Abstract
Despite the defined function of the β-catenin pathway in thymocytes, its functional role in peripheral T cells is poorly understood. We report that in a mouse model, β-catenin protein is constitutively degraded in peripheral T cells. Introduction of stabilized β-catenin into primary T cells inhibited proliferation and cytokine secretion after TCR stimulation and blunted effector cell differentiation. Functional and biochemical studies revealed that β-catenin selectively inhibited linker for activation of T cells phosphorylation on tyrosine 136, which was associated with defective phospholipase C-γ1 phosphorylation and calcium signaling but normal ERK activation. Our findings indicate that β-catenin negatively regulates T cell activation by a previously undescribed mechanism and suggest that conditions under which β-catenin might be inducibly stabilized in vivo would be inhibitory for T cell-based immunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Differentiation / immunology
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Cell Proliferation
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Cells, Cultured
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Coxsackie and Adenovirus Receptor-Like Membrane Protein
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Cytokines / metabolism
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Down-Regulation / immunology*
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology
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Lymphocyte Activation / immunology*
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Phospholipase C gamma / antagonists & inhibitors*
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Phospholipase C gamma / metabolism
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Phosphoproteins / antagonists & inhibitors*
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Phosphoproteins / metabolism
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Phosphorylation / genetics
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Phosphorylation / immunology
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Receptors, Antigen, T-Cell / physiology
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Receptors, Virus / antagonists & inhibitors
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Receptors, Virus / genetics
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Receptors, Virus / metabolism
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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Transcription, Genetic / immunology
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beta Catenin / deficiency
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beta Catenin / genetics
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beta Catenin / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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CLMP protein, mouse
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CTNNB1 protein, mouse
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Coxsackie and Adenovirus Receptor-Like Membrane Protein
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Cytokines
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Immunosuppressive Agents
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Lat protein, mouse
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Membrane Proteins
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Phosphoproteins
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Receptors, Antigen, T-Cell
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Receptors, Virus
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beta Catenin
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Phospholipase C gamma