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.

  • Article
  • Published:

A structural basis for immunodominant human T cell receptor recognition

Nature Immunology volume 4, pages 657–663 (2003)Cite this article

Abstract

The anti-influenza CD8+ T cell response in HLA-A2–positive adults is almost exclusively directed at residues 58–66 of the virus matrix protein (MP(58–66)). Vβ17Vα10.2 T cell receptors (TCRs) containing a conserved arginine-serine-serine sequence in complementarity determining region 3 (CDR3) of the Vβ segment dominate this response. To investigate the molecular basis of immunodominant selection in an outbred population, we have determined the crystal structure of Vβ17Vα10.2 in complex with MP(58–66)–HLA-A2 at a resolution of 1.4 Å. We show that, whereas the TCR typically fits over an exposed side chain of the peptide, in this structure MP(58–66) exposes only main chain atoms. This distinctive orientation of Vβ17Vα10.2, which is almost orthogonal to the peptide-binding groove of HLA-A2, facilitates insertion of the conserved arginine in Vβ CDR3 into a notch in the surface of MP(58–66)–HLA-A2. This previously unknown binding mode underlies the immunodominant T cell response.

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: High-resolution crystal structure of the JM22–MP(58–66)– HLA-A2 complex.
Figure 2: Global features of the JM22–MP(58–66)–HLA-A2 interaction.
Figure 3: Key interactions conferring specificity and affinity in the JM22–MP(58–66)–HLA-A2 complex.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Gotch, F., Rothbard, J., Howland, K., Townsend, A. & McMichael, A. Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA A2. Nature 326, 881–882 (1987).

    Article  CAS  Google Scholar 

  2. Morrison, J. et al. Identification of the nonamer peptide from influenza A matrix protein and the role of pockets of HLA A2 in its recognition by cytotoxic T lymphocytes. Eur. J. Immunol. 22, 903–907 (1992).

    Article  CAS  Google Scholar 

  3. Moss, P.A. et al. Extensive conservation of α and β chains of the human T-cell antigen receptor recognizing HLA A2 and influenza A matrix peptide. Proc. Natl. Acad. Sci. USA 88, 8987–8990 (1991).

    Article  CAS  Google Scholar 

  4. Lehner, P.J. et al. Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the Vβ17 gene segment. J. Exp. Med. 181, 79–91 (1995).

    Article  CAS  Google Scholar 

  5. Lawson, T.M. et al. Influenza A antigen exposure selects dominant Vβ17+ TCR in human CD8+ cytotoxic T cell responses. Int. Immunol. 13, 1373–1381 (2001).

    Article  CAS  Google Scholar 

  6. Argaet, V.P. et al. Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein–Barr virus. J. Exp. Med. 180, 2335–2340 (1994).

    Article  CAS  Google Scholar 

  7. Burrows, S.R. et al. T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen. J. Exp. Med. 182, 1703–1715 (1995).

    Article  CAS  Google Scholar 

  8. Man, S., Ridge, J.P. & Engelhard, V.H. Diversity and dominance among TCR recognizing HLA A2.1+ influenza matrix peptide in human MHC class I transgenic mice. J. Immunol. 153, 4458–4467 (1994).

    CAS  PubMed  Google Scholar 

  9. Yewdell, J.W. & Bennink, J.R. Immunodominance in major histocompatibility complex class I–restricted T lymphocyte responses. Annu. Rev. Immunol. 17, 51–88 (1999).

    Article  CAS  Google Scholar 

  10. Man, S. et al. Definition of a human T cell epitope from influenza A non-structural protein 1 using HLA A2.1 transgenic mice. Int. Immunol. 7, 597–605 (1995).

    Article  CAS  Google Scholar 

  11. Willcox, B.E. et al. TCR binding to peptide-MHC stabilizes a flexible recognition interface. Immunity 10, 357–365 (1999).

