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

Int Immunol. 2007 Apr;19(4):487-95. doi: 10.1093/intimm/dxm015. Epub 2007 Feb 27.

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 TCRzeta, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • CD3 Complex / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression
  • Interleukin-2 / metabolism
  • Interleukin-2 / pharmacology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Phosphorylation / drug effects
  • Protein Binding
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / physiology*
  • Sequence Homology, Amino Acid
  • Signal Transduction / immunology*
  • Spleen / cytology
  • Spleen / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • CD3 Complex
  • Cd3e protein, mouse
  • DNA-Binding Proteins
  • Dok1 protein, mouse
  • Dok2 protein, mouse
  • Dok3 protein, mouse
  • Interleukin-2
  • Membrane Proteins
  • Phosphoproteins
  • RNA-Binding Proteins
  • Receptors, Antigen, T-Cell
  • antigen T cell receptor, zeta chain
  • Extracellular Signal-Regulated MAP Kinases