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.
Bibliographical noteFunding Information:
We would like to thank Dr Alexander Chervonsky for generously providing CD11c-cre mice, and the UCCCC Cytometry and Antibody Technology Core for sorting and flow cytometry support. This work was supported by a Ragins-Goldsmith Fellowship, University of Chicago (to M.Y.T.), and National Institutes of Health Grants R21AI094408-01 (to A.I.S.), 5T32HL007237-35 (to J.W.W.), and 5T32HL007605 (to B.S.C. and C.L.H.).