Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice

Abstract

Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints1,2,3. Although CD4+ T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4+ T cells are generated and activated1,2,3. Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease4,5. Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells6, causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Arthritis in SKG mice.
Figure 2: Genetic study of SKG arthritis.
Figure 3: T-cell abnormalities in SKG mice.
Figure 4: Altered thymic T-cell selection in SKG mice.

References

  1. Harris, E. D. Rheumatoid Arthritis (W. B. Saunders, Philadelphia, 1997)

    Google Scholar 

  2. Feldmann, M., Brennan, F. M. & Maini, R. N. Rheumatoid arthritis. Cell 85, 307–310 (1996)

    CAS  Article  Google Scholar 

  3. Firestein, G. F. in Textbook of Rheumatology 5th edn (eds Kelley, W. N., Ruddy, S., Harris, E. D. & Sledge, C. B.) 851–897 (W. B. Saunders, Philadelphia, 1997)

    Google Scholar 

  4. Marrack, P., Kappler, J. & Kotzin, B. L. Autoimmune disease: why and where it occurs. Nature Med. 7, 899–905 (2001)

    CAS  Article  Google Scholar 

  5. von Boehmer, H. et al. Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003)

    CAS  Article  Google Scholar 

  6. Chan, A. C., Iwashima, M., Turck, C. W. & Weiss, A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 71, 649–662 (1992)

    CAS  Article  Google Scholar 

  7. Sakaguchi, S. & Sakaguchi, N. Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease. J. Exp. Med. 172, 537–545 (1990)

    CAS  Article  Google Scholar 

  8. Itoh, M. et al. Thymus and autoimmunity: production of CD25+ CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326 (1999)

    CAS  PubMed  Google Scholar 

  9. Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438 (1995)

    ADS  CAS  Article  Google Scholar 

  10. van Oers, N. S. et al. The 21- and 23-kD forms of TCR zeta are generated by specific ITAM phosphorylations. Nature Immunol. 1, 322–328 (2000)

    CAS  Article  Google Scholar 

  11. Iwashima, M. et al. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136–1139 (1994)

    ADS  CAS  Article  Google Scholar 

  12. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P. & Samelson, L. E. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83–92 (1998)

    CAS  Article  Google Scholar 

  13. Rincon, M. MAP-kinase signaling pathway in T cells. Curr. Opin. Immunol. 13, 339–345 (2001)

    CAS  Article  Google Scholar 

  14. Noraz, N. et al. Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk. J. Biol. Chem. 275, 15832–15838 (2000)

    CAS  Article  Google Scholar 

  15. Murphy, K. M., Heimberger, A. B. & Loh, D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250, 1720–1723 (1990)

    ADS  CAS  Article  Google Scholar 

  16. Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  18. Wiest, D. L. et al. A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. Immunity 6, 663–671 (1997)

    CAS  Article  Google Scholar 

  19. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995)

    CAS  PubMed  Google Scholar 

  20. Keffer, J. et al. Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  22. Pals, S. T., Radaszkiewicz, T., Roozendaal, L. & Gleichman, E. Chronic progressive polyarthritis and other symptoms of collagen vascular disease induced by graft-versus-host reaction. J. Immunol. 134, 1475–1482 (1985)

    CAS  Google Scholar 

  23. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999)

    CAS  Article  Google Scholar 

  24. Horai, R. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191, 313–320 (2000)

    CAS  Article  Google Scholar 

  25. Atsumi, T. et al. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp. Med. 196, 979–990 (2002)

    CAS  Article  Google Scholar 

  26. Dayer, J. M. & Burger, D. Cytokines and direct cell contact in synovitis: relevance to therapeutic intervention. Arthritis Res. 1, 17–20 (1999)

    CAS  Article  Google Scholar 

  27. Naka, T., Nishimoto, N. & Kishimoto, T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 4(Suppl. 3), S233–S242 (2002)

    Article  Google Scholar 

  28. Werlen, G., Hausmann, B., Naeher, D. & Palmer, E. Signaling life and death in the thymus: timing is everything. Science 299, 1859–1863 (2003)

    ADS  CAS  Article  Google Scholar 

  29. Nambiar, M. P. et al. T cell signalling abnormalities in systemic lupus erythematosus are associated with increased mutations/polymorphisms and splice variants of T cell receptor zeta chain messenger RNA. Arthritis Rheum. 44, 1336–1350 (2001)

    CAS  Article  Google Scholar 

  30. Takeuchi, T. et al. TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus. Int. Immunol. 10, 911–921 (1998)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank H. von Boemer for transgenic mice; M. Singh (GBF, Germany) for a gift of recombinant HSP-70 through the support of the UNDP/World Bank/WHO Special Program for Research and Training on Tropical Diseases; F. Melchers, R. Zinkernagel, K. Yamamoto, R. Suzuki and Z. Fehervari for discussion; A. Kosugi and T. Nakayama for reagents; and E. Moriizumi for immunohistochemistry and histology. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture, the Ministry of Human Welfare, Japan Science and Technology Corporation, and the Organization for Pharmaceutical Safety and Research of Japan. Authors' contributions. The SKG strain was established by S.S. and N.S. The experiments in Figs 1, 2a–d, 3f–h, 4, Supplementary Figs 1, 4 and 6 were conducted by N.S. and S.S.; those in Fig. 2b–d by Ta.T., N.S., H.H., To.T., S.Y., T. S., S.N. and S.S.; those in Figs 2e, f, 3a–c, e and Supplementary Fig. 2 by Ta.T.; that in Fig. 3d by To.T.; that in Supplementary Fig. 3 by T.N., and that in Supplementary Fig. 5 by T.M. ZAP-70-deficient mice were provided by I.N.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shimon Sakaguchi.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sakaguchi, N., Takahashi, T., Hata, H. 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). https://doi.org/10.1038/nature02119

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02119

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing