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CD1d-lipid antigen recognition by the γδ TCR

Nature Immunology volume 14, pages 1137–1145 (2013)Cite this article

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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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Figure 1: Identification of Vδ1+ cells reactive to CD1d–α-GalCer.
Figure 2: Lipid antigen reactivity of autoreactive CD1d-restricted γδ T cells.
Figure 3: 9C2 γδ−TCR reacts with CD1d–α-GalCer.
Figure 4: γδ TCR and type I NKT TCR structures.
Figure 5: Overview of the CD1d-antigen complex with the γδ TCR.
Figure 6: Interactions at the γδ TCR–CD1d–α-GalCer interface.

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References

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

    CAS  PubMed  Google Scholar 

  2. Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Rossjohn, J., Pellicci, D.G., Patel, O., Gapin, L. & Godfrey, D.I. Recognition of CD1d-restricted antigens by natural killer T cells. Nat. Rev. Immunol. 12, 845–857 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Brenner, M.B. et al. Identification of a putative second T-cell receptor. Nature 322, 145–149 (1986).

    CAS  PubMed  Google Scholar 

  5. Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of gamma delta T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Schild, H. et al. The nature of major histocompatibility complex recognition by gamma delta T cells. Cell 76, 29–37 (1994).

    CAS  PubMed  Google Scholar 

  7. Crowley, M.P. et al. A population of murine gammadelta T cells that recognize an inducible MHC class Ib molecule. Science 287, 314–316 (2000).

    CAS  PubMed  Google Scholar 

  8. Wingren, C., Crowley, M.P., Degano, M., Chien, Y. & Wilson, I.A. Crystal structure of a gammadelta T cell receptor ligand T22: a truncated MHC-like fold. Science 287, 310–314 (2000).

    CAS  PubMed  Google Scholar 

  9. Willcox, C.R. et al. Cytomegalovirus and tumor stress surveillance by binding of a human gammadelta T cell antigen receptor to endothelial protein C receptor. Nat. Immunol. 13, 872–879 (2012).

    CAS  PubMed  Google Scholar 

  10. Constant, P. et al. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264, 267–270 (1994).

    CAS  PubMed  Google Scholar 

  11. Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human [gamma][delta] T cells. Nat. Immunol. 14, 908–916 (2013).

    CAS  PubMed  Google Scholar 

  12. Russano, A.M. et al. Recognition of pollen-derived phosphatidyl-ethanolamine by human CD1d-restricted gamma delta T cells. J. Allergy Clin. Immunol. 117, 1178–1184 (2006).

    CAS  PubMed  Google Scholar 

  13. Dieude, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted gammadelta T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011).

    CAS  PubMed  Google Scholar 

  14. Bai, L. et al. The majority of CD1d-sulfatide-specific T cells in human blood use a semiinvariant Vdelta1 TCR. Eur. J. Immunol. 42, 2505–2510 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Godfrey, D.I. & Rossjohn, J. New ways to turn on NKT cells. J. Exp. Med. 208, 1121–1125 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Girardi, E. et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat. Immunol. 13, 851–856 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Patel, O. et al. Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. Nat. Immunol. 13, 857–863 (2012).

    CAS  PubMed  Google Scholar 

  18. Xu, B. et al. Crystal structure of a gammadelta T-cell receptor specific for the human MHC class I homolog MICA. Proc. Natl. Acad. Sci. USA 108, 2414–2419 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Allison, T.J., Winter, C.C., Fournie, J.J., Bonneville, M. & Garboczi, D.N. Structure of a human gammadelta T-cell antigen receptor. Nature 411, 820–824 (2001).

    CAS  PubMed  Google Scholar 

  20. Li, H. et al. Structure of the Vdelta domain of a human gammadelta T-cell antigen receptor. Nature 391, 502–506 (1998).

    CAS  PubMed  Google Scholar 

  21. Adams, E.J., Chien, Y.H. & Garcia, K.C. Structure of a gammadelta T cell receptor in complex with the nonclassical MHC T22. Science 308, 227–231 (2005).

    CAS  PubMed  Google Scholar 

  22. Adams, E.J., Strop, P., Shin, S., Chien, Y.H. & Garcia, K.C. An autonomous CDR3delta is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by gammadelta T cells. Nat. Immunol. 9, 777–784 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wun, K.S. et al. A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR. J. Exp. Med. 205, 939–949 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kjer-Nielsen, L. et al. A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition. J. Exp. Med. 203, 661–673 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Borg, N.A. et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448, 44–49 (2007).

