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A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule

Nature Immunology volume 8, pages 268–276 (2007)Cite this article

Abstract

Plasticity of the T cell receptor (TCR) is a hallmark of major histocompatibility complex (MHC)–restricted T cell recognition. However, it is unclear whether interactions of TCR and peptide–MHC class I (pMHCI) always conform to this paradigm. Here we describe the structure of a TCR, ELS4, in its non-ligand-bound form and in complex with a prominent 'bulged' Epstein-Barr virus peptide bound to HLA-B*3501. This complex was atypical of previously characterized TCR-pMHCI interactions in that a rigid face of the TCR crumpled the bulged antigenic determinant. This peptide 'bulldozing' created a more featureless pMHCI determinant, allowing the TCR to maximize MHC class I contacts essential for MHC class I restriction of TCR recognition. Our findings represent a mechanism of antigen recognition whereby the plasticity of the T cell response is dictated mainly by adjustments in the MHC-bound peptide.

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Figure 1: Structure of the ELS4–HLA-B*3501–EPLP complex.
Figure 2: TCR 'footprint' on pMHCI molecules.
Figure 3: CDR loop interactions with pMHCI.
Figure 4: Deformed peptide conformation upon TCR ligation.
Figure 5: HLA-B*3501–EPLP versus HLA-B*3508–EPLP.

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References

  1. Unanue, E.R. & Allen, P.M. The basis for the immunoregulatory role of macrophages and other accessory cells. Science 236, 551–557 (1987).

    Article  CAS  Google Scholar 

  2. Townsend, A. & Bodmer, H. Antigen recognition by class I-restricted T lymphocytes. Annu. Rev. Immunol. 7, 601–624 (1989).

    Article  CAS  Google Scholar 

  3. Bjorkman, P.J. et al. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329, 512–518 (1987).

    Article  CAS  Google Scholar 

  4. Arstila, T.P. et al. A direct estimate of the human T cell receptor diversity. Science 286, 958–961 (1999).

    Article  CAS  Google Scholar 

  5. Maverakis, E., van den Elzen, P. & Sercarz, E.E. Self-reactive T cells and degeneracy of T cell recognition: evolving concepts–from sequence homology to shape mimicry and TCR flexibility. J. Autoimmun. 16, 201–209 (2001).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. Reiser, J.-B. et al. A T cell receptor CDR3β loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex. Immunity 16, 345–354 (2002).

    Article  CAS  Google Scholar 

  8. 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 

  9. Wu, L.C., Tuot, D.S., Lyons, D.S., Garcia, K.C. & Davis, M.M. Two-step binding mechanism for T-cell receptor recognition of peptide-MHC. Nature 418, 552–556 (2002).

    Article  CAS  Google Scholar 

  10. 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 

  11. Reiser, J.B. et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 4, 241–247 (2003).

    Article  CAS  Google Scholar 

  12. Borg, N.A. et al. The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide-MHC recognition. Nat. Immunol. 6, 171–180 (2005).

    Article  CAS  Google Scholar 

  13. Boniface, J.J., Reich, Z., Lyons, D.S. & Davis, M.M. Thermodynamics of T cell receptor binding to peptide–MHC: Evidence for a general mechanism of molecular scanning. Proc. Natl. Acad. Sci. USA 96, 11446–11451 (1999).

    Article  CAS  Google Scholar 

  14. Housset, D. & Malissen, B. What do TCR-pMHC crystal structures teach us about MHC restriction and alloreactivity? Trends Immunol. 24, 429–437 (2003).

    Article  CAS  Google Scholar 

  15. Ding, Y.-H., Baker, B.M., Garboczi, D.N., Biddison, W.E. & Wiley, D.C. Four A6-TCR/peptide/HLA-A2 structures that generate very different T cell signals are nearly identical. Immunity 11, 45–56 (1999).

    Article  CAS  Google Scholar 

  16. Chen, J.-L. et al. Structural and kinetic basis for heightened immunogenicity of T cell vaccines. J. Exp. Med. 201, 1243–1255 (2005).

