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Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction 'codon'

Nature Immunology volume 8, pages 975–983 (2007)Cite this article

Abstract

All complexes of T cell receptors (TCRs) bound to peptide–major histocompatibility complex (pMHC) molecules assume a stereotyped binding 'polarity', despite wide variations in TCR-pMHC docking angles. However, existing TCR-pMHC crystal structures have failed to show broadly conserved pairwise interaction motifs. Here we determined the crystal structures of two TCRs encoded by the variable β-chain 8.2 (Vβ8.2), each bound to the MHC class II molecule I-Au, and did energetic mapping of Vα and Vβ contacts with I-Au. Together with two previously solved structures of Vβ8.2-containing TCR-MHC complexes, we found four TCR–I-A complexes with structurally superimposable interactions between the Vβ loops and the I-A α-helix. This examination of a narrow 'slice' of the TCR-MHC repertoire demonstrates what is probably one of many germline-derived TCR-MHC interaction 'codons'.

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Figure 1: Structural overview of three experimental autoimmune encephalomyelitis–related TCRs in complex with I-Au–MBP1-11.
Figure 2: Superposition of 1934.4, cl19 and 172.10 complexes aligned on I-Au–MBP1-11.
Figure 3: Heterogeneous interactions of CDR1α and CDR2α loops with the I-Au β-helix.
Figure 4: Recognition 'codon' between Vβ8.2 and I-A.
Figure 5: Main-chain interactions dominate contacts between TCR CDR3 loops and MBP1-11.
Figure 6: Large CDR3 conformational changes in the bound versus free structures of 1934.4.
Figure 7: Effects of substitutions of CDR1 and CDR2 on the interactions of 1934.4 and 172.10 with IAu–MBP1-11.
Figure 8: Recurrent involvement of aromatic residues in the CDR2β recognition strategy of different MHC class I and class II helices.

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References

  1. 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 

  2. Buslepp, J., Wang, H., Biddison, W.E., Appella, E. & Collins, E.J. A correlation between TCR Vα docking on MHC and CD8 dependence: implications for T cell selection. Immunity 19, 595–606 (2003).

    Article  CAS  Google Scholar 

  3. Jerne, N.K. The somatic generation of immune recognition. Eur. J. Immunol. 1, 1–9 (1971).

    Article  CAS  Google Scholar 

  4. Blackman, M. et al. The T cell repertoire may be biased in favor of MHC recognition. Cell 47, 349–357 (1986).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Matsui, K. et al. Low affinity interaction of peptide-MHC complexes with T cell receptors. Science 254, 1788–1791 (1991).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. 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 

  9. Huseby, E.S. et al. How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005).

    Article  CAS  Google Scholar 

  10. Huseby, E.S., Crawford, F., White, J., Marrack, P. & Kappler, J.W. Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide. Nat. Immunol. 7, 1191–1199 (2006).

    Article  CAS  Google Scholar 

  11. Zamvil, S.S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579–621 (1990).

    Article  CAS  Google Scholar 

  12. Zamvil, S.S. et al. T cell specificity for class II (I-A) and the encephalitogenic N- terminal epitope of the autoantigen myelin basic protein. J. Immunol. 139, 1075–1079 (1987).

    CAS  PubMed  Google Scholar 

  13. Goverman, J. Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein. Immunol. Rev. 169, 147–159 (1999).

    Article  CAS  Google Scholar 

  14. Acha-Orbea, H. et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54, 263–273 (1988).

    Article  CAS  Google Scholar 

  15. Urban, J.L. et al. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell 54, 577–592 (1988).

    Article  CAS  Google Scholar 

  16. Maynard, J. et al. Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity 22, 81–92 (2005).

    CAS  PubMed  Google Scholar 

  17. 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 

  18. Pearson, C.I., van Ewijk, W. & McDevitt, H.O. Induction of apoptosis and T helper 2 (Th2) responses correlates with peptide affinity for the major histocompatibility complex in self- reactive T cell receptor transgenic mice. J. Exp. Med. 185, 583–599 (1997).

    Article  CAS  Google Scholar 

  19. Lafaille, J.J., Nagashima, K., Katsuki, M. & Tonegawa, S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78, 399–408 (1994).

