title: Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells.
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.
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14867
authors.forename: Sara B
authors.initials: SB
authors.lastname: Cohen
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14867
authors.forename: Norah L
authors.initials: NL
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14867
authors.forename: Courtney
authors.initials: C
authors.lastname: McDougal
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.affiliation: Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101
authors.forename: Suhagi
authors.initials: S
authors.lastname: Shah
authors.affiliation: Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101
authors.forename: George S
authors.initials: GS
authors.lastname: Yap
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263
authors.forename: Aimin
authors.initials: A
authors.lastname: Jiang
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
authors.forename: Bjorn E
authors.initials: BE
authors.lastname: Clausen
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14867
authors.forename: Brian D
authors.initials: BD
authors.lastname: Rudd
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14867
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Denkers
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D039521:CD11c Antigen / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D004789:Enzyme Activation; D005260:Female; D007249:Inflammation / Q000276:immunology*; D039001:Integrin alpha Chains / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059208:Parasite Load; D011401:Promoter Regions, Genetic; D011744:Pyrimidinones / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D000099185:Interferon Regulatory Factor-8
chemical_list: D015703:Antigens, CD; D019086:Bridged Bicyclo Compounds, Heterocyclic; D039521:CD11c Antigen; D016827:CD8 Antigens; D039001:Integrin alpha Chains; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D011744:Pyrimidinones; D011956:Receptors, Cell Surface; D051176:beta Catenin; D000099185:Interferon Regulatory Factor-8; C431698:CD8alpha antigen; C492448:ICG 001; C091367:alpha E integrins