Interferon regulatory factor 4 (IRF4) directs dendritic cells to promote Th2 responses (57.11)

Abstract

Abstract Respiratory dendritic cells (DC) are the primary initiator of T cells during lung allergic responses. DCs process inhaled allergen, traffic to the lung draining lymph node, present antigen to T cells, and guide the type of T-helper response initiated. However, the mechanisms by which DCs direct Th2 specific differentiation are poorly understood. We previously found that signaling through FcγRIII is able to modulate TLR4 signaling in DCs, and that these DCs now skew toward a predominant Th2 response. Microarray analysis identified IRF4 as a gene downstream of FcγRIII signaling in bone marrow derived DCs (BMDCs). In respiratory DCs, IRF4 was induced within 3 hrs of stimulation with known Th2-agonists. Using mice with conditional deletion of IRF4 in CD11c cells, we demonstrated reduced Th2 responses after house dust mite-induced allergic challenge, while DC trafficking and T cell activation remained intact. Direct effects between IRF4 in DCs and Th2 development was demonstrated using sorted pulmonary DCs from IRF4-deficient mice to skew T cells in vitro. Surprisingly, when IRF4-deficient DCs were used the resulting T cells produced decreased Th2 cytokines, but augmented IFNγ and IL-17. Further, we found that increasing IRF4 expression alone in BMDCs was sufficient to drive T cells toward a Th2 phenotype. Together these data identify IRF4 as a key transcriptional regulator in DCs necessary for the development of Th2 responses.