Dendritic cell expression of interferon regulatory factor 4 drives Th2 responses and regulates IL-10 and IL-33 production (P6239)

Abstract

Abstract Dendritic cells (DCs) are known for promoting adaptive immune responses; however the molecular mechanisms that drive DCs to promote Th2-responses are poorly understood. We now demonstrate that house dust mite (HDM) allergen stimulation induces Interferon Regulatory Factor 4 (IRF4) expression in bone-marrow derived DCs as well as respiratory DCs. Mice deficient for IRF4 specifically in CD11c+ cells (CD11c-IRF4-/-) had dramatic defects in eliciting Th2-mediated HDM allergic inflammation, as measured by lung eosinophilia and Th2 cytokine production. Yet, the ability of CD11c-IRF4-/- mice to mount protective pulmonary Th1 viral responses remained intact. To determine whether defects in Th2 responses in vivo were due to direct effects of DCs on T cells, in vitro co-culture experiments were performed. CD11c-IRF4-/- DCs failed to induce Th2 differentiation compared to T cells stimulated by WT DCs. Further, genetically increasing IRF4 specifically in DCs augmented Th2 differentiation. Interestingly, we found that stimulation with HDM of WT DCs, but not CD11c-IRF4-/- DCs, increased expression of IL-10 and IL-33; both of which have been reported to play central roles in the development of Th2 responses. Together, these findings identify IRF4 expression in DCs and its ability to modulate cytokine production as a novel mechanism by which DCs regulate Th2 inflammatory responses.