    Article  CAS  Google Scholar 

  20. Goverman, J. et al. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72, 551–560 (1993).

    Article  CAS  Google Scholar 

  21. He, X.L. et al. Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immunodominant epitope of MBP complexed with I-Au. Immunity 17, 83–94 (2002).

    Article  CAS  Google Scholar 

  22. Maynard, J. et al. High-level bacterial secretion of single-chain αβ T-cell receptors. J. Immunol. Methods 306, 51–67 (2005).

    Article  CAS  Google Scholar 

  23. 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 

  24. Garcia, K.C., Radu, C.G., Ho, J., Ober, R.J. & Ward, E.S. Kinetics and thermodynamics of T cell receptor-autoantigen interactions in murine experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 98, 6818–6823 (2001).

    Article  CAS  Google Scholar 

  25. Cunningham, B.C. & Wells, J.A. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 244, 1081–1085 (1989).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Baker, B.M., Turner, R.V., Gagnon, S.J., Wiley, D.C. & Biddison, W.E. Identification of a crucial energetic footprint on the alpha1 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 

  29. 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 

  30. Colf, L.A. et al. How a single T cell receptor recognizes both self and foreign MHC. Cell 129, 135–146 (2007).

    Article  CAS  Google Scholar 

  31. Hennecke, J., Carfi, A. & Wiley, D.C. Structure of a covalently stabilized complex of a human αβ T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1. EMBO J. 19, 5611–5624 (2000).

    Article  CAS  Google Scholar 

  32. 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 

  33. 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 

  34. 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 

  35. 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 

  36. Mazza, C. et al. How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides? EMBO J. 26, 1972–1983 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Chothia, C. & Lesk, A.M. Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901–917 (1987).

    Article  CAS  Google Scholar 

  40. Mian, I.S., Bradwell, A.R. & Olson, A.J. Structure, function and properties of antibody binding sites. J. Mol. Biol. 217, 133–151 (1991).

    Article  CAS  Google Scholar 

  41. Fellouse, F.A. et al. Molecular recognition by a binary code. J. Mol. Biol. 348, 1153–1162 (2005).

    Article  CAS  Google Scholar 

  42. Al-Lazikani, B., Lesk, A.M. & Chothia, C. Canonical structures for the hypervariable regions of T cell αβ receptors. J. Mol. Biol. 295, 979–995 (2000).

    Article  CAS  Google Scholar 

  43. Otwinowski, Z., Minor, W. & Carter, C.W., Jr. in Methods in Enzymology Vol. 276 (eds. Abelson, J.N., Simon, M.I., Carter, C.W. Jr. & Sweet, R.M.) 307–326 (Academic, New York, 1997).

    Google Scholar 

  44. Vagin, A. & Teplyakov, A. MOLREP: an automated program for molecular replacement. J. Appl. Crystallogr. 30, 1022–1025 (1997).

    Article  CAS  Google Scholar 

  45. Li, H., Lebedeva, M.I., Ward, E.S. & Mariuzza, R.A. Dual conformations of a T cell receptor Vα homodimer: implications for variability in VαVβ domain association. J. Mol. Biol. 269, 385–394 (1997).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. Read, R. Pushing the boundaries of molecular replacement with maximum likelihood. Acta Crystallographica D Biol. Crystallogr. 57, 1373–1382 (2001).

    Article  CAS  Google Scholar 

  49. DeLano, W.L. The PyMol molecular graphics system. (DeLano Scientific, San Carlos, California, 2002).

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Acknowledgements

We acknowledge M. Davis for discussions and access to a BIAcore 3000. Supported by the National Institutes of Health (AI48540 to K.C.G.), the Howard Hughes Medical Institute (K.C.G.) and the National Health and Medical Research Council of Australia (CJ Martin Fellowship to L.K.E.).

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  1. Jennifer Maynard

    Present address: Present address: Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA.,

Authors and Affiliations

  1. Department of Molecular & Cellular Physiology, Department of Structural Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, 94305, California, USA

    Dan Feng, Christopher J Bond, Lauren K Ely, Jennifer Maynard & K Christopher Garcia

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D.F., X-ray crystallographic analyses; D.F., C.J.B, L.K.E. and J.M., biochemical and biophysical studies; and K.C.G., project direction.

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Correspondence to K Christopher Garcia.

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Feng, D., Bond, C., Ely, L. et al. Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction 'codon'. Nat Immunol 8, 975–983 (2007). https://doi.org/10.1038/ni1502

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