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Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors

Nature Immunology volume 12, pages 827833 (2011) | Download Citation

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Abstract

The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding these disparate antigens, the NKT cell TCRs docked onto CD1d similarly, achieving this by flattening the conformation of the β-linked ligands regardless of the size of the glycosyl head group. Unexpectedly, the antigenicity of iGb3 was attributable to its terminal sugar group making compensatory interactions with CD1d. Thus, the NKT cell TCR molds the β-linked self ligands to resemble the conformation of foreign α-linked ligands, which shows that induced-fit molecular mimicry can underpin the self-reactivity of NKT cell TCRs to β-linked antigens.

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Change history

  • 04 August 2011

    In the version of this article initially published online, in the diagrams at right in Figure 1, α-GalCer incorrectly included a second NH group and the acyl chain length of iGb3 was incorrect. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank F. Carbone for critically reading the manuscript; K. Wun, R. Koh and M. Sandoval for assistance; and J. Vivian and the staff at the MX2 beamline of the Australian synchrotron for assistance with data collection. Supported by the Cancer Council of Victoria, the National Health and Medical Research Council of Australia, the Australian Research Council, The Royal Society (G.S.B.), The Wellcome Trust (084923/B/08/Z to G.S.B.), the Medical Research Council (G1001750 to G.S.B.) and the US National Institutes of Health (AI45889 to S.A.P., and AI076463 and AI078246 to L.G.).

Author information

Author notes

    • Daniel G Pellicci
    •  & Andrew J Clarke

    These authors contributed equally to this work.

Affiliations

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

    • Daniel G Pellicci
    • , Adam P Uldrich
    • , James McCluskey
    •  & Dale I Godfrey
  2. The Protein Crystallography Unit, Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University,Clayton, Victoria, Australia.

    • Andrew J Clarke
    • , Onisha Patel
    • , Travis Beddoe
    • , Jérôme Le Nours
    •  & Jamie Rossjohn
  3. Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, USA.

    • Thierry Mallevaey
    •  & Laurent Gapin
  4. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.

    • Gurdyal S Besra
  5. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Steven A Porcelli

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Contributions

D.G.P. and A.J.C., isolation and characterization of NKT cell TCR–CD1d–β-antigen complexes; T.B. and A.P.U., surface plasmon resonance studies; J.L.N., crystallographic analyses; T.M., functional studies; O.P., crystallization and solution of the structure of the human NKT cell TCR complex; G.S.B., S.A.P. and J.M., intellectual input; and L.G., D.I.G. and J.R., investigation leadership and project conception. L.G., D.I.G. and J.R. contributed equally to this work.

Competing interests

S.A.P. has received payments as a consultant for Vaccinex for work related to the development of therapeutics based on CD1d-presented glycolipids.

Corresponding authors

Correspondence to Dale I Godfrey or Jamie Rossjohn.

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DOI

https://doi.org/10.1038/ni.2076