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Influence of a dominant cryptic epitope on autoimmune T cell tolerance

Nature Immunology volume 3, pages 175–181 (2002)Cite this article

Abstract

The rules governing which T cells are inactivated during peptide-induced tolerance are unclear. Here we show that MBP(89–101) contains three overlapping but distinct T cell epitopes that are restricted by a single major histocompatibility complex (MHC) class II molecule. The dominant epitope is not processed from MBP and is not relevant to the induction of autoimmunity. Pathogenic T cells recognize two minor epitopes that are processed from MBP but are presented only poorly after exposure to MBP(89–101). Induction of immunological tolerance by MBP(89–101) therefore inactivates T cells that recognize the dominant epitope and disease-relevant T cells escape tolerance. The topology of the three epitopes implicates asparagine endopeptidase as the enzyme that controls recognition of this region of MBP. Our results highlight the need to use peptides that mimic the binding of processed antigen fragments to MHC molecules for successful modulation of disease-relevant T cells.

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Figure 1: Generation and epitopes specificity of MBP(89–101)-reactive TCLs.
Figure 2: Identification of three T cell epitopes in the MBP(89–101) sequence.
Figure 3: T cell responsiveness to MBP is determined by epitope recognition.
Figure 4: T cell clones derived from mice immunized with MBP(89–101) recognize the MBP(92–98) epitope and fail to respond to intact MBP.
Figure 5: The MBP(92–98) epitope is not generated after immunization with intact MBP.
Figure 6: Only naturally processed MBP epitopes induce EAE.
Figure 7: The complexity of T cell epitope recognition in the MBP(89–101) sequence.
Figure 8: The MBP(89–101) peptide fails to induce tolerance to T cells that recognize the MBP(89–94) epitope.

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References

  1. Watts, C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu. Rev. Immunol. 15, 821–850 (1997).

    Article  CAS  Google Scholar 

  2. Sercarz, E. E. et al. Dominance and crypticity of T cell antigenic determinants. Annu. Rev. Immunol. 11, 729–766 (1993).

    Article  CAS  Google Scholar 

  3. Sakai, K. et al. Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J. Neuroimmunol. 19, 21–32 (1988).

    Article  CAS  Google Scholar 

  4. Zamvil, S. S. et al. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature 324, 258–260 (1986).

    Article  CAS  Google Scholar 

  5. Chou, Y. K., Vandenbark, A. A., Jones, R. E., Hashim, G. & Offner, H. Selection of encephalitogenic rat T-lymphocyte clones recognizing an immunodominant epitope on myelin basic protein. J. Neurosci. Res. 22, 181–187 (1989).

    Article  CAS  Google Scholar 

  6. Kono, D. H. et al. Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice. J. Exp. Med. 168, 213–227 (1988).

    Article  CAS  Google Scholar 

  7. Offner, H. et al. T cell determinants of myelin basic protein include a unique encephalitogenic I-E-restricted epitope for Lewis rats. J. Exp. Med. 170, 355–367 (1989).

    Article  CAS  Google Scholar 

  8. Tuohy, V. K., Lu, Z., Sobel, R. A., Laursen, R. A. & Lees, M. B. Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. J. Immunol. 142, 1523–1527 (1989).

    CAS  PubMed  Google Scholar 

  9. Martin, R. & McFarland, H. F. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit. Rev. Clin. Lab. Sci. 32, 121–182 (1995).

    Article  CAS  Google Scholar 

  10. Wraith, D. C., Smilek, D. E., Mitchell, D. J., Steinman, L. & McDevitt, H. O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59, 247–255 (1989).

    Article  CAS  Google Scholar 

  11. Metzler, B. & Wraith, D. C. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int. Immunol. 5, 1159–1165 (1993).

    Article  CAS  Google Scholar 

  12. Liu, G. Y. & Wraith, D. C. Affinity for class II MHC determines the extent to which soluble peptides tolerize autoreactive T cells in naive and primed adult mice—implications for autoimmunity. Int. Immunol. 7, 1255–1263 (1995).

