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