β-Catenin Signaling Drives Differentiation and Proinflammatory Function of IRF8-Dependent Dendritic Cells

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 CD8 alpha(+), plasmacytoid, and CD103(+) CD11b(-) DCs. beta-Catenin-stabilized CD8 alpha(+) 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.