    Article  CAS  Google Scholar 

  17. Luz, J.G. et al. Structural comparison of allogeneic and syngeneic T cell receptor-peptide-major histocompatibility complex complexes: a buried alloreactive mutation subtly alters peptide presentation substantially increasing Vβ Interactions. J. Exp. Med. 195, 1175–1186 (2002).

    Article  CAS  Google Scholar 

  18. van der Merwe, P.A. & Davis, S.J. Molecular interactions mediating T cell antigen recognition. Annu. Rev. Immunol. 21, 659–684 (2003).

    Article  CAS  Google Scholar 

  19. 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 

  20. Ding, Y.-H. et al. 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 

  21. 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 75, 693–708 (1993).

    Article  CAS  Google Scholar 

  22. Burrows, S.R., Rossjohn, J. & McCluskey, J. Have we cut ourselves too short in mapping CTL epitopes? Trends Immunol. 27, 11–16 (2006).

    Article  CAS  Google Scholar 

  23. Tynan, F.E. et al. T cell receptor recognition of a 'super-bulged' major histocompatability complex class I-bound peptide. Nat. Immunol. 6, 1114–1122 (2005).

    Article  CAS  Google Scholar 

  24. Miles, J.J. et al. CTL Recognition of a bulged viral peptide involves biased TCR selection. J. Immunol. 175, 3826–3834 (2005).

    Article  CAS  Google Scholar 

  25. Stewart-Jones, G.B., McMichael, A.J., Bell, J.I., Stuart, D.I. & Jones, E.Y. A structural basis for immunodominant human T cell receptor recognition. Nat. Immunol. 4, 657–663 (2003).

    Article  CAS  Google Scholar 

  26. Rudolph, M.G., Stanfield, R.L. & Wilson, I.A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466 (2006).

    Article  CAS  Google Scholar 

  27. Tynan, F.E. et al. High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I: implications for T-cell receptor engagement and T-cell immunodominance. J. Biol. Chem. 280, 23900–23909 (2005).

    Article  CAS  Google Scholar 

  28. Turner, S.J., Doherty, P.C., McCluskey, J. & Rossjohn, J. Structural determinants of T-cell receptor bias in immunity. Nat. Rev. Immunol. 6, 883–894 (2006).

    Article  CAS  Google Scholar 

  29. Lefranc, M.P. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. 31, 307–310 (2003).

    Article  CAS  Google Scholar 

  30. Kjer-Nielsen, L. et al. The 1.5 Å crystal structure of a highly selected antiviral T cell receptor provides evidence for a structural basis of immunodominance. Structure 10, 1521–1532 (2002).

    Article  CAS  Google Scholar 

  31. Webb, A.I. et al. The structure of H-2Kb and Kbm8 complexed to a herpes simplex virus determinant: evidence for a conformational switch that governs T cell repertoire selection and viral resistance. J. Immunol. 173, 402–409 (2004).

    Article  CAS  Google Scholar 

  32. Krogsgaard, M. & Davis, M.M. How T cells 'see' antigen. Nat. Immunol. 6, 239–245 (2005).

    Article  CAS  Google Scholar 

  33. Baker, B.M., Turner, R.V., Gagnon, S.J., Wiley, D.C. & Biddison, W.E. Identification of a crucial energetic footprint on the α1 helix of human histocompatibility leukocyte antigen (HLA)-A2 that provides functional interactions for recognition by tax peptide/HLA-A2-specific T cell receptors. J. Exp. Med. 193, 551–562 (2001).

    Article  CAS  Google Scholar 

  34. Davis-Harrison, R.L., Armstrong, K.M. & Baker, B.M. Two different T cell receptors use different thermodynamic strategies to recognize the same peptide/MHC ligand. J. Mol. Biol. 346, 533–550 (2005).

    Article  CAS  Google Scholar 

  35. Ely, L.K. et al. Disparate thermodynamics governing T cell receptor-MHC-I interactions implicate extrinsic factors in guiding MHC restriction. Proc. Natl. Acad. Sci. USA 103, 6641–6646 (2006).

