International Immunology Advance Access originally published online on February 27, 2007
International Immunology 2007 19(4):487-495; doi:10.1093/intimm/dxm015
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Dok-1 and Dok-2 are negative regulators of T cell receptor signaling
1 Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
2 Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
3 Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
4 Laboratory of Stem Cell Therapy
5 Division of Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
6 Ogata Institute for Medical and Chemical Research, Tokyo 102-8230, Japan
7 Division of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Correspondence to: Y. Yamanashi; E-mail: yamanashi.creg{at}mri.tmd.ac.jp
Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein–tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCR
, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3+CD4+ T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease.
Keywords: antigen receptor, protein–tyrosine kinase, signal transduction
Transmitting editor: T. Kurosaki
Received 9 November 2006, accepted 14 January 2007.
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