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Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice

Nature Medicine volume 10, pages 920–926 (2004)Cite this article

Abstract

Thyroid autoimmune disorders comprise more than 30% of all organ-specific autoimmune diseases and are characterized by autoantibodies and infiltrating T cells. The pathologic role of infiltrating T cells is not well defined. To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope. Here we show that mouse major histocompatibility complex molecules sustain selection and activation of the transgenic T cells, as coexpression of histocompatibility leukocyte antigen molecules was not needed. Furthermore, the transgenic T cells had an activated phenotype in vivo, and mice spontaneously developed destructive thyroiditis with histological, clinical and hormonal signs comparable with human autoimmune hypothyroidism. These results highlight the pathogenic role of human T cells specific for cryptic self epitopes. This new 'humanized' model will provide a unique tool to investigate how human pathogenic self-reactive T cells initiate autoimmune diseases and to determine how autoimmunity can be modulated in vivo.

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Figure 1: Generation of TAZ10 transgenic mice in a CBA genetic background.
Figure 2: TCR+ Rag1−/− T cells are specific for TPO536–547 and are restricted by H2-Ak.
Figure 3: Molecular modeling of TPO536–547 complexed to mouse and human MHC.
Figure 4: Activation markers on peripheral T cells from transgenic mice.
Figure 5: Clinical and hormonal signs of thyroiditis in TCR+ Rag1−/− mice.
Figure 6: Histological changes in thyroiditis.

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References

  1. Jacobson, D.L., Gange, S.J., Rose, N.R. & Graham, N.M. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84, 223–243 (1997).

    Article  CAS  Google Scholar 

  2. Dayan, C. & Daniels, G. Chronic autoimmune thyroiditis. N. Engl. J. Med. 335, 99–107 (1996).

    Article  CAS  Google Scholar 

  3. Weetman, A.P. Determinants of autoimmune thyroid disease. Nat. Immunol. 2, 769–770 (2001).

    Article  CAS  Google Scholar 

  4. Walker, L.S. & Abbas, A.K. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat. Rev. Immunol. 2, 11–19 (2002).

    Article  CAS  Google Scholar 

  5. Jordan, M.S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

  6. Manoury, B. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat. Immunol. 3, 169–174 (2002).

    Article  CAS  Google Scholar 

  7. Anderton, S.M., Viner, N.J., Matharu, P., Lowrey, P.A. & Wraith, D.C. Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nat. Immunol. 3, 175–181 (2002).

    Article  CAS  Google Scholar 

  8. Dayan, C. et al. Autoantigen recognition by thyroid-infiltrating T cells in Graves's disease. Proc. Natl. Acad. Sci. USA 88, 7415–7419 (1991).

    Article  CAS  Google Scholar 

  9. Quaratino, S., Feldmann, M., Dayan, C.M., Acuto, O. & Londei, M. Human self-reactive T cell clones expressing identical T cell receptor β chains differ in their ability to recognize a cryptic self-epitope. J. Exp. Med. 183, 349–358 (1996).

    Article  CAS  Google Scholar 

  10. Quaratino, S., Thorpe, C.J., Travers, P.J. & Londei, M. Similar antigenic surfaces, rather than sequence homology, dictate T-cell epitope molecular mimicry. Proc. Natl. Acad. Sci. USA 92, 10398–10402 (1995).

    Article  CAS  Google Scholar 

  11. Quaratino, S., Duddy, L.P. & Londei, M. Fully competent dendritic cells as inducers of T cell anergy in autoimmunity. Proc. Natl. Acad. Sci. USA 97, 10911–10916 (2000).

    Article  CAS  Google Scholar 

  12. Londei, M., Bottazzo, G.F. & Feldmann, M. Human T-cell clones from autoimmune thyroid glands: specific recognition of autologous thyroid cells. Science 228, 85–89 (1985).

    Article  CAS  Google Scholar 

  13. Viney, J.L. et al. Analysis of T cell repertoire and function in mice transgenic for the human V β 3 TCR. Int. Immunol. 5, 1541–1549 (1993).

