Abstract

The T cell repertoire comprises αβ and γδ T cell lineages. Although it is established how αβ T cell antigen receptors (TCRs) interact with antigen presented by antigen-presenting molecules, this is unknown for γδ TCRs. We describe a population of human Vδ1+ γδ T cells that exhibit autoreactivity to CD1d and provide a molecular basis for how a γδ TCR binds CD1d–α-galactosylceramide (α-GalCer). The γδ TCR docked orthogonally, over the A′ pocket of CD1d, in which the Vδ1-chain, and in particular the germ line–encoded CDR1δ loop, dominated interactions with CD1d. The TCR γ-chain sat peripherally to the interface, with the CDR3γ loop representing the principal determinant for α-GalCer specificity. Accordingly, we provide insight into how a γδ TCR binds specifically to a lipid-loaded antigen-presenting molecule.

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Acknowledgements

We thank the staff at the MX1 and MX2 beamlines of the Australian Synchrotron for assistance with data collection, M. Sandoval, M. Ciula, D. Littler, R. Berry, J. Waddington, P. Neeson and D. Ritchie for technical assistance, provision of reagents and/or advice, staff from the flow cytometry facilities in the Melbourne Brain Centre and the Department of Microbiology and Immunology at The University of Melbourne and D. Maksel from the Macromolecular Crystallization Facility at Monash University for technical assistance, P. Savage (Brigham Young University) for providing PBS44 glycolipid, G. Besra (University of Birmingham, UK) and S. Porcelli (Albert Einstein College of Medicine) for providing α-glucosylceramide and the α-GalCer analog OCH, and D. Vignali (St. Jude Children's Research Hospital) and S. Turner (The University of Melbourne) for providing pMIG expression vector. This work was supported by the Australian Research Council and the National Health and Medical Research Council of Australia (NHMRC). N.A.G. is supported by a Leukaemia Foundation of Australia Postgraduate Scholarship; T.B. is supported by a Pfizer Australia Fellowship; S.G. and O.P. are supported by Australian Research Council Future Fellowships; D.G.P. is supported by an NHMRC Peter Doherty Fellowship; J.R. is supported by an NHMRC Australia Fellowship; D.I.G. is supported by an NHMRC Senior Principal Research Fellowship.

Author information

Author notes

    • Adam P Uldrich
    •  & Jérôme Le Nours

    These authors contributed equally to this work.

    • Jamie Rossjohn
    •  & Dale I Godfrey

    These authors jointly directed this work.

Affiliations

  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.

    • Adam P Uldrich
    • , Daniel G Pellicci
    • , Nicholas A Gherardin
    • , Kirsty G McPherson
    • , Ricky T Lim
    •  & Dale I Godfrey
  2. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.

    • Jérôme Le Nours
    • , Onisha Patel
    • , Travis Beddoe
    • , Stephanie Gras
    •  & Jamie Rossjohn
  3. Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria, Australia.

    • Jérôme Le Nours
    •  & Jamie Rossjohn
  4. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK.

    • Jamie Rossjohn

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Contributions

A.P.U. identified and performed cellular and molecular characterization of γδ T cells, and produced TCR protein complexes for crystallographic studies. J.L.N., A.P.U. and S.G. solved the crystal structures and performed structural analysis. T.B. undertook SPR investigations. O.P. designed and generated human CD1d-BirA constructs. R.T.L. generated C1R-CD1d transductants. A.P.U., D.G.P., N.A.G., K.G.M. and R.T.L. performed cell-based experiments, including glycolipid specificity and functional studies. J.R. and D.I.G. were joint senior authors: co-led the investigation, devised the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jamie Rossjohn or Dale I Godfrey.

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DOI

https://doi.org/10.1038/ni.2713

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