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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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.
The authors declare no competing financial interests.
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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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