Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells

Sara B Cohen; Norah L Smith; Courtney McDougal; Marion Pepper; Suhagi Shah; George S Yap; Hans Acha-Orbea; Aimin Jiang; Bjorn E Clausen; Brian D Rudd; Eric Y Denkers

doi:10.4049/jimmunol.1402453

Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells

J Immunol. 2015 Jan 1;194(1):210-22. doi: 10.4049/jimmunol.1402453.

Authors

Affiliations

¹ Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14867
² Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101
³ Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101
⁴ Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland
⁵ Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263
⁶ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

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

Animals
Antigens, CD / immunology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
CD11c Antigen / immunology
CD8 Antigens / immunology
CD8-Positive T-Lymphocytes / immunology
Cell Differentiation / immunology
Dendritic Cells / cytology*
Dendritic Cells / immunology*
Enzyme Activation
Female
Inflammation / immunology*
Integrin alpha Chains / immunology
Interferon Regulatory Factors / genetics*
Interferon Regulatory Factors / immunology
Interleukin-12 / biosynthesis
Interleukin-12 / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Parasite Load
Promoter Regions, Genetic
Pyrimidinones / pharmacology
Receptors, Cell Surface / genetics
Signal Transduction / immunology
Spleen / cytology
Spleen / immunology
Th1 Cells / immunology
Toxoplasma / immunology
Toxoplasmosis / immunology
Vaccinia / immunology
Vaccinia virus / immunology
beta Catenin / antagonists & inhibitors
beta Catenin / biosynthesis
beta Catenin / immunology*

Substances

Antigens, CD
Bridged Bicyclo Compounds, Heterocyclic
CD11c Antigen
CD8 Antigens
CD8alpha antigen
ICG 001
Integrin alpha Chains
Interferon Regulatory Factors
Pyrimidinones
Receptors, Cell Surface
alpha E integrins
beta Catenin
interferon regulatory factor-8
Interleukin-12

Abstract

MeSH terms

Substances

Grants and funding