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

J Immunol. 2014 Nov 21. pii: 1402453. [Epub ahead of print]

 

Cohen SB¹, Smith NL¹, McDougal C¹, Pepper M², Shah S³, Yap GS³, Acha-Orbea H⁴, Jiang A⁵, Clausen BE⁶, Rudd BD¹, Denkers EY⁷.

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.
Copyright © 2014 by The American Association of Immunologists, Inc.

PMID:

25416805

[PubMed - as supplied by publisher]