Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

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

    Article  CAS  ADS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Godfrey, D. I., Rossjohn, J. & McCluskey, J. Fighting infection with your MAITs. Nature Immunol. 11, 693–695 (2010)

    Article  CAS  Google Scholar 

  7. Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Tilloy, F. 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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Huang, S. 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)

    Article  CAS  ADS  Google Scholar 

  14. Goldfinch, N. 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)

    Article  Google Scholar 

  15. Chua, W.-J. 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)

    Article  CAS  Google Scholar 

  16. Shimamura, M. 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)

    Article  CAS  Google Scholar 

  17. Kjer-Nielsen, L. 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)

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Gras, S. 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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  25. Garrett, T. P., Saper, M. A., Bjorkman, P. J., Strominger, J. L. & Wiley, D. C. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 342, 692–696 (1989)

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  27. Godfrey, D. I., Rossjohn, J. & McCluskey, J. The fidelity, occasional promiscuity, and versatility of T cell receptor recognition. Immunity 28, 304–314 (2008)

    Article  CAS  Google Scholar 

  28. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012)

    Article  CAS  ADS  Google Scholar 

  29. The Human Microbiome Project Consortium . Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012)

    Article  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  31. Garboczi, D. N., Hung, D. T. & Wiley, D. C. 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)

    Article  CAS  ADS  Google Scholar 

  32. Borg, N. A. 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)

    Article  CAS  Google Scholar 

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

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

    Article  Google Scholar 

  35. Clements, C. S. 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)

    Article  CAS  ADS  Google Scholar 

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

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

    Google Scholar 

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

    Article  ADS  Google Scholar 

  39. DeLano, W. L. The PyMOL Molecular Graphics System. http://www.pymol.org (2002)

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

    Article  CAS  Google Scholar 

  41. Plaut, G. W. E., Smith, C. M. & Alworth, W. L. Biosynthesis of water-soluble vitamins. Annu. Rev. Biochem. 43, 899–922 (1974)

    Article  CAS  Google Scholar 

  42. Tynan, F. E. 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)

    Article  CAS  Google Scholar 

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

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.

Corresponding authors

Correspondence to Jamie Rossjohn or James McCluskey.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11605

This article is cited by

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.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing