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Two-step binding mechanism for T-cell receptor recognition of peptide–MHC

Abstract

T cells probe a diverse milieu of peptides presented by molecules of the major histocompatibility complex (MHC) by using the T-cell receptor (TCR) to scan these ligands with high sensitivity and specificity1. Here we describe a physical basis for this scanning process by studying the residues involved in both the initial association and the stable binding of TCR to peptide–MHC, using the well-characterized TCR and peptide–MHC pair of 2B4 and MCC-IEk (moth cytochrome c, residues 88–103)2. We show that MHC contacts dictate the initial association, guiding TCR docking in a way that is mainly independent of the peptide. Subsequently, MCC-IEk peptide contacts dominate stabilization, imparting specificity and influencing T-cell activation by modulating the duration of binding. This functional subdivision of the peptide–MHC ligand suggests that a two-step process for TCR recognition facilitates the efficient scanning of diverse peptide–MHC complexes on the surface of cells and also makes TCRs inherently crossreactive towards different peptides bound by the same MHC.

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Figure 1: Binding of 2B4 TCR to wild-type MCC-IEk and selected point mutants in the peptide–MHC epitope, monitored by surface plasmon resonance (BIAcore).
Figure 2: Structures of MCC-IEk, showing the amino acid residues mutated in this study and their effects on TCR complex stability and association.
Figure 3: Model for TCR sampling of peptide–MHC (pMHC), showing formation of specific MHC and peptide contacts during the course of the binding reaction.

References

  1. Germain, R. N. & Stefanova, I. The dynamics of T cell receptor signalling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999)

    CAS  Article  Google Scholar 

  2. Davis, M. M. et al. Ligand recognition by αβ T cell receptors. Annu. Rev. Immunol. 16, 523–544 (1998)

    ADS  MathSciNet  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. Fremont, D. H. et al. Structural basis of cytochrome c presentation by IEk. J. Exp. Med. 195, 1043–1052 (2002)

    CAS  Article  Google Scholar 

  5. 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)

    CAS  Article  Google Scholar 

  6. Ehrich, E. W. et al. T cell receptor interactions with peptide/major histocompatibility complex (MHC) and superantigen/MHC ligands is dominated by antigen. J. Exp. Med. 178, 713–722 (1993)

    CAS  Article  Google Scholar 

  7. Reay, P., Kantor, R. M. & Davis, M. M. Use of global amino acid replacements to define the requirements for MHC binding and T cell recognition of moth cytochrome c (93–103). J. Immunol. 152, 3946–3957 (1994)

    CAS  PubMed  Google Scholar 

  8. Manning, T. C. et al. Alanine scanning mutagenesis of an αβ T cell receptor: mapping the energy of antigen recognition. Immunity 8, 413–425 (1998)

    CAS  Article  Google Scholar 

  9. Lee, P. U., Churchill, H. R., Daniels, M., Jameson, S. C. & Kranz, D. M. Role of 2C T cell receptor residues in the binding of self- and allo-major histocompatibility complexes. J. Exp. Med. 191, 1355–1364 (2000)

    CAS  Article  Google Scholar 

  10. Degano, M. et al. A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 12, 251–261 (2000)

    CAS  Article  Google Scholar 

  11. 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)

    ADS  CAS  Article  Google Scholar 

  12. Kersh, G. J., Kersh, E. N., Fremont, D. H. & Allen, P. M. High- and low-potency ligands with similar affinities for the TCR: the importance of kinetics in TCR signaling. Immunity 9, 817–826 (1998)

    CAS  Article  Google Scholar 

  13. Baker, B. M., Ding, Y.-H., Garboczi, D. N., Biddison, W. E. & Wiley, D. C. Structural, biochemical, and biophysical studies of HLA-A2/altered peptide ligands binding to viral-peptide-specific human T-cell receptors. Cold Spring Harb. Symp. Quant. Biol. 64, 235–241 (1999)

    CAS  Article  Google Scholar 

  14. Fersht, A. R. Nucleation steps in protein folding. Curr. Opin. Struct. Biol. 7, 3–9 (1997)

    CAS  Article  Google Scholar 

  15. Schreiber, G. & Fersht, A. R. Rapid electrostatically assisted association of proteins. Nature Struct. Biol. 3, 427–431 (1996)

    CAS  Article  Google Scholar 

  16. Davis, S. J., Davies, E. A., Tucknott, M. G., Jones, E. Y. & van der Merwe, P. A. The role of charged residues mediating low affinity protein-protein recognition at the cell surface by CD2. Proc. Natl Acad. Sci. USA 95, 5490–5494 (1998)

    ADS  CAS  Article  Google Scholar 

  17. Hare, B. J. et al. Structure, specificity, and CDR mobility of a class II restricted single-chain T cell receptor. Nature Struct. Biol. 6, 574–581 (1999)

    CAS  Article  Google Scholar 

  18. 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)

    CAS  Article  Google Scholar 

  19. 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)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  21. Mason, D. A very high level of cross-reactivity is an essential feature of the T-cell receptor. Immunol. Today 19, 395–404 (1998)

    CAS  Article  Google Scholar 

  22. Clackson, T. & Wells, J. A. A hot spot of binding energy in a hormone-receptor interface. Science 267, 383–386 (1995)

    ADS  CAS  Article  Google Scholar 

  23. Bevan, M. J. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature 269, 417–418 (1977)

    ADS  CAS  Article  Google Scholar 

  24. Zinkernagel, R. M. et al. On the thymus in the differentiation of ‘H-2 self-recognition’ by T cells: evidence for dual recognition? J. Exp. Med. 147, 882–896 (1978)

    CAS  Article  Google Scholar 

  25. Zerrahn, J., Held, W. & Raulet, D. H. The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636 (1997)

    CAS  Article  Google Scholar 

  26. Hennecke, J. & Wiley, D. C. Structure of a complex of the human α/β T cell receptor (TCR) HA1. (7), influenze hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity. J. Exp. Med. 195, 571–581 (2002)

    CAS  Article  Google Scholar 

  27. 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)

    CAS  Article  Google Scholar 

  28. Savage, P. A. & Davis, M. M. A kinetic window constricts the T cell receptor repertoire in the thymus. Immunity 14, 243–252 (2001)

    CAS  Article  Google Scholar 

  29. Tanchot, C., Lemonnier, F. A., Pérarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naïve or memory T cells. Science 276, 2057–2058 (1997)

    CAS  Article  Google Scholar 

  30. Kraulis, P. J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991)

    Article  Google Scholar 

Download references

Acknowledgements

We thank J. Boniface, C. Gerke, S. Hedrick, D. Herschlag, J. Huppa, M. Krogsgaard, M. Kuhns, Z. Reich, R. Sciammas and members of the Davis lab for discussions and comments on the manuscript; B. Malissen and D. Fremont for communicating results before publication; N. Prado for assistance with TCR production; and A. Cochran and H. Lowman for use of their BIAcore 2000. L.C.W. is a postdoctoral fellow of the Cancer Research Fund of the Damon Runyon Walter Winchell Foundation. D.S.L. was a Howard Hughes Medical Institute predoctoral fellow. This work was supported by the NIH (M.M.D. and K.C.G.), the Howard Hughes Medical Institute (M.M.D.), the Multiple Sclerosis Society (K.C.G.), and the Cancer Research Institute (K.C.G.).

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Correspondence to Mark M. Davis.

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Wu, L., Tuot, D., Lyons, D. et al. Two-step binding mechanism for T-cell receptor recognition of peptide–MHC. Nature 418, 552–556 (2002). https://doi.org/10.1038/nature00920

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