    Article  CAS  Google Scholar 

  13. Anderton, S. M. & Wraith, D. C. Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin. Eur. J. Immunol. 28, 1251–1261 (1998).

    Article  CAS  Google Scholar 

  14. Karin, N., Mitchell, D. J., Brocke, S., Ling, N. & Steinman, L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon γ and tumor necrosis factor α production. J. Exp. Med. 180, 2227–2237 (1994).

    Article  CAS  Google Scholar 

  15. Brocke, S. et al. Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature 379, 343–346 (1996).

    Article  CAS  Google Scholar 

  16. Viner, N. J., Nelson, C. A., Deck, B. & Unanue, E. R. Complexes generated by the binding of free peptides to class II MHC molecules are antigenically diverse compared with those generated by intracellular processing. J. Immunol. 156, 2365–2368 (1996).

    CAS  PubMed  Google Scholar 

  17. Nelson, C. A., Viner, N. J. & Unanue, E. R. Appreciating the complexity of MHC class II peptide binding: lysozyme peptide and I-Ak. Immunol. Rev. 151, 81–105 (1996).

    Article  CAS  Google Scholar 

  18. Gaur, A. et al. Amelioration of relapsing experimental autoimmune encephalomyelitis with altered myelin basic protein peptides involves different cellular mechanisms. J. Neuroimmunol. 74, 149–158 (1997).

    Article  CAS  Google Scholar 

  19. Wauben, M. H. et al. Inhibition of experimental autoimmune encephalomyelitis by MHC class II binding competitor peptides depends on the relative MHC binding affinity of the disease-inducing peptide. J. Immunol. 152, 4211–4220 (1994).

    CAS  PubMed  Google Scholar 

  20. Franco, A. et al. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur. J. Immunol. 24, 940–946 (1994).

    Article  CAS  Google Scholar 

  21. Anderton, S. M., Kissler, S., Lamont, A. G. & Wraith, D. C. Therapeutic potential of TCR antagonists is determined by their ability to modulate a diverse repertoire of autoreactive T cells. Eur. J. Immunol. 29, 1850–1857 (1999).

    Article  CAS  Google Scholar 

  22. Sakai, K. et al. Involvement of distinct murine T-cell receptors in the autoimmune encephalitogenic response to nested epitopes of myelin basic protein. Proc. Natl Acad. Sci. USA 85, 8608–8612 (1988).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Martin, R. et al. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J. Immunol. 145, 540–548 (1990).

    CAS  Google Scholar 

  25. Valli, A. et al. Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class-II molecules and their recognition by T cells from multiple sclerosis patients. J. Clin. Invest. 91, 616–628 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6, 1167–1175 (2000).

    Article  CAS  Google Scholar 

  28. Kappos L. et al. Induction of a non-encephalitogenic type 2 helper T cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomised phase II trial. Nature Med. 6, 1176–1182 (2000).

    Article  CAS  Google Scholar 

  29. Bodmer, H., Viville, S., Benoist, C. & Mathis, D. Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. Science 263, 1284–1286 (1994).

    Article  CAS  Google Scholar 

  30. Inaba, K. et al. The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro. J. Exp. Med. 180, 1849–1860 (1994).

    Article  CAS  Google Scholar 

  31. Vremec, D. & Shortman, K. Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. J. Immunol. 159, 565–573 (1997).

    CAS  Google Scholar 

  32. Summers, K. L., Hock, B. D., McKenzie, J. L. & Hart, D. N. Phenotypic characterization of five dendritic cell subsets in human tonsils. Am. J. Pathol. 159, 285–295 (2001).

