icg-001 and Vaccinia

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.

Topics: Animals; Antigens, CD; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; CD11c Antigen; CD8 Antigens; CD8-Positive T-Lymphocytes; Cell Differentiation; Dendritic Cells; Enzyme Activation; Female; Inflammation; Integrin alpha Chains; Interferon Regulatory Factors; Interleukin-12; Mice; Mice, Inbred C57BL; Mice, Knockout; Parasite Load; Promoter Regions, Genetic; Pyrimidinones; Receptors, Cell Surface; Signal Transduction; Spleen; Th1 Cells; Toxoplasma; Toxoplasmosis; Vaccinia; Vaccinia virus