    Article  CAS  Google Scholar 

  14. Lacorazza, H.D., Tucek-Szabo, C., Vasovic, L.V., Remus, K. & Nikolich-Zugich, J. Premature TCR α β expression and signaling in early thymocytes impair thymocyte expansion and partially block their development. J. Immunol. 166, 3184–3193 (2001).

    Article  CAS  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).

    Article  CAS  Google Scholar 

  17. Germain, R.N. et al. “Exon-shuffling” maps control of antibody- and T-cell-recognition sites to the NH2-terminal domain of the class II major histocompatibility polypeptide A β. Proc. Natl. Acad. Sci. USA 82, 2940–2944 (1985).

    Article  CAS  Google Scholar 

  18. Siebold, C. et al. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc. Natl. Acad. Sci. USA 101, 1999–2004 (2004).

    Article  CAS  Google Scholar 

  19. Fremont, D.H., Monnaie, D., Nelson, C.A., Hendrickson, W.A. & Unanue, E.R. Crystal structure of I-Ak in complex with a dominant epitope of lysozyme. Immunity 8, 305–317 (1998).

    Article  CAS  Google Scholar 

  20. Chen, K., Wei, Y., Sharp, G.C. & Braley-Mullen, H. Inhibition of TGFβ1 by anti-TGFβ1 antibody or lisinopril reduces thyroid fibrosis in granulomatous experimental autoimmune thyroiditis. J. Immunol. 169, 6530–6538 (2002).

    Article  CAS  Google Scholar 

  21. Panciera, D. Conditions associated with canine hypothyroidism. Vet. Clin. North Am. Small Anim. Pract. 31, 935–950 (2001).

    Article  CAS  Google Scholar 

  22. Wick, G. et al. The obese strain of chickens: an animal model with spontaneous autoimmune thyroiditis. Adv. Immunol. 47, 433–500 (1989).

    Article  CAS  Google Scholar 

  23. Wortsman, J., Rosner, W. & Dufau, M.L. Abnormal testicular function in men with primary hypothyroidism. Am. J. Med. 82, 207–212 (1987).

    Article  CAS  Google Scholar 

  24. Becks, G.P. & Burrow, G.N. Thyroid disease and pregnancy. Med. Clin. North Am. 75, 121–150 (1991).

    Article  CAS  Google Scholar 

  25. Stassi, G. & De Maria, R. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat. Rev. Immunol 2, 195–204 (2002).

    Article  CAS  Google Scholar 

  26. Verma, S. et al. Role of MHC class I expression and CD8+ T cells in the evolution of iodine-induced thyroiditis in NOD-H2h4 and NOD mice. Eur. J. Immunol. 30, 1191–1202 (2000).

    Article  CAS  Google Scholar 

  27. Chen, K., Wei, Y., Sharp, G.C. & Braley-Mullen, H. Mechanisms of spontaneous resolution versus fibrosis in granulomatous experimental autoimmune thyroiditis. J. Immunol. 171, 6236–6243 (2003).

    Article  CAS  Google Scholar 

  28. Lechler, R.I. et al. Structural and functional studies of HLA-DR restricted antigen recognition by human helper T lymphocyte clones by using transfected murine cell lines. J. Immunol. 141, 3003–3009 (1988).

    CAS  PubMed  Google Scholar 

  29. Ignatowicz, L. et al. T cells can be activated by peptides that are unrelated in sequence to their selecting peptide. Immunity 7, 179–186 (1997).

    Article  CAS  Google Scholar 

  30. Podolin, P.L. et al. I-E+ nonobese diabetic mice develop insulitis and diabetes. J. Exp. Med. 178, 793–803 (1993).

    Article  CAS  Google Scholar 

  31. Cucca, F. et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum. Mol. Genet. 10, 2025–2037 (2001).

    Article  CAS  Google Scholar 

  32. Lee, K.H., Wucherpfennig, K.W. & Wiley, D.C. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat. Immunol. 2, 501–507 (2001).

    Article  CAS  Google Scholar 

  33. McDevitt, H.O. The role of MHC class II molecules in susceptibility and resistance to autoimmunity. Curr. Opin. Immunol. 10, 677–681 (1998).