    Article  CAS  Google Scholar 

  33. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  Google Scholar 

  34. Metzler, B., Anderton, S. M., Manickasingham, S. P. & Wraith, D. C. Kinetics of peptide uptake and tissue distribution following a single intranasal dose of peptide. Immunol. Invest. 29, 61–70 (2000).

    Article  CAS  Google Scholar 

  35. Moudgil, K. D., Sercarz, E. E. & Grewal, I. S. Modulation of the immunogenicity of antigenic determinants by their flanking residues. Immunol. Today 19, 217–220 (1998).

    Article  CAS  Google Scholar 

  36. Anderton, S. M., van der Zee, R., Prakken, B., Noordzij, A. & van Eden, W. Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J. Exp. Med. 181, 943–952 (1995).

    Article  CAS  Google Scholar 

  37. Fairchild, P. J., Pope, H. & Wraith, D. C. The nature of cryptic epitopes within the self-antigen myelin basic protein. Int. Immunol. 8, 1035–1043 (1996).

    Article  CAS  Google Scholar 

  38. Yu, M., Johnson, J. M. & Tuohy, V. K. A preditable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. J. Exp. Med. 183, 1777–1788 (1996).

    Article  CAS  Google Scholar 

  39. Cross, A. H., Hashim, G. A. & Raine, C. S. Adoptive transfer of experimental allergic encephalomyelitis and localization of the encephalitogenic epitope in the SWR mouse. J. Neuroimmunol. 31, 59–66 (1991).

    Article  CAS  Google Scholar 

  40. Manoury, B. et al. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 396, 695–699 (1998).

    Article  CAS  Google Scholar 

  41. Antoniou, A. N., Blackwood, S. L., Mazzeo, D. & Watts, C. Control of antigen presentation by a single protease cleavage site. Immunity 12, 391–398 (2000).

    Article  CAS  Google Scholar 

  42. Manoury, B. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in myelin basic protein. Nature Immunol. 3 10.1038/ni754 (2002).

  43. Hemmer, B. et al. Human T-cell response to myelin basic protein peptide (83–99): extensive heterogeneity in antigen recognition, function, and phenotype. Neurology 49, 1116–1126 (1997).

    Article  CAS  Google Scholar 

  44. Martin, R. et al. Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87–106. J. Immunol. 148, 1359–1366 (1992).

    CAS  PubMed  Google Scholar 

  45. Jones, P. P., Murphy, D. B. & McDevitt, H. O. Variable synthesis and expression of Eα and Ae (Eβ) Ia polypeptide chains in mice of different H-2 haplotypes. Immunogenetics 12, 321–337 (1981).

    Article  CAS  Google Scholar 

  46. Mathis, D. J., Benoist, C., Williams, V. E., Kanter, M. & McDevitt, H. O. Several mechanisms can account for defective Eα gene expression in different mouse haplotypes. Proc. Natl Acad. Sci. USA 80, 273–277 (1983).

    Article  CAS  Google Scholar 

  47. Bates, I. R. et al. Characterization of a recombinant murine 18.5-kDa myelin basic protein. Protein Expres. Purif. 20, 285–299 (2000).

    Article  CAS  Google Scholar 

  48. Anderton, S. M. et al. Fine specificity of the myelin-reactive T cell repertoire: implications for TCR antagonism in autoimmunity. J. Immunol. 161, 3357–3364 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Wellcome Trust and the Medical Research Council (MRC). S. M. A. is an MRC research fellow.

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Authors and Affiliations

  1. University of Edinburgh, Institute of Cell, Animal and Population Biology, King's Buildings, West Mains Road, Edinburgh, EH9 3JT, UK

    Stephen M. Anderton

  2. Department of Pathology and Microbiology, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK

    Nicholas J. Viner, Philip Matharu, Pauline A. Lowrey & David C. Wraith

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Correspondence to Stephen M. Anderton.

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Anderton, S., Viner, N., Matharu, P. et al. Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nat Immunol 3, 175–181 (2002). https://doi.org/10.1038/ni756

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