    CAS  PubMed  Google Scholar 

  26. Mallevaey, T. et al. A molecular basis for NKT cell recognition of CD1d-self-antigen. Immunity 34, 315–326 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Matulis, G. et al. Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop. PLoS Biol. 8, e1000402 (2010).

    PubMed  PubMed Central  Google Scholar 

  28. Pellicci, D.G. et al. Recognition of beta-linked self glycolipids mediated by natural killer T cell antigen receptors. Nat. Immunol. 12, 827–833 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Garcia, K.C. et al. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279, 1166–1172 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Godfrey, D.I., McCluskey, J. & Rossjohn, J. CD1d antigen presentation: treats for NKT cells. Nat. Immunol. 6, 754–756 (2005).

    CAS  PubMed  Google Scholar 

  32. Russano, A.M. et al. CD1-restricted recognition of exogenous and self-lipid antigens by duodenal gamma delta+ T lymphocytes. J. Immunol. 178, 3620–3626 (2007).

    CAS  PubMed  Google Scholar 

  33. Cerundolo, V., Silk, J.D., Masri, S.H. & Salio, M. Harnessing invariant NKT cells in vaccination strategies. Nat. Rev. Immunol. 9, 28–38 (2009).

    CAS  PubMed  Google Scholar 

  34. Wieland Brown, L.C. et al. Production of alpha-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol. 11, e1001610 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. Brennan, P.J. et al. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat. Immunol. 12, 1202–1211 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brigl, M. et al. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp. Med. 208, 1163–1177 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Nick, S. et al. T cell receptor gamma delta repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive gamma delta clones. Eur. J. Immunol. 25, 355–363 (1995).

    CAS  PubMed  Google Scholar 

  38. Matsuda, J.L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kedzierska, K., Turner, S.J. & Doherty, P.C. Conserved T cell receptor usage in primary and recall responses to an immunodominant influenza virus nucleoprotein epitope. Proc. Natl. Acad. Sci. USA 101, 4942–4947 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Szymczak, A.L. et al. Correction of multi-gene deficiency in vivo using a single ′self-cleaving′ 2A peptide-based retroviral vector. Nat. Biotechnol. 22, 589–594 (2004).

    CAS  PubMed  Google Scholar 

  41. Heemskerk, M.H. et al. Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102, 3530–3540 (2003).

    CAS  PubMed  Google Scholar 

  42. Shima, E.A. et al. Gene encoding the alpha chain of the T-cell receptor is moved immediately downstream of c-myc in a chromosomal 8;14 translocation in a cell line from a human T-cell leukemia. Proc. Natl. Acad. Sci. USA 83, 3439–3443 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Aricescu, A.R., Lu, W. & Jones, E.Y. A time- and cost-efficient system for high-level protein production in mammalian cells. Acta Crystallogr. D Biol. Crystallogr. 62, 1243–1250 (2006).

    PubMed  Google Scholar 

  44. Kabsch, W. XDS. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. McCoy, A.J. Solving structures of protein complexes by molecular replacement with Phaser. Acta Crystallogr. D Biol. Crystallogr. 63, 32–41 (2007).

    CAS  PubMed  Google Scholar 

  46. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Baker, N.A., Sept, D., Joseph, S., Holst, M.J. & McCammon, J.A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl. Acad. Sci. USA 98, 10037–10041 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Holst, M., Baker, N.A. & Wang, F. Adaptive multilevel finite element solution of the Poisson-Boltzmann equation I. Algorithms and examples. J. Comput. Chem. 21, 1319–1342 (2000).

    CAS  Google Scholar 

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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.

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Author notes

  1. Adam P Uldrich and Jérôme Le Nours: These authors contributed equally to this work.

  2. Jamie Rossjohn and Dale I Godfrey: These authors jointly directed this work.

Authors and 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.

Corresponding authors

Correspondence to Jamie Rossjohn or Dale I Godfrey.

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The authors declare no competing financial interests.

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Uldrich, A., Le Nours, J., Pellicci, D. et al. CD1d-lipid antigen recognition by the γδ TCR. Nat Immunol 14, 1137–1145 (2013). https://doi.org/10.1038/ni.2713

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