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.

T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide

Abstract

Unusually long major histocompatibility complex (MHC) class I–restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to αβ T cell receptor (TCR)–MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B*3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR–peptide–MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR–MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Overview of the SB27 TCR in complex with HLA-B*3508–LPEP.
Figure 2: SB27 TCR contacts at the interface.
Figure 3: The SB27 CTL clone is both MHC restricted and alloreactive with HLA-B*4402, with which it shares structural features in the region of the TCR footprint.
Figure 4: SB27 TCR recognition of the HLA-B*3508–LPEP complex is antibody like and is dominated by TCR-peptide interactions.
Figure 5: The SB27 TCR–HLA-B*3508–LPEP complex forms a TCR 'superdimer' with two subtly different TCR–pMHC-I orientations.

Accession codes

Accessions

Protein Data Bank

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Rammensee, H.G., Falk, K. & Rotzschke, O. Peptides naturally presented by MHC class I molecules. Annu. Rev. Immunol. 11, 213–244 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Zinkernagel, R.M. & Doherty, P.C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–702 (1974).

    Article  CAS  PubMed  Google Scholar 

  4. Garboczi, D.N. & Biddison, W.E. Shapes of MHC restriction. Immunity 10, 1–7 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Rudolph, M.G. & Wilson, I.A. The specificity of TCR/pMHC interaction. Curr. Opin. Immunol. 14, 52–65 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. 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  PubMed  Google Scholar 

  8. 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  PubMed  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. Hahn, M., Nicholson, M.J., Pyrdol, J. & Wucherpfennig, K.W. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol. 6, 490–496 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fremont, D.H., Matsumura, M., Stura, E.A., Peterson, P.A. & Wilson, I.A. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science 257, 919–927 (1992).

    Article  CAS  PubMed  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 75, 693–708 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, W., Young, A.C., Imarai, M., Nathenson, S.G. & Sacchettini, J.C. Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. Proc. Natl. Acad. Sci. USA 89, 8403–8407 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goldberg, A.L., Cascio, P., Saric, T. & Rock, K.L. The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol. Immunol. 39, 147–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Momburg, F., Neefjes, J.J. & Hammerling, G.J. Peptide selection by MHC-encoded TAP transporters. Curr. Opin. Immunol. 6, 32–37 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Fruci, D. et al. Quantifying recruitment of cytosolic peptides for HLA class I presentation: impact of TAP transport. J. Immunol. 170, 2977–2984 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Serwold, T., Gonzalez, F., Kim, J., Jacob, R. & Shastri, N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419, 480–483 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. York, I.A. et al. The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nat. Immunol. 3, 1177–1184 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Horig, H., Young, A.C., Papadopoulos, N.J., DiLorenzo, T.P. & Nathenson, S.G. Binding of longer peptides to the H-2Kb heterodimer is restricted to peptides extended at their C terminus: refinement of the inherent MHC class I peptide binding criteria. J. Immunol. 163, 4434–4441 (1999).

    CAS  PubMed  Google Scholar 

  20. Guo, H.C. et al. Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle. Nature 360, 364–366 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Chen, Y. et al. Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations. J. Immunol. 152, 2874–2881 (1994).

    CAS  PubMed  Google Scholar 

  22. Urban, R.G. et al. A subset of HLA-B27 molecules contains peptides much longer than nonamers. Proc. Natl. Acad. Sci. USA 91, 1534–1538 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Speir, J.A., Stevens, J., Joly, E., Butcher, G.W. & Wilson, I.A. Two different, highly Exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. Immunity 14, 81–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Probst-Kepper, M. et al. Conformational restraints and flexibility of 14-meric peptides in complex with HLA-B*3501. J. Immunol. 173, 5610–5616 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Green, K.J. et al. Potent T cell response to a class I-binding 13-mer viral epitope and the influence of HLA micropolymorphism in controlling epitope length. Eur. J. Immunol. 34, 2510–2519 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Collins, E., Garboczi, D., Karpusas, M. & Wiley, D. The three-dimensional structure of a class I major histocompatibility complex molecule missing the α3 domain of the heavy chain. Proc. Natl. Acad. Sci. USA 92, 1218–1221 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zavala-Ruiz, Z., Strug, I., Walker, B.D., Norris, P.J. & Stern, L.J. A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition. Proc. Natl. Acad. Sci. USA 101, 13279–13284 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Probst-Kepper, M. et al. An alternative open reading frame of the human macrophage colony-stimulating factor gene is independently translated and codes for an antigenic peptide of 14 amino acids recognized by tumor-infiltrating CD8 T lymphocytes. J. Exp. Med. 193, 1189–1198 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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  PubMed  Google Scholar 

  31. Garcia, K.C., Teyton, L. & Wilson, I.A. Structural basis of T cell recognition. Annu. Rev. Immunol. 17, 369–397 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. 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  PubMed  Google Scholar 

