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

Tomoharu Yasuda1, Kenji Bundo, Ayako Hino

  • 1Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

International Immunology
|March 3, 2007
PubMed

Insights

Mice lacking Dok-1 and Dok-2 adaptor proteins show enhanced T cell receptor (TCR) signaling and autoimmune disease. These proteins negatively regulate TCR activation through an unknown mechanism.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • T cell receptor (TCR) complex interaction with peptides is crucial for immune responses.
  • ZAP-70, a protein-tyrosine kinase (PTK), is essential for T cell activation upon TCR stimulation.
  • Dok-1 and Dok-2 are adaptor proteins involved in cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of Dok-1 and Dok-2 adaptor proteins in T cell receptor (TCR) signaling.
  • To elucidate the mechanism by which Dok-1 and Dok-2 regulate T cell activation.
  • To determine the in vivo consequences of Dok-1 and Dok-2 deficiency on immune responses and autoimmunity.

Main Methods:

  • Analysis of T cell responses in mice lacking Dok-1 and Dok-2.
  • Assessment of ZAP-70 activation, T cell proliferation, and cytokine production upon TCR stimulation.
  • Forced expression of Dok-1 or Dok-2 in T cell clones to evaluate their inhibitory effects.
  • Investigation of the role of specific Dok-1 and Dok-2 domains in regulating TCR signaling.

Main Results:

  • Mice lacking Dok-1 and Dok-2 exhibited augmented responses to thymus-dependent antigens and elevated T cell activation upon TCR stimulation.
  • T cells from these mice showed increased ZAP-70 activation, proliferation, and cytokine production.
  • Forced expression of Dok-1 or Dok-2 inhibited ZAP-70 activation, indicating a negative regulatory role.
  • The COOH-terminal moieties of Dok-1 and Dok-2 were dispensable for this negative regulation, suggesting a novel mechanism.

Conclusions:

  • Dok-1 and Dok-2 play an essential role in the negative regulation of T cell receptor (TCR) signaling through an unidentified mechanism.
  • Deficiency in Dok-1 and Dok-2 leads to enhanced T cell activation and autoimmune manifestations, including lupus-like renal disease.
  • The adaptor functions of Dok-1 and Dok-2 are not required for their inhibitory role in TCR signaling.

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