Dok-1 and Dok-2 are negative regulators of T cell receptor signaling

Tomoharu Yasuda, Kenji Bundo, Ayako Hino, Kazuho Honda, Akane Inoue, Masaki Shirakata, Mitsujiro Osawa, Toshiki Tamura, Hideo Nariuchi, Hideaki Oda, Tadashi Yamamoto, Yuji Yamanashi

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Abstract

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 TCRζ, 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.

Original languageEnglish
Pages (from-to)487-495
Number of pages9
JournalInternational Immunology
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Yasuda, T., Bundo, K., Hino, A., Honda, K., Inoue, A., Shirakata, M., ... Yamanashi, Y. (2007). Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. International Immunology, 19(4), 487-495. https://doi.org/10.1093/intimm/dxm015