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MR1 presents microbial vitamin B metabolites to MAIT cells

Abstract

Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.

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Figure 1: Refolding of MR1 in the presence of 6-FP.
Figure 2: Overview of the crystal structure of MR1–antigen complex.
Figure 3: Comparison of MR1, MHC-I and MHC-I-like binding clefts.
Figure 4: Identification of bacterially-derived MAIT-cell antigens.
Figure 5: MAIT-cell activation with MR1-restricted antigens.

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Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates and structure factors for theMR1–antigen complex were deposited in the Protein Data Bank (PDB) under accession code 4GUP.

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Acknowledgements

We thank R. Strugnell, T. Stinear, T. Mulhern, P. O’Donnell, J. Pyke, T. Rupasinghe, D. L. Tull, J. Ralton, L. Foster, S. H. Ramarathinam, M. Bharadwaj, D. Pellicci and K. Wun for discussions and technical advice, T. Hansen for the anti-MR1 monoclonal antibody and the staff of the Australian Synchrotron for assistance with data collection. This research was supported by the National Health and Medical Research Council of Australia (NHMRC) and the Australian Research Council. O.P. was supported by an ARC Future Fellowship; A.W.P. by an NHMRC Senior Research Fellowship; M.J.M. by a NHMRC Principal Research Fellowship; D.I.G. and D.P.F. were supported by NHMRC Senior Principal Research Fellowships; J.R. was supported by an NHMRC Australia Fellowship.

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Authors and Affiliations

Authors

Contributions

L.K.-N. identified the MR1 and MAIT ligands, undertook analysis, performed experiments and contributed to manuscript preparation. O.P. and J.L.N. solved the structure of MR1, conducted analyses and contributed to manuscript preparation. B.M., A.J.C., M.B., A.J.C., L.K., R.R., N.A.W., A.W.P., N.L.D., M.J.M., R.A.J.O.’H., G.N.K. and D.I.G. performed experiments and/or analysed data and/or provided intellectual input or helped to write the manuscript. L.L. and D.P.F. synthesized and devised the MAIT-cell activating ligands and contributed to writing the manuscript. J.M. and J.R. co-led the investigation and contributed to design and interpretation of data, project management, and writing of the manuscript.

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Correspondence to Jamie Rossjohn or James McCluskey.

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The authors declare no competing financial interests.

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This file contains Supplementary Tables 1-3 and Supplementary Figures 1-13. (PDF 3868 kb)

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Kjer-Nielsen, L., Patel, O., Corbett, A. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012). https://doi.org/10.1038/nature11605

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