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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

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.

References

  1. 1.

    et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003)

  2. 2.

    et al. Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 8, e1000407 (2010)

  3. 3.

    et al. Antimicrobial activity of mucosal-associated invariant T cells. Nature Immunol. 11, 701–708 (2010)

  4. 4.

    Where do MAIT cells fit in the family of unconventional T cells? PLoS Biol. 7, e1000070 (2009)

  5. 5.

    et al. Mucosal-associated invariant T cells: unconventional development and function. Trends Immunol. 32, 212–218 (2011)

  6. 6.

    , & Fighting infection with your MAITs. Nature Immunol. 11, 693–695 (2010)

  7. 7.

    , & The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007)

  8. 8.

    et al. Antigen recognition by CD1d-restricted NKT T cell receptors. Semin. Immunol. 22, 61–67 (2010)

  9. 9.

    et al. Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor. J. Exp. Med. 209, 761–774 (2012)

  10. 10.

    et al. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999)

  11. 11.

    et al. Evidence for MR1 antigen presentation to mucosal-associated invariant T cells. J. Biol. Chem. 280, 21183–21193 (2005)

  12. 12.

    et al. MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. J. Exp. Med. 205, 1201–1211 (2008)

  13. 13.

    et al. MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proc. Natl Acad. Sci. USA 106, 8290–8295 (2009)

  14. 14.

    et al. Conservation of mucosal associated invariant T (MAIT) cells and the MR1 restriction element in ruminants, and abundance of MAIT cells in spleen. Vet. Res. 41, 62 (2010)

  15. 15.

    et al. Endogenous MHC-related protein 1 is transiently expressed on the plasma membrane in a conformation that activates mucosal-associated invariant T cells. J. Immunol. 186, 4744–4750 (2011)

  16. 16.

    et al. Modulation of Vα19 NKT cell immune responses by α-mannosyl ceramide derivatives consisting of a series of modified sphingosines. Eur. J. Immunol. 37, 1836–1844 (2007)

  17. 17.

    et al. The structure of HLA-B8 complexed to an immunodominant viral determinant: peptide-induced conformational changes and a mode of MHC class I dimerization. J. Immunol. 169, 5153–5160 (2002)

  18. 18.

    et al. Ultraviolet photodegradation of folic acid. J. Photochem. Photobiol. B 80, 47–55 (2005)

  19. 19.

    et al. Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope. J. Immunol. 183, 430–437 (2009)

  20. 20.

    et al. The crystal structure of human CD1d with and without α-galactosylceramide. Nature Immunol. 6, 819–826 (2005)

  21. 21.

    et al. Structure of a classical MHC class I molecule that binds “non-classical” ligands. PLoS Biol. 8, e1000557 (2010)

  22. 22.

    et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93, 111–123 (1998)

  23. 23.

    et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506–512 (1987)

  24. 24.

    et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368, 215–221 (1994)

  25. 25.

    , , , & Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 342, 692–696 (1989)

  26. 26.

    et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486, 554–558 (2012)

  27. 27.

    , & The fidelity, occasional promiscuity, and versatility of T cell receptor recognition. Immunity 28, 304–314 (2008)

  28. 28.

    , & Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012)

  29. 29.

    . Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012)

  30. 30.

    et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012)

  31. 31.

    , & HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc. Natl Acad. Sci. USA 89, 3429–3433 (1992)

  32. 32.

    et al. The CDR3 regions of an immunodominant T cell receptor dictate the ‘energetic landscape’ of peptide-MHC recognition. Nature Immunol. 6, 171–180 (2005)

  33. 33.

    Recent changes to the MOSFLM package for processing film and image plate data. Joint CCP4 ESF-EAMCB Newsletter Protein Crystallogr. 26, (1992)

  34. 34.

    . The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

  35. 35.

    et al. Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetal-maternal interface. Proc. Natl Acad. Sci. USA 102, 3360–3365 (2005)

  36. 36.

    et al. autoBUSTER v. 1.6.0 (Global Phasing, 2011)

  37. 37.

    & Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

  38. 38.

    et al. MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res. 35, W375–W383 (2007)

  39. 39.

    The PyMOL Molecular Graphics System. (2002)

  40. 40.

    , & LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins. J. Mol. Graph. Model. 15, 359–363 (1997)

  41. 41.

    , & Biosynthesis of water-soluble vitamins. Annu. Rev. Biochem. 43, 899–922 (1974)

  42. 42.

    et al. A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nature Immunol. 8, 268–276 (2007)

Download references

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.

Author information

Author notes

    • Jamie Rossjohn
    •  & James McCluskey

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

    • Lars Kjer-Nielsen
    • , Alexandra J. Corbett
    • , Bronwyn Meehan
    • , Zhenjun Chen
    • , Lyudmila Kostenko
    • , Rangsima Reantragoon
    • , Dale I. Godfrey
    •  & James McCluskey
  2. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia

    • Onisha Patel
    • , Jérôme Le Nours
    • , Mugdha Bhati
    • , Anthony W. Purcell
    • , Nadine L. Dudek
    •  & Jamie Rossjohn
  3. Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria 3800, Australia

    • Jérôme Le Nours
    •  & Jamie Rossjohn
  4. Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia

    • Ligong Liu
    •  & David P. Fairlie
  5. Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, Metabolomics Australia, University of Melbourne, Parkville, Victoria 3010, Australia

    • Nicholas A. Williamson
    • , Anthony W. Purcell
    • , Nadine L. Dudek
    •  & Malcolm J. McConville
  6. School of Chemistry, Bio21 Molecular Science and Biotechnology Institute and ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, University of Melbourne, Melbourne, Victoria 3010, Australia

    • Richard A. J. O’Hair
    •  & George N. Khairallah
  7. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK

    • Jamie Rossjohn

Authors

  1. Search for Lars Kjer-Nielsen in:

  2. Search for Onisha Patel in:

  3. Search for Alexandra J. Corbett in:

  4. Search for Jérôme Le Nours in:

  5. Search for Bronwyn Meehan in:

  6. Search for Ligong Liu in:

  7. Search for Mugdha Bhati in:

  8. Search for Zhenjun Chen in:

  9. Search for Lyudmila Kostenko in:

  10. Search for Rangsima Reantragoon in:

  11. Search for Nicholas A. Williamson in:

  12. Search for Anthony W. Purcell in:

  13. Search for Nadine L. Dudek in:

  14. Search for Malcolm J. McConville in:

  15. Search for Richard A. J. O’Hair in:

  16. Search for George N. Khairallah in:

  17. Search for Dale I. Godfrey in:

  18. Search for David P. Fairlie in:

  19. Search for Jamie Rossjohn in:

  20. Search for James McCluskey in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jamie Rossjohn or James McCluskey.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-3 and Supplementary Figures 1-13.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature11605

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.