    Article  CAS  Google Scholar 

  36. Davis, M.M. The problem of plain vanilla peptides. Nat. Immunol. 4, 649–650 (2003).

    Article  CAS  Google Scholar 

  37. Turner, S.J. et al. Lack of prominent peptide-major histocompatibility complex features limits repertoire diversity in virus-specific CD8+ T cell populations. Nat. Immunol. 6, 382–389 (2005).

    Article  CAS  Google Scholar 

  38. Miles, J.J. et al. TCRα genes direct MHC restriction in the potent human T cell response to a class I-bound viral epitope. J. Immunol. 177, 6804–6814 (2006).

    Article  CAS  Google Scholar 

  39. Clements, C.S. et al. The production, purification and crystallisation of a soluble, heterodimeric form of a highly selected T-cell receptor in its unliganded and liganded state. Acta Crystallogr. D Biol. Crystallogr. 58, 2131–2134 (2002).

    Article  Google Scholar 

  40. Boulter, J.M. et al. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng. 16, 707–711 (2003).

    Article  CAS  Google Scholar 

  41. Macdonald, W. et al. Identification of a dominant self-ligand bound to three HLA B44 alleles and the preliminary crystallographic analysis of recombinant forms of each complex. FEBS Lett. 527, 27–32 (2002).

    Article  CAS  Google Scholar 

  42. 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 

  43. Leslie, A.G.W. Recent changes to the MOSFLM package for processing film and image plate data. Joint CCP4 + ESF-EAMCB Newsletter on Protein Crystallography 26 (1992).

  44. Collaborative. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).

  45. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  Google Scholar 

  46. Humphrey, W., Dalke, A. & Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).

    Article  CAS  Google Scholar 

  47. Ferrieu, C., Ballester, B., Mathieu, J. & Drouet, E. Flow cytometry analysis of γ-radiation-induced Epstein-Barr virus reactivation in lymphocytes. Radiat. Res. 159, 268–273 (2003).

    Article  CAS  Google Scholar 

  48. Williamson, N.A. & Purcell, A.W. Use of proteomics to define targets of T-cell immunity. Expert Rev. Proteomics 2, 367–380 (2005).

    Article  CAS  Google Scholar 

  49. Purcell, A.W. et al. Quantitative and qualitative influences of tapasin on the class I peptide repertoire. J. Immunol. 166, 1016–1027 (2001).

    Article  CAS  Google Scholar 

  50. Tynan, F.E. et al. The immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation. J. Exp. Med. 202, 1249–1260 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the staff of Advanced Photon Source of the Industrial Macromolecular Crystallography Association for assistance in data collection, and D. El-Hassen for reagents. Supported by the Australian Research Council (Federation Fellowship to J.R.) and National Health and Medical Research Council (Peter Doherty Fellowship to N.A.B. and T.B.; Senior Research Fellowship to S.R.B. and to M.C.W.) and by grants from the Roche Organ Transplant Research Fund, the National Health and Medical Research Council and the Australian Research Council.

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  1. Fleur E Tynan and Hugh H Reid: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, School of Biomedical Sciences, Monash University, Clayton, 3800, Victoria, Australia

    Fleur E Tynan, Hugh H Reid, Matthew C J Wilce, Natalie A Borg, Travis Beddoe & Jamie Rossjohn

  2. Department of Microbiology & Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Lars Kjer-Nielsen, Lyudmila Kostenko & James McCluskey

  3. Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, 4029, Australia

    John J Miles & Scott R Burrows

  4. Department of Biochemistry, University of Melbourne, Parkville, 3010, Victoria, Australia

    Nicholas A Williamson & Anthony W Purcell

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Contributions

F.E.T. and H.H.R. did experiments, interpreted data and helped prepare the manuscript; L.K.-N., J.J.M., M.C.J.W., L.K., N.A.B., N.A.W., T.B., A.W.P. and S.R.B. did experiments and interpreted data; and S.R.B., J.M., J.R. conceived experiments, interpreted data, supervised the project and helped prepare the manuscript.

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Correspondence to James McCluskey or Jamie Rossjohn.

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Tynan, F., Reid, H., Kjer-Nielsen, L. et al. A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nat Immunol 8, 268–276 (2007). https://doi.org/10.1038/ni1432

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