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Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals

Nature Immunology volume 12, pages 1202–1211 (2011)Cite this article

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Abstract

Invariant natural killer T cells (iNKT cells) have a prominent role during infection and other inflammatory processes, and these cells can be activated through their T cell antigen receptors by microbial lipid antigens. However, increasing evidence shows that they are also activated in situations in which foreign lipid antigens would not be present, which suggests a role for lipid self antigen. We found that an abundant endogenous lipid, β-D-glucopyranosylceramide (β-GlcCer), was a potent iNKT cell self antigen in mouse and human and that its activity depended on the composition of the N-acyl chain. Furthermore, β-GlcCer accumulated during infection and in response to Toll-like receptor agonists, contributing to iNKT cell activation. Thus, we propose that recognition of β-GlcCer by the invariant T cell antigen receptor translates innate danger signals into iNKT cell activation.

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Figure 1: Reactivity of iNKT cells to a panel of GSLs.
Figure 2: β-GlcCer is present in primary lymphoid tissues and activates iNKT cells.
Figure 3: Reactivity of iNKT cells to a β-GlcCer panel with differing N-acyl chains.
Figure 4: β-GlcCer presented by CD1d activates iNKT cells through cognate TCR interaction.
Figure 5: β-GlcCer is a cognate antigen for human iNKT cells.
Figure 6: β-GlcCer contributes to iNKT cell self-reactivity.
Figure 7: A role for β-GlcCer in the iNKT cell response to LPS-exposed BMDCs.
Figure 8: β-GlcCer contributes to microbial activation of iNKT cells.

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Acknowledgements

We thank M. Exley (Beth Israel Deaconess Medical Center) for Cd1d−/− mice on a C57BL/6 background; K. Kawakami (Tohoku University) for S. pneumoniae (stain URF918); H. Kim for assistance with flow cytometry; and the tetramer facility of the US National Institutes of Health for ongoing support. Supported by the US National Institutes of Health (R01AI063428; T32AI007306 to P.J.B.; T32HL007633 to E.Y.K.; K08AI077795 to M.B.; P41-RR00954, P30-DK56341 and P60-DK20579 to F.-F.H.; and P41-RR05351 (Research Resource for Integrated Glycotechnology) to P. Azadi at the Complex Carbohydrate Research Center for nuclear magnetic resonance spectroscopy analysis), the Higher Education Funding Council for England (S.D.G. and J.P.S.), J. Bardrick (G.S.B.), the Royal Society (G.S.B.), the Medical Research Council (G.S.B.) and The Wellcome Trust (084923/B/08/Z to G.S.B.).

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Author notes

  1. Patrick J Brennan and Raju V V Tatituri: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Patrick J Brennan, Raju V V Tatituri, Manfred Brigl, Edy Y Kim, Amit Tuli & Michael B Brenner

  2. Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, Sir Henry Wellcome and 'Hope' Laboratories, University of Southampton, Southampton, UK

    Joseph P Sanderson & Stephan D Gadola

  3. Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri, USA

    Fong-Fu Hsu

  4. School of Biosciences, University of Birmingham, Birmingham, UK

    Gurdyal S Besra

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Contributions

P.J.B. and R.V.V.T. conceived of, did and interpreted data from the experiments; P.J.B. was the main author of the manuscript; M.B., A.T., F.-F.H., J.P.S., S.D.G. and E.Y.K. assisted with the experimental design and data interpretation, did experiments and edited the manuscript; G.S.B. assisted with the design of the experiments and synthesized key materials; and M.B.B. assisted with the design of the experiments and data interpretation, supervised the research and substantially contributed to the manuscript.

Corresponding authors

Correspondence to Gurdyal S Besra or Michael B Brenner.

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Brennan, P., Tatituri, R., Brigl, M. et al. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat Immunol 12, 1202–1211 (2011). https://doi.org/10.1038/ni.2143

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