Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

Jesse W. Williams, Melissa Y. Tjota, Bryan S. Clay, Bryan Vander Lugt, Hozefa S. Bandukwala, Cara L. Hrusch, Donna C. Decker, Kelly M. Blaine, Bethany R. Fixsen, Harinder Singh, Roger Sciammas and Anne I. Sperling ()
Additional contact information
Jesse W. Williams: Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago
Melissa Y. Tjota: Committee on Immunology, University of Chicago
Bryan S. Clay: Committee on Immunology, University of Chicago
Bryan Vander Lugt: Genentech Inc.
Hozefa S. Bandukwala: Committee on Immunology, University of Chicago
Cara L. Hrusch: Section of Pulmonary and Critical Care Medicine, University of Chicago
Donna C. Decker: Section of Pulmonary and Critical Care Medicine, University of Chicago
Kelly M. Blaine: Section of Pulmonary and Critical Care Medicine, University of Chicago
Bethany R. Fixsen: Section of Pulmonary and Critical Care Medicine, University of Chicago
Harinder Singh: Genentech Inc.
Roger Sciammas: University of Chicago
Anne I. Sperling: Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.

Date: 2013
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DOI: 10.1038/ncomms3990

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