MR1 cleft.
Figure 7: Complexes of MR1–MAIT TCR with DCF and a specific metabolite.

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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.).

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Author notes

  1. Andrew N Keller, Sidonia B G Eckle and Weijun Xu: These authors contributed equally to this work.

  2. David P Fairlie, James McCluskey and Jamie Rossjohn: These authors jointly directed this work.

Authors and 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.

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

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Integrated supplementary information

Supplementary Figure 1 In silico screening of MR1 ligands.

a) Superimposition of 9 drugs (sticks) on 5-OP-RU. These drugs are consistent with the shape matching to 6-FP. Colored chemical structures of drugs (e.g. Acyclovir, Lamivudine, Methotrexate) correspond to colored sticks, with other drugs shown in grey. b) Side view of all 20 virtual screening drug hits (shown as surfaces) in complementarity with the MR1 binding site. Carbon (white); oxygen (red); nitrogen (blue); chlorine (green); fluorine (cyan). c) Classification of twenty-two representative structures of active compounds (including 9 drugs) according to their chemical substructures: pyrimidines (black), phenols/anilines (green), enones (red), aromatic aldehydes (orange), aromatic carboxylates (olive), quinones (dark blue), flavones (light blue), isoflavones (pink).

Supplementary Figure 2 Upregulation of MR1 expression and activation of MAIT cells.

a) Graphical display of percentages MR1 upregulating versus agonistic compounds identified as part of the functional screen in Figure 2a. b) gMFI of 26.5 (mean of triplicate samples and SEM) and isotype control (single samples) staining at 7 hours for Nil, vehicle controls (V) and ligands (left panel). Repeat experiment of Figure 2c including 5-F-SA (right panel) showing single samples. c) First 2 rows: Drug/small molecule dose dependent inhibition of Jurkat.MAIT-#6 and Jurkat.MAIT-C-F7 activated by 5-OP-RU in the presence of C1R.MR1 cells and assayed by flow cytometric staining for CD69 as a marker of activation. Displayed is gMFI CD69 fold of background control for one representative of three experiments. 5-OP-RU activation with nil inhibitor/activator was assayed in triplicate displaying mean and SEM (error bars). Third row: gMFI of CD69 (mean of triplicate samples and SEM) for Nil (PBS), vehicle controls with maximum concentration of 5-OP-RU, and ligands co-incubated with PMA/Ionomycin are displayed for Jurkat.MAIT-A-F7, Jurkat.MAIT-#6 and Jurkat.MAIT-C-F7. d) IL-2 production in the presence of PBS, vehicle controls with maximum concentration of 5-OP-RU, and ligands co-incubated with PMA/Ionomycin. Displayed are mean of triplicate samples except for ligands co-incubated with PMA/Ionomycin where single samples are shown. e) Repeat experiment of Figure 2d/f including in addition gMFI of CD69 (mean of triplicate samples and SEM) for vehicle controls with maximum concentration of 5-OP-RU, ligands and ligands co-incubated with PMA/Ionomycin (left panel). In parallel the effect of ligands and vehicles on Jurkat.CD8.LC13 activation by C1R.HLA-B*08:01 in the presence of FLR peptide was tested (right panel).

Supplementary Figure 3 Degradation of 2,4-DA-6-FP.

a) Chemical structures of aminopterin/folic acid (I) as they decompose to form respective formyl pterin (II) and aminobenzoylglutamic acid (III). The aldehyde on (II) then further degrades to carboxylic acid (IV). b) Absorbance spectra of aminopterin after exposure to a fluorescent lamp for 0h (green), 18h (orange) and 48h (red). c&d) MR1 surface upregulation by C1R.MR1 cells treated with 20μM or 2μM of photodegraded aminopterin from (b), shown as histogram of 26.5 (c) and as MFI 26.5-fold of PBS vehicle control (mean of triplicate samples with SEM). Representative of two separate experiments. e) Mass spectra and elemental analysis of compound extracted from MR1 refolded in the presence of photodegraded aminopterin compared with theoretical spectra for 2,4-DA-6-FP.

Supplementary Figure 4 Activation of MR1-restricted T cell lines by DCF and DCF metabolites.

Effect of Diclofenac and its metabolites on MR1 restricted T cell lines and Jurkat.CD8.LC13 activation by C1R.HLA-B*08:01 co-incubated with FLR peptide. Displayed are fold of background MFI CD69 (a) or MFI CD69 (b) for one representative of two experiments.

Supplementary Figure 5 Inhibition of the activation of MAIT cells by drugs and drug-related molecules ex vivo.

a) % cytokine production gated on live, CD3+, TRAV1-2+ 5-OP-RU-MR1-tetramer- (representative of non MAIT T cells) or TRAV1-2+ 5-OP-RU-MR1-tetramer+ (MAIT cells) cells. Samples include titrating amounts of 5-OP-RU, vehicle controls in the presence of maximum concentration of 5-OP-RU, Nil (PBS), and maximum concentration of inhibitors in the presence or absence of PMA/Ionomycin stimulus. Displayed is data of one representative donor. b) % CTV dilution gated on live, CD3+, TRAV1-2+ 5-OP-RU-MR1-tetramer- (representative of non MAIT T-cells) or TRAV1-2+ 5-OP-RU-MR1-tetramer+ (MAIT cells) cells. Samples include titrating amounts of 5-OP-RU (triplicate samples, SEM) and Nil (triplicate samples, SEM), vehicles (triplicate samples, SEM) and maximum concentrations of inhibitors in the presence (triplicate samples, SEM) or absence (single samples) of plate bound CD3/CD28. Displayed is data of one representative donor.

Supplementary Figure 6 Inhibition of the activation of MAIT cells by small molecules in vivo.

(a) Inhibitory effect of intranasally administered Ac-6-FP and 3-F-SA on MAIT cell accumulation in the lungs of C57BL/6 mice upon 5-OP-RU and Salm.BRD509ΔribDH stimulus. Matching data in Figure 4c, absolute numbers of MAIT cells and non-MAIT αβ T cells (mean values +/- SEM as error bars of four mice as well as CFU counts in the lungs are shown. (b) Repeat experiment at the maximum inhibitor concentration including in addition IL17 production by non-MAIT αβ T cells in response to Salm.BRD509ΔribDH stimulus in the presence or absence of inhibitors.

Supplementary Figure 7 TCR contacts with MR1.

Contact regions of the CDR1α(teal), CDR2α(pink), CDR3α(yellow), CDR1β(cyan), CDR2β(red), CDR3β(orange) and framework residues (slate and deep purple for α- and β-chains, respectively) of A-F7 MAIT TCR on MR1 (white surface), which is presenting 5-OP-RU (A), 6-FP (B), 2,4-DA-6-FP (C), 2-OH-1-NA (D), HMB (E), 3-F-SA (F), DCF (G) or 5-OH-DCF (H).

Supplementary Figure 8 Chemical synthesis of metabolites.

Synthesis of 2,4-diamino-6-formylpteridine (A), 4′,5-dihydroxy diclofenac (B) and 5-hydroxy diclofenac (C).

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Keller, A., Eckle, S., Xu, W. et al. Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. Nat Immunol 18, 402–411 (2017). https://doi.org/10.1038/ni.3679

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