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Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor

Abstract

Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide–major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.

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Figure 1: Unconventional binding site for a human autoreactive TCR on its peptide-MHC target.
Figure 2: Footprint of the Ob.1A12 TCR on the MBP peptide-DR2 surface.
Figure 3: TCR CDR3 loops create a large cavity for histidine residues from peptide and MHC.
Figure 4: Relationship between structure and function.
Figure 5: Differences in peptide recognition by the Ob.1A12 and HA1.7 TCRs.
Figure 6: MHC contacts made by the Ob.1A12 and HA1.7 TCRs.
Figure 7: Consequence of altered topology on the geometry of CD4 coreceptor engagement.

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References

  1. Steinman, L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85, 299–302 (1996).

    CAS  Google Scholar 

  2. Davis, M.M. & Chien, Y.-H. T-cell antigen receptors. in Fundamental Immunology (ed. Paul, W.E.) 227–258 (Lippincott Williams & Wilkins, Philadelphia, 2003).

    Google Scholar 

  3. Kisielow, P., Teh, H.S., von Bluthmann, H. & Boehmer, H. Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 335, 730–733 (1988).

    CAS  Google Scholar 

  4. Kappler, J.W., Roehm, N. & Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280 (1987).

    CAS  Google Scholar 

  5. Alam, S.M. et al. T-cell-receptor affinity and thymocyte positive selection. Nature 381, 616–620 (1996).

    CAS  Google Scholar 

  6. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2, 1032–1039 (2001).

    CAS  Google Scholar 

  7. The Finnish-German APECED Consortium. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17, 399–403 (1997).

  8. Anderson, M.S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

    CAS  Google Scholar 

  9. Harrington, C.J. et al. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 8, 571–580 (1998).

    CAS  Google Scholar 

  10. Anderson, A.C. et al. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191, 761–770 (2000).

    CAS  Google Scholar 

  11. Wucherpfennig, K.W. et al. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J. Exp. Med. 179, 279–290 (1994).

    CAS  Google Scholar 

  12. Pribyl, T.M., Campagnoni, C., Kampf, K., Handley, V.W. & Campagnoni, A.T. The major myelin protein genes are expressed in the human thymus. J. Neurosci. Res. 45, 812–819 (1996).

    CAS  Google Scholar 

  13. Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).

    CAS  Google Scholar 

  14. Garboczi, D.N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).

    CAS  Google Scholar 

  15. 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).

    CAS  Google Scholar 

  16. 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  Google Scholar 

  17. 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).

    CAS  Google Scholar 

  18. 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).

    CAS  Google Scholar 

  19. 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).

    CAS  Google Scholar 

  20. 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  Google Scholar 

  21. Reiser, J.B. et al. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nat. Immunol. 1, 291–297 (2000).

    CAS  Google Scholar 

  22. Sun, R. et al. Evidence that the antigen receptors of cytotoxic T lymphocytes interact with a common recognition pattern on the H-2Kb molecule. Immunity 3, 573–582 (1995).

    CAS  Google Scholar 

  23. Rudolph, M.G., Luz, J.G. & Wilson, I.A. Structural and thermodynamic correlates of T cell signaling. Annu. Rev. Biophys. Biomol. Struct. 31, 121–149 (2002).

    CAS  Google Scholar 

  24. 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).

    CAS  Google Scholar 

  25. Wucherpfennig, K.W. et al. Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide. J. Immunol. 152, 5581–5592 (1994).

    CAS  Google Scholar 

  26. Ota, K. et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346, 183–187 (1990).

    CAS  Google Scholar 

  27. Pette, M. et al. Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors. Proc. Natl. Acad. Sci. USA 87, 7968–7972 (1990).

    CAS  Google Scholar 

  28. Krogsgaard, M. et al. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85–99 complex. J. Exp. Med. 191, 1395–1412 (2000).

    CAS  Google Scholar 

  29. Madsen, L.S. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat. Genet. 23, 343–347 (1999).

    CAS  Google Scholar 

  30. Hausmann, S., Martin, M., Gauthier, L. & Wucherpfennig, K.W. Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition. J. Immunol. 162, 338–344 (1999).

    CAS  Google Scholar 

  31. Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998).

    CAS  Google Scholar 

  32. 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  Google Scholar 

  33. Wang, J.H. et al. Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc. Natl. Acad. Sci. USA 98, 10799–10804 (2001).

    CAS  Google Scholar 

  34. Sim, B.C., Zerva, L., Greene, M.I. & Gascoigne, N.R. Control of MHC restriction by TCR Vα CDR1 and CDR2. Science 273, 963–966 (1996).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  36. Busch, D.H. & Pamer, E.G. T cell affinity maturation by selective expansion during infection. J. Exp. Med. 189, 701–710 (1999).

    CAS  Google Scholar 

  37. Appel, H., Gauthier, L., Pyrdol, J. & Wucherpfennig, K.W. Kinetics of T-cell receptor binding by bivalent HLA-DR peptide complexes that activate antigen-specific human T-cells. J. Biol. Chem. 275, 312–321 (2000).

    CAS  Google Scholar 

  38. Monks, C.R., Freiberg, B.A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).

    CAS  Google Scholar 

  39. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).

    CAS  Google Scholar 

  40. Ehrlich, L.I., Ebert, P.J., Krummel, M.F., Weiss, A. & Davis, M.M. Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation. Immunity 17, 809–822 (2002).

    CAS  Google Scholar 

  41. Richie, L.I. et al. Imaging synapse formation during thymocyte selection: inability of CD3ζ to form a stable central accumulation during negative selection. Immunity 16, 595–606 (2002).

    CAS  Google Scholar 

  42. Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    CAS  Google Scholar 

  43. 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  Google Scholar 

  44. Smith, K.J., Pyrdol, J., Gauthier, L., Wiley, D.C. & Wucherpfennig, K.W. Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J. Exp. Med. 188, 1511–1520 (1998).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    Google Scholar 

  47. Sundberg, E.J. et al. Structures of two streptococcal superantigens bound to TCR beta chains reveal diversity in the architecture of T cell signaling complexes. Structure (Camb.) 10, 687–699 (2002).

    CAS  Google Scholar 

  48. 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).

    CAS  Google Scholar 

  49. 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).

    Google Scholar 

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Acknowledgements

This paper is dedicated to the memory of D.C. Wiley. We thank V. Stojanoff, M. Allaire (beamline X6A), A. Soares, D. Schneider (beamline X12B), A. Saxena and H. Robinson (beamline X29) at Brookhaven National Laboratories for support; M. Eck for access to X-ray facilities at the Dana-Farber Cancer Institute; K. Arnett, M. Call and S. Turley for reading the manuscript; T. Springer and T. Xiao for help and advice in evaluating Fluidigm crystallization chips; D. Zaller for the S2 cell line expressing HLA-DM; and L. Stern and K.C. Garcia for discussions. Supported by the National Institutes of Health (AI045757 and AI064177 to K.W.W.).

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Correspondence to Kai W Wucherpfennig.

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Supplementary Fig. 1

Ribbon diagram of the structure of the complex composed of HLA-DR2 (blue), peptide (green), Ob.1A12 TCR Vα domain (yellow) as well as Ob.1A12 TCR Vβ and Cβ domains (red). (PDF 260 kb)

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Hahn, M., Nicholson, M., Pyrdol, J. et al. Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol 6, 490–496 (2005). https://doi.org/10.1038/ni1187

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