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.

  • Letter
  • Published:

Structure of a human γδ T-cell antigen receptor

Nature volume 411, pages 820–824 (2001)Cite this article

Abstract

T-cell antigen receptors composed of γ and δ polypeptide chains (γδTCRs) can directly recognize antigens in the form of intact proteins or non-peptide compounds, unlike αβTCRs, which recognize antigens bound to major histocompatibility complex molecules (MHC). About 5% of peripheral blood T cells bear γδTCRs, most of which recognize non-peptide phosphorylated antigens1,2. Here we describe the 3.1 Å resolution structure of a human γδTCR from a T-cell clone3 that is phosphoantigen-reactive. The orientation of the variable (V) and constant (C) regions of the γδTCR is unique when compared with αβTCRs or antibodies, and results from an unusually small angle between the Vγ and Cγ domains. The complementarity-determining regions (CDRs) of the V domains exhibit a chemically reasonable binding site for phosphorylated antigens, providing a possible explanation for the canonical usage of the Vγ9 and Vδ2 gene segments by phosphoantigen-reactive receptors. Although the γδTCR V domains are similar in overall structure to those of αβTCRs, γδTCR C domains are markedly different. Structural differences in Cγ and Cδ, and in the location of the disulphide bond between them, may enable γδTCRs to form different recognition/signalling complexes than αβTCRs.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Views of the G115 Vγ9Vδ2 TCR.
Figure 2: Overall structure of a γδTCR, αβTCR and Fabs.
Figure 3: Surface representations of G115.
Figure 4: Comparison of the γδTCR and αβTCR C domains.

Similar content being viewed by others

References

  1. Hayday, A. C. γδ cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18, 975–1026 (2000).

    Article  CAS  Google Scholar 

  2. Chien, Y. H., Jores, R. & Crowley, M. P. Recognition by γ/δ T cells. Annu. Rev. Immunol. 14, 511–532 (1996).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Rock, E. P., Sibbald, P. R., Davis, M. M. & Chien, Y. H. CDR3 length in antigen-specific immune receptors. J. Exp. Med. 179, 323–328 (1994).

    Article  CAS  Google Scholar 

  5. Sciammas, R. et al. Unique antigen recognition by a herpesvirus-specific TCR-γδ cell. J. Immunol. 152, 5392–5397 (1994).

    Article  CAS  Google Scholar 

  6. Morita, C. T. et al. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells. Immunity 3, 495–507 (1995).

    Article  CAS  Google Scholar 

  7. Lang, F. et al. Early activation of human Vγ9Vδ2 T cell broad cytotoxicity and TNF production by nonpeptidic mycobacterial ligands. J. Immunol. 154, 5986–5994 (1995).

    Article  CAS  Google Scholar 

  8. Davodeau, F. et al. Close correlation between Daudi and mycobacterial antigen recognition by human γδ T cells and expression of V9JPC1γ/V2DJCδ-encoded T cell receptors. J. Immunol. 151, 1214–1223 (1993).

    Article  CAS  Google Scholar 

  9. Fournié, J. J. & Bonneville, M. Stimulation of γδ T cells by phosphoantigens. Res. Immunol. 147, 338–347 (1996).

    Article  Google Scholar 

  10. Belmant, C. et al. 3-formyl-1-butyl pyrophosphate: a novel mycobacterial metabolite-activating human γδ T cells. J. Biol. Chem. 274, 32079–32084 (1999).

    Article  CAS  Google Scholar 

  11. Tanaka, Y., Morita, C. T., Nieves, E., Brenner, M. B. & Bloom, B. R. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375, 155–158 (1995).

    Article  ADS  CAS  Google Scholar 

  12. Bukowski, J. F., Morita, C. T. & Brenner, M. B. Human γδ T cells recognize alkylamines derived from microbes, edible plants, and tea: implications for innate immunity. Immunity 11, 57–65 (1999).

    Article  CAS  Google Scholar 

  13. Kunzmann, V. et al. Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 96, 384–392 (2000).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  15. Loh, E. Y. et al. Gene transfer studies of T cell receptor-γδ recognition. Specificity for staphylococcal enterotoxin A is conveyed by Vγ9 alone. J. Immunol. 152, 3324–3332 (1994).

    Article  CAS  Google Scholar 

  16. Li, H. et al. Three-dimensional structure of the complex between a T cell receptor β chain and the superantigen staphylococcal enterotoxin B. Immunity 9, 807–816 (1998).

    Article  CAS  Google Scholar 

  17. Morita, C. T. et al. Superantigen recognition by γδ T Cells: SEA recognition site for human Vγ2 T cell receptors. Immunity 14, 331–344 (2001).

    Article  CAS  Google Scholar 

  18. Belmant, C. et al. A chemical basis for selective recognition of nonpeptide antigens by human γδ T cells. FASEB J. 14, 1669–1670 (2000).

    Article  CAS  Google Scholar 

  19. Davodeau, F. et al. Peripheral selection of antigen receptor junctional features in a major human γδ subset. Eur. J. Immunol. 23, 804–808 (1993).

