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Crystal structure of a T cell receptor bound to an allogeneic MHC molecule

Nature Immunology volume 1, pages 291–297 (2000)Cite this article

An Erratum to this article was published on 01 November 2000

Abstract

Many T cell receptors (TCRs) that are selected to respond to foreign peptide antigens bound to self major histocompatibility complex (MHC) molecules are also reactive with allelic variants of self-MHC molecules. This property, termed alloreactivity, causes graft rejection and graft-versus-host disease. The structural features of alloreactivity have yet to be defined. We now present a basis for this cross-reactivity, elucidated by the crystal structure of a complex involving the BM3.3 TCR and a naturally processed octapeptide bound to the H-2Kb allogeneic MHC class I molecule. A distinguishing feature of this complex is that the eleven-residue-long complementarity-determining region 3 (CDR3) found in the BM3.3 TCRα chain folds away from the peptide binding groove and makes no contact with the bound peptide, the latter being exclusively contacted by the BM3.3 CDR3β. Our results formally establish that peptide-specific, alloreactive TCRs interact with allo-MHC in a register similar to the one they use to contact self-MHC molecules.

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Figure 1: The affinity of BM3.3 scFv TCR binding to the pBM1–H-2Kb alloantigen.
Figure 2: Structure of the BM3.3–pBM1–H-2Kb complex.
Figure 3: Peptide-TCR interactions occurring at the interface of four TCR-pMHC class I complexes.
Figure 4: Identification of pBMI amino acids critical for BM3.3 transgenic TCR recognition.
Figure 5: Docking of TCRs to pMHC class I ligands.

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References

  1. Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402 , 255–262 (1999).

    Article  CAS  Google Scholar 

  2. 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 

  3. 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 

  4. 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, 1–20 ( 1998).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Rock E. P., Sibbald, P. R., Davis, M. M. & Chien, Y. CDR3 length in antigen-specific immune receptors. J. Exp. Med. 179, 323–328 (1994).

    Article  CAS  Google Scholar 

  7. Guimezanes, A., Schumacher, T. N. M., Ploegh, H. L. & Schmitt-Verhulst, A.-M. A viral peptide can mimic an endogeneous peptide for allorecognition of a major histocompatibility complex class I product. Eur. J. Immunol . 22, 1651–1654 ( 1992).

    Article  CAS  Google Scholar 

  8. Daniel, C., Horvath, S. & Allen, P. M. A basis for alloreactivity: MHC helical residues broaden peptide recognition by the TCR. Immunity 8, 543–552.

  9. Speir, J. A. et al. Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes. Immunity 8, 553–562 (1998).

    Article  CAS  Google Scholar 

  10. Wang, J. et al. Atomic structure of an αβ T cell receptor (TCR) heterodimer in complex with an anti-TCR Fab fragment derived from a mitogenic antibody . EMBO J. 17, 10–26 (1998).

    Article  Google Scholar 

  11. Young, A. C., Zhang, W., Sacchettini, J. C. & Nathenson, S. G. The three-dimensional structure of H-2Db at 2.4Å resolution: implications for antigen-determinant selection. Cell 76, 39–50 (1994).

    Article  CAS  Google Scholar 

  12. Braden, B. C., Goldman, E. R., Mariuzza, R. A. & Poljak, R. J. Anatomy of an antibody molecule: structure, kinetics, thermodynamics and mutational studies of the anti lysozyme antibody D1.3. Immunol. Rev. 163, 45–57 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Merkenschlager, M. et al. How many thymocytes audition for selection? J. Exp. Med. 186, 1149–1158 (1997).

    Article  CAS  Google Scholar 

  15. Jouvin-Marche, E. et al. Genomic organization of the mouse T cell receptor Vα family. EMBO J. 9, 2141– 2150 (1990).

    Article  CAS  Google Scholar 

  16. 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  Google Scholar 

  17. Malissen, M. et al. A T cell clone expresses two T cell receptor α genes but uses one αβ heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell 55, 49– 59 (1988).

    Article  CAS  Google Scholar 

  18. Bevan, M. J. High determinant density may explain the phenomenon of alloreactivity Immunol. Today 5, 128– 130 (1984).

    CAS  Google Scholar 

  19. Matzinger, P. & Bevan, M. J. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell. Immunol. 29, 1–5 (1977).

    Article  CAS  Google Scholar 

  20. Albert, F., Boyer, C., Buferne, M. & Schmitt-Verhulst, A.-M. Interaction between MHC-encoded products and cloned T cells. II. Analyses of physiological requirements indicate two different pathways of stimulation by class I alloantigens . Immunogenetics 19, 279– 294 (1984).

    Article  CAS  Google Scholar 

  21. Pullen, J. K., Horton, R. M., Cai, Z. & Pease, L. R. Structural diversity of the classical H-2 genes: K, D, and L. J. Immunol. 148, 953–967 (1992).

