Abstract
Beta-catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for beta-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express beta-catenin, and DCs from mice with CD11c-specific constitutive beta-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8a+, plasmacytoid, and CD103+ CD11b2 DCs. beta-catenin–stabilized CD8a+ DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological beta-catenin inhibition blocked this response in wild-type cells. Upon infections with Toxoplasma gondii and vaccinia virus, mice with stabilized DC beta-catenin displayed abnormally high Th1 and CD8+ T lymphocyte responses, respectively. Collectively, these results reveal a novel and unexpected function for beta-catenin in programming DC differentiation toward subsets that orchestrate proinflammatory immunity to infection.
MeSH terms
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Animals
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Antigens, CD / immunology
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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CD11c Antigen / immunology
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CD8 Antigens / immunology
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CD8-Positive T-Lymphocytes / immunology
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Cell Differentiation / immunology
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Dendritic Cells / cytology*
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Dendritic Cells / immunology*
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Enzyme Activation
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Female
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Inflammation / immunology*
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Integrin alpha Chains / immunology
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Interferon Regulatory Factors / genetics*
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Interferon Regulatory Factors / immunology
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Interleukin-12 / biosynthesis
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Interleukin-12 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Parasite Load
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Promoter Regions, Genetic
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Pyrimidinones / pharmacology
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Receptors, Cell Surface / genetics
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Signal Transduction / immunology
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Spleen / cytology
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Spleen / immunology
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Th1 Cells / immunology
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Toxoplasma / immunology
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Toxoplasmosis / immunology
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Vaccinia / immunology
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Vaccinia virus / immunology
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beta Catenin / antagonists & inhibitors
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beta Catenin / biosynthesis
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beta Catenin / immunology*
Substances
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Antigens, CD
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Bridged Bicyclo Compounds, Heterocyclic
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CD11c Antigen
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CD8 Antigens
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CD8alpha antigen
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ICG 001
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Integrin alpha Chains
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Interferon Regulatory Factors
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Pyrimidinones
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Receptors, Cell Surface
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alpha E integrins
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beta Catenin
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interferon regulatory factor-8
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Interleukin-12