Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

• NIHPA Author Manuscripts
• PMC4003872

Nat Commun. Author manuscript; available in PMC Apr 29, 2014.

Published in final edited form as:

Nat Commun. 2013; 4: 2990.

doi:  10.1038/ncomms3990

PMCID: PMC4003872

NIHMSID: NIHMS565877

Jesse W. Williams,1 Melissa Y. Tjota,2,3 Bryan S. Clay,2 Bryan Vander Lugt,4 Hozefa S. Bandukwala,2 Cara L. Hrusch,6 Donna C. Decker,6 Kelly M. Blaine,6 Bethany R. Fixsen,6 Harinder Singh,4 Roger Sciammas,5 and Anne I. Sperling1,2,6

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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 anti-viral 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 Il10 and Il33 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.

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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 anti-viral 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 Il10 and Il33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4