    Article  CAS  Google Scholar 

  20. Panchamoorthy, G. et al. A predominance of the T cell receptor Vγ2/Vδ2 subset in human mycobacteria-responsive T cells suggests germline gene encoded recognition. J. Immunol. 147, 3360–3369 (1991).

    Article  CAS  Google Scholar 

  21. Bentley, G. A., Boulot, G., Karjalainen, K. & Mariuzza, R. A. Crystal structure of the β chain of a T cell antigen receptor. Science 267, 1984–1987 (1995).

    Article  ADS  CAS  Google Scholar 

  22. Wang, J. et al. Atomic structure of an αβ T cell receptor (TCR) heterodimer in complex with an anti-TCR Fab fragment derived from a mitogenic antibody. EMBO J. 17, 10–26 (1998).

    Article  Google Scholar 

  23. Davodeau, F. et al. Secretion of disulfide-linked human T-cell receptor γδ heterodimers. J. Biol. Chem. 268, 15455–15460 (1993).

    Article  CAS  Google Scholar 

  24. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  Google Scholar 

  25. Smith, G. D., Nagar, B., Rini, J. M., Hauptman, H. A. & Blessing, R. H. The use of SnB to determine an anomalous scattering substructure. Acta Crystallogr. D 54, 799–804 (1998).

    Article  CAS  Google Scholar 

  26. de la Fortelle, E. & Bricogne, G. Maximum-likelihood heavy-atom parameter refinement for multiple isomorphous replacement and multiwavelength anomalous diffraction methods. Methods Enzymol. 276, 472–494 (1997).

    Article  CAS  Google Scholar 

  27. Bailey, S. The CCP4 suite—programs for protein crystallography. Acta Crystallogr D 50, 760–763 (1994).

    Article  Google Scholar 

  28. Kleywegt, G. J. & Jones, T. A. in From First Map to Final Model (eds. Bailey, S., Hubbard, R. & Waller, D.) 59–66 (SERC Daresbury Laboratory, Warrington, 1994).

    Google Scholar 

  29. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for binding protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  30. Brünger, A. T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998).

    Article  Google Scholar 

Download references

Acknowledgements

We thank C. Hammer for mass spectrometry; M. Garfield for amino-acid sequencing; S. Garman for advice and discussions; and Z. Dauter and K. R. Rajashankar for help at beamline X9B at the National Synchrotron Light Source at Brookhaven National Laboratory, which is supported by the US Department of Energy, Division of Materials Sciences and Division of Chemical Sciences. T.J.A. is supported by a postdoctoral fellowship from the Cancer Research Institute. This work is supported by the intramural program of the National Institute of Allergy and Infectious Diseases.

Author information

Authors and Affiliations

  1. Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, 12441 Parklawn Drive, Rockville, 20852, Maryland, USA

    Timothy J. Allison, Christine C. Winter & David N. Garboczi

  2. INSERM U395, CHU Purpan BP3028, Toulouse, 31024, France

    Jean-Jacques Fournié

  3. INSERM U463, Institut de Biologie, Nantes, 44035, France

    Marc Bonneville

Authors
  1. Timothy J. Allison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine C. Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Jacques Fournié
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc Bonneville
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David N. Garboczi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David N. Garboczi.

Supplementary information

Figure S1. (GIF 38 KB)

Comparison of the four domains of G115 with an αβTCR and an Fab. The Vδ, Vβ, Cδ, and Cβ domains of G115 (in red) are superimposed on to Vα, Vβ, Cα, Cβ TCR domains (top row, in green, 1qsf) and on to VL, VH, CL, CH Fab domains (bottom row, in blue, 8fab). Differences are highlighted (bold colors). Domains were aligned using 64 V- and 50 C-domain core residues (the Cδ:Cα alignment used only 20 residues). The r.m.s. deviations (in Å) over Cα atoms for each domain-domain pair are: Vδ:Vα 0.8, Vβ:Vβ 1.1, Cδ:Cα 0.8, Cβ:Cβ 1.0 and Vδ:VL 0.7 (with VH, 0.8), Vβ:VH 0.8 (with VL, 0.8), Cδ:CL 1.0, Cβ:CH 0.9. Comparisons with other αβTCRs and Fabs are similar.

Figure S2. (GIF 48 KB)

2Fo-Fc simulated annealing omit map for the FG loop of Cβ shows strong density for the entire loop and no density for the region occupied by the FG loop of Cβ. Backbone and side-chain atoms of Cβ are colored in red and pink, respectively; backbone atoms of a superimposed Cβ domain are shown in green. The map is contoured at 1.1δ with a cover radius of 2.3 Å.

Table 1 Data collection and model refinement statistics
Full size table

Rights and permissions

Reprints and permissions

About this article

Cite this article

Allison, T., Winter, C., Fournié, JJ. et al. Structure of a human γδ T-cell antigen receptor. Nature 411, 820–824 (2001). https://doi.org/10.1038/35081115

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35081115

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

Advanced 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