    Article  CAS  Google Scholar 

  34. Ban, Y., Davies, T.F., Greenberg, D.A., Concepcion, E.S. & Tomer, Y. The influence of human leucocyte antigen (HLA) genes on autoimmune thyroid disease (AITD): results of studies in HLA-DR3 positive AITD families. Clin. Endocrinol. 57, 81–88 (2002).

    Article  CAS  Google Scholar 

  35. Kotani, T., Umeki, K., Hirai, K. & Ohtaki, S. Experimental murine thyroiditis induced by porcine thyroid peroxidase and its transfer by the antigen-specific T cell line. Clin. Exp. Immunol. 80, 11–18 (1990).

    Article  CAS  Google Scholar 

  36. Ng, H.P., Paul Banga, J. & Kung, A.W.C. Development of a murine model of autoimmune thyroiditis induced with homologous mouse thyroid peroxidase. Endocrinology 145, 809–816 (2004).

    Article  CAS  Google Scholar 

  37. Kong, Y.C., Flynn, J.C., Wan, Q. & David, C.S. HLA and H2 class II transgenic mouse models to study susceptibility and protection in autoimmune thyroid disease. Autoimmunity 36, 397–404 (2003).

    Article  CAS  Google Scholar 

  38. Roddis, M. et al. Fully functional HLA B27-restricted CD4+ as well as CD8+ T cell responses in TCR transgenic mice. J. Immunol. 172, 155–161 (2004).

    Article  CAS  Google Scholar 

  39. Salgame, P., Convit, J. & Bloom, B.R. Immunological suppression by human CD8+ T cells is receptor dependent and HLA-DQ restricted. Proc. Natl. Acad. Sci. USA 88, 2598–2602 (1991).

    Article  CAS  Google Scholar 

  40. Kirberg, J. et al. Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J. Exp. Med. 180, 25–34 (1994).

    Article  CAS  Google Scholar 

  41. Tyznik, A.J., Sun, J.C. & Bevan, M.J. The CD8 population in CD4-deficient mice is heavily contaminated with MHC class II-restricted T cells. J. Exp. Med. 199, 559–565 (2004).

    Article  CAS  Google Scholar 

  42. Boyle, L.H., Goodall, J.C., Opat, S.S. & Gaston, J.S. The recognition of HLA-B27 by human CD4+ T lymphocytes. J. Immunol. 167, 2619–2624 (2001).

    Article  CAS  Google Scholar 

  43. Zhumabekov, T., Corbella, P., Tolaini, M. & Kioussis, D. Improved version of a human CD2 minigene based vector for T cell-specific expression in transgenic mice. J. Immunol. Methods 185, 133–140 (1995).

    Article  CAS  Google Scholar 

  44. Maiuri, L. et al. Interleukin 15 mediates epithelial changes in celiac disease. Gastroenterology 119, 996–1006 (2000).

    Article  CAS  Google Scholar 

  45. Maiuri, L. et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362, 30–37 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Reid and his staff for the animal facilities; B. Rapaport, R. Lechler and R. Germain for the cell lines; and B. Askonas and T. Elliott for discussions and critical reading of the manuscript. This work was supported by a Wellcome Trust Career Development Research Fellowship (S.Q.) and Cancer Research UK grant C7056/A31.

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Authors and Affiliations

  1. Cancer Sciences Division, Cancer Research UK Oncology Unit, University of Southampton, MP824, Southampton, SO16 6YD, UK

    Sonia Quaratino, Ester Badami & Yun Yun Pang

  2. MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Istvan Bartok & Julian Dyson

  3. Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Dimitris Kioussis

  4. Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

    Marco Londei & Luigi Maiuri

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  1. Sonia Quaratino
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Correspondence to Sonia Quaratino.

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Supplementary information

Supplementary Fig. 1

Peripheral expression of human TCRBV1. (PDF 117 kb)

Supplementary Table 1

Cellularity in TAZ-10 transgenic mice. (PDF 19 kb)

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Quaratino, S., Badami, E., Pang, Y. et al. Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice. Nat Med 10, 920–926 (2004). https://doi.org/10.1038/nm1092

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