  34. Bourcier, K.D. et al. Conserved CDR3 regions in T-cell receptor (TCR) CD8+ T cells that recognize the TAX11–19/HLA-A*0201 complex in a subject infected with human T-cell leukemia virus type 1: relationship of T-cell fine specificity and major histocompatibility complex/peptide/tcr crystal structure. J. Virol. 75, 9836–9843 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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  PubMed  Google Scholar 

  36. 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 

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

    Article  CAS  PubMed  Google Scholar 

  38. 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  PubMed  Google Scholar 

  39. 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  PubMed  Google Scholar 

  40. 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  PubMed  PubMed Central  Google Scholar 

  41. 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  PubMed  PubMed Central  Google Scholar 

  42. Baxter, T.K. et al. Strategic mutations in the class I major histocompatibility complex HLA-A2 independently affect both peptide binding and T cell receptor recognition. J. Biol. Chem. 279, 29175–29184 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. 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  PubMed  Google Scholar 

  44. Macdonald, W.A. et al. A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition. J. Exp. Med. 198, 679–691 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Davies, D.R. & Cohen, G.H. Interactions of protein antigens with antibodies. Proc. Natl. Acad. Sci. USA 93, 7–12 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tormo, J. et al. Crystal structure of a human rhinovirus neutralizing antibody complexed with a peptide derived from viral capsid protein VP2. EMBO J. 13, 2247–2256 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Krogsgaard, M. et al. Evidence that structural rearrangements and/or flexibility during TCR binding can contribute to T cell activation. Mol. Cell 12, 1367–1378 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Sim, B.C., Lo, D. & Gascoigne, N.R. Preferential expression of TCR Vα regions in CD4/CD8 subsets: class discrimination or co-receptor recognition? Immunol. Today 19, 276–282 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Krogsgaard, M. et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238–243 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Irvine, D.J., Purbhoo, M.A., Krogsgaard, M. & Davis, M.M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Purbhoo, M.A., Irvine, D.J., Huppa, J.B. & Davis, M.M. T cell killing does not require the formation of a stable mature immunological synapse. Nat. Immunol. 5, 524–530 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Jin, L. & Wells, J.A. Dissecting the energetics of an antibody-antigen interface by alanine shaving and molecular grafting. Protein Sci. 3, 2351–2357 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bass, S.H., Mulkerrin, M.G. & Wells, J.A. A systematic mutational analysis of hormone-binding determinants, in the human growth hormone receptor. Proc. Natl. Acad. Sci. USA 88, 4498–4502 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Claverie, J.M. & Kourilsky, P. The peptidic self model: a reassessment of the role of the major histocompatibility complex molecules in the restriction of the T-cell response. Ann. Inst. Pasteur Immunol. 137D, 425–442 (1986).

    CAS  PubMed  Google Scholar 

  56. 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  PubMed  Google Scholar 

  57. 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. D 58, 2131–2134 (2002).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Storoni, L.C., McCoy, A.J. & Read, R.J. Likelihood-enhanced fast rotation functions. Acta Crystallogr D Biol Crystallogr. D 60, 432–438 (2004).

    Article  Google Scholar 

  60. Murshudov, G.N., Vagin, A.A. & Dodson, E.J. Refinement of molecular structures by maximum-likelihood method. Acta Crystallogr D Biol Crystallogr D 53, 240–255 (1997).

    Article  CAS  Google Scholar 

  61. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard . 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  PubMed  Google Scholar 

  62. Winn, M.D., Isupov, M.N. & Murshudov, G.N. Use of TLS parameters to model anisotropic displacements in macromolecular refinement. Acta Crystallogr D Biol Crystallogr D 57, 122–133 (2001).

    Article  CAS  Google Scholar 

  63. Salter, R.D. & Cresswell, P. Impaired assembly and transport of HLA-A and -B antigens in a mutant TxB cell hybrid. EMBO J. 5, 943–949 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Alexander, J., Payne, J.A., Murray, R., Frelinger, J.A. & Cresswell, P. Differential transport requirements of HLA and H-2 class I glycoproteins. Immunogenetics 29, 380–388 (1989).

    Article  CAS  PubMed  Google Scholar 

  65. 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  PubMed  Google Scholar 

  66. Lefranc, M.P. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. 29, 207–209 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank A. Brooks and D. El-hassen for discussions and reagents; P. Doherty, F. Carbone and S. Turner for critical reading of the manuscript; and the BioCars staff for assistance in data collection at Advanced Photon Source (Chicago, Illinois). J.R. and J.M. are joint senior authors. Supported by the National Health and Medical Research Council Australia, Roche Organ Transplantation Research Fund, Australian Research Council, National Health and Medical Research Council Career Development Award (S.B.), National Health and Medical Research Council Peter Doherty Training Fellowship (T.B.) and Wellcome Trust (J.R.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to James McCluskey or Jamie Rossjohn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Contacts at the TCD-pMHC interface for complex B. (PDF 108 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tynan, F., Burrows, S., Buckle, A. et al. T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide. Nat Immunol 6, 1114–1122 (2005). https://doi.org/10.1038/ni1257

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1257

This article is cited by

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