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Nature 426, 454-460 (27 November 2003) | doi:10.1038/nature02119; Received 4 August 2003; Accepted 13 October 2003

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

Noriko Sakaguchi1,2,5, Takeshi Takahashi1,5, Hiroshi Hata1, Takashi Nomura1, Tomoyuki Tagami1, Sayuri Yamazaki1, Toshiko Sakihama1, Takaji Matsutani3, Izumi Negishi4, Syuichi Nakatsuru1 & Shimon Sakaguchi1,2

  1. Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
  2. Laboratory for Immunopathology, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan
  3. Department of Immunology, Shionogi Institute for Medical Science, Settsu, Osaka 566-0022, Japan
  4. Department of Dermatology, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
  5. These authors contributed equally to this work

Correspondence to: Shimon Sakaguchi1,2 Email: shimon@frontier.kyoto-u.ac.jp

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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.