Abstract
CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex zeta chain in primary T cells. The association of TCRzeta with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56(lck)-induced tyrosine phosphorylation. Coexpression of the CTLA-4-associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRzeta bound to CTLA-4 and abolished the p56(lck)-inducible TCRzeta-CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRzeta and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Animals
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Antigens, CD
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Antigens, Differentiation / metabolism*
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CTLA-4 Antigen
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Cell Line
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Cells, Cultured
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Humans
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Immunoconjugates*
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Intracellular Signaling Peptides and Proteins
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Lymphocyte Activation*
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred BALB C
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Models, Immunological
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Phosphorylation
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Phosphotyrosine / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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Receptors, Antigen, T-Cell / metabolism*
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Recombinant Fusion Proteins / metabolism
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Signal Transduction*
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T-Lymphocytes / immunology*
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Transfection
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src Homology Domains
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Immunoconjugates
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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antigen T cell receptor, zeta chain
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Phosphotyrosine
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Abatacept
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse
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SH2 Domain-Containing Protein Tyrosine Phosphatases