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RESEARCH PRODUCT
β-Catenin Signaling Drives Differentiation and Proinflammatory Function of IRF8-Dependent Dendritic Cells
Norah L. SmithEric Y. DenkersBjörn E. ClausenGeorge S. YapCourtney McdougalSara B. CohenMarion PepperBrian D. RuddSuhagi ShahAimin JiangHans Acha-orbeasubject
CD8 AntigensCellular differentiationImmunologyReceptors Cell SurfaceVaccinia virusPyrimidinonesCD8-Positive T-LymphocytesBiologyParasite LoadArticleProinflammatory cytokineMiceAntigens CDVacciniaAnimalsImmunology and AllergyPromoter Regions Geneticbeta CateninInflammationMice KnockoutCell DifferentiationDendritic CellsT lymphocyteTh1 CellsBridged Bicyclo Compounds HeterocyclicInterleukin-12CD11c AntigenCell biologyEnzyme ActivationMice Inbred C57BLInterferon Regulatory FactorsInterleukin 12FemaleIRF8Signal transductionIntegrin alpha ChainsToxoplasmaSpleenToxoplasmosisCD8Signal TransductionInterferon regulatory factorsdescription
Abstract β-Catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for β-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express β-catenin, and DCs from mice with CD11c-specific constitutive β-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8α+, plasmacytoid, and CD103+CD11b− DCs. β-Catenin–stabilized CD8α+ DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological β-catenin inhibition blocked this response in wild-type cells. Upon infections with Toxoplasma gondii and vaccinia virus, mice with stabilized DC β-catenin displayed abnormally high Th1 and CD8+ T lymphocyte responses, respectively. Collectively, these results reveal a novel and unexpected function for β-catenin in programming DC differentiation toward subsets that orchestrate proinflammatory immunity to infection.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-11-23 | The Journal of Immunology |