    CAS  PubMed  Google Scholar 

  22. Little, M. T. & Storb, R. The future of allogeneic stem cell transplantation: minimizing pain, maximizing gain. J. Clin. Invest. 105, 1679–1681 ( 2000).

    Article  CAS  Google Scholar 

  23. Obst, R., Netuschil, N., Klopfer, K., Stevanovic, S. & Rammensee, H. G. The role of peptides in T cell alloreactivity is determined by self-major histocompatibility complex molecules . J. Exp. Med. 191, 805– 812 (2000).

    Article  CAS  Google Scholar 

  24. Couez, D., Malissen M., Buferne, M., Schmitt-Verhulst, A. M. & Malissen, B. Each of the two productive T cell receptor α-gene rearrangements found in both the A10 and BM3-3 T cell clones give rise to an α chain which can contribute to the constitution of a surface-expressed αβ dimer. Int. Immunol. 3, 719– 729 (1991).

    Article  CAS  Google Scholar 

  25. Grégoire, C., Malissen, B. & Mazza, G. Characterization of T cell receptor single-chain Fv fragments secreted by myeloma cells. Eur. J. Immunol. 26, 2410–2416 (1996).

    Article  Google Scholar 

  26. Zhang, W., Young, A. C. M., 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Wlodawer, A. & Hodgson, K. O. Crystallization and crystal data of monellin. Proc. Natl Acad. Sci. USA 72, 398–399 (1975).

    Article  CAS  Google Scholar 

  29. Leslie, A. G. W. in Crystallographic Computing (eds Moras, D., Podjarny, A. D. & Thierry, J. C.) 50–60 (Oxford Univ. Press, 1991).

    Google Scholar 

  30. Computational Project Number 4, CCP4, The CCP4 Suite: Programs for Protein Crystallography. Acta Cryst. D50, 760 (1994).

  31. Navaza, J. AMoRe: an automated package for molecular replacement. Acta Cryst. A50, 157–163 ( 1994).

    Article  CAS  Google Scholar 

  32. Housset, D. et al. The three-dimensional structure of a T-cell antigen receptor Vα Vβ heterodimer reveals a novel arrangement of the Vβ domain . EMBO J. 16, 4205–4216 (1997).

    Article  CAS  Google Scholar 

  33. Fremont, D. H., Stura, E. A., Matsumura, M., Peterson, P. A. & Wilson, I. A. Crystal structure of an H-2Kb-ovalbumin peptide complex reveals the interplay of primary and secondary anchor positions in the major histocompatibility complex binding groove. Proc. Natl Acad. Sci. USA 92, 2479– 2483 (1995).

    Article  CAS  Google Scholar 

  34. 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 Cryst. A47, 110– 119 (1991).

    Article  CAS  Google Scholar 

  35. Hubbard, S. J. & Thornton, J. P. “NACCESS” Computer Program, Department of Biochemistry and Molecular Biology, University College London (1993).

  36. Nicholls, A., Scharp, K. A. & Honig, B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins Struct. Funct. Genet. 11, 281–296 (1991).

    Article  CAS  Google Scholar 

  37. 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 

  38. Merrit, E. A. & Bacon, D. J. Raster 3D: photorealistic molecular graphics. Meth. Enzymol. 277, 505– 524 (1997).

    Article  Google Scholar 

Download references

Acknowledgements

We thank S. Nathenson for the pET-3a Kb and pET-3a B2m plasmids; P. A. van der Merwe for advice on surface plasmon resonance; P. Fourquet for peptide synthesis; J.Bonicel for mass spectrometry analysis; L. Leserman, J. Howard and P. Golstein for comments on the manuscript, W. Burmeister for help with synchrotron data collection at ESFR ID4eh3 beamline and N. Guglietta for editing the manuscript. T. M. was supported by a fellowship from ARC. This work was supported by institutional grants from CNRS, CEA, INSERM and a specific grant from ARC.

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Authors and Affiliations

  1. Laboratoire de Cristallographie et Cristallogénèse des Protéines, Institut de Biologie Structurale J.-P. Ebel, CEA-CNRS-UJF , 41, rue Jules Horowitz, Grenoble, Cedex 1, F-38027, France

    Jean-Baptiste Reiser, Claudine Darnault, Juan Carlos Fontecilla-Camps & Dominique Housset

  2. Centre d'Immunologie INSERM-CNRS de Marseille-Luminy , Case 906, Marseille, Cedex 9, F-13288, France

    Annick Guimezanes, Claude Grégoire, Thomas Mosser, Anne-Marie Schmitt-Verhulst, Bernard Malissen & Gilbert Mazza

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  1. Jean-Baptiste Reiser
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Correspondence to Dominique Housset.

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Reiser, JB., Darnault, C., Guimezanes, A. et al. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule . Nat Immunol 1, 291–297 (2000). https://doi.org/10.1038/79728

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