    Article  CAS  Google Scholar 

  12. Madden, D.R., Garboczi, D.N. & Wiley, D.C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA A2. Cell 19, 693–708 (1993).

    Article  Google Scholar 

  13. Garcia, K.C. et al. An αβ T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 274, 209–219 (1996).

    Article  CAS  Google Scholar 

  14. Garboczi, D.N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA A2. Nature 384, 134–141 (1996).

    Article  CAS  Google Scholar 

  15. Rudolph, M.G., Luz, J.G. & Wilson, I.A. Structural and thermodynamic correlates of T cell signaling. Annu. Rev. Biophys. Biomol. Struct. 31, 121–149 (2002).

    Article  CAS  Google Scholar 

  16. Reinherz, E.L. et al. The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286, 1913–1921 (1999).

    Article  CAS  Google Scholar 

  17. Ding, Y.H., Baker, B.M., Garboczi, D.N., Biddison, W.E. & Wiley, D.C. Two human T cell receptors bind in a similar diagonal mode to the HLA A2/Tax peptide complex using different TCR amino acids. Immunity 8, 403–411 (1998).

    Article  CAS  Google Scholar 

  18. Reiser, J.B. et al. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nat. Immunol. 1, 291–297 (2000).

    Article  CAS  Google Scholar 

  19. Kjer-Nielsen, L. et al. A structural basis for the selection of dominant αβ T cell receptors in antiviral immunity. Immunity 18, 53–64 (2003).

    Article  CAS  Google Scholar 

  20. Garboczi, D.N., Madden, D.R. & Wiley, D.C. Five viral peptide-HLA A2 co-crystals. Simultaneous space group determination and X-ray data collection. J. Mol. Biol. 239, 581–587 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Kissinger, C.R., Gehlhaar D.K. & Fogel, D.B. Rapid automated molecular replacement by evolutionary search. Acta Crystallogr. D 55, 484–491 (1999).

    Article  CAS  Google Scholar 

  23. Brunger, A.T. et al. Crystallography and NMR System: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  25. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

  26. Lawrence, M.C. & Colman, P.M. Shape complementarity at protein/protein interfaces J. Mol. Biol. 234, 946–950 (1993).

    Article  CAS  Google Scholar 

  27. Hubbard, S.J. & Thornton, J.M. 'NACCESS' computer program version 2.1.1 (Univ. College London, London, 1996).

    Google Scholar 

  28. Esnouf, R.M. Further additions to MolScript version 1.4, including reading and contouring of electron-density maps. Acta Crystallogr. D 55, 938–940 (1999).

    Article  CAS  Google Scholar 

  29. Merrit, E.A. & Murphy, M.E.P. Raster3D version 2.0: a program for photorealistic molecular graphics. Acta Crystallogr. D 50, 869–873 (1994).

    Article  Google Scholar 

  30. Sayle R.A. & Milner-White, E.J. RasMol: biomolecular graphics for all. Trends Biochem. Sci. 20, 374–376 (1995).

    Article  CAS  Google Scholar 

  31. Humphrey, W., Dalke, A. & Schulten, K. VMD—visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Harlos and the staff of the ESRF and the European Molecular Biology Laboratory outstation at Grenoble for assistance with data collection. This work was funded by the MRC. D.I.S. is an MRC Research Professor and E.Y.J. is a Cancer Research UK Principal Research Fellow.

Author information

Authors and Affiliations

  1. Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford, OX3 7BN, UK

    Guillaume B E Stewart-Jones, David I Stuart & E Yvonne Jones

  2. Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK

    Andrew J McMichael & John I Bell

  3. Office of the Regius Professor of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK

    John I Bell

Authors
  1. Guillaume B E Stewart-Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew J McMichael
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John I Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David I Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Yvonne Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Yvonne Jones.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart-Jones, G., McMichael, A., Bell, J. et al. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol 4, 657–663 (2003). https://doi.org/10.1038/ni942

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni942

This article is cited by

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