IRF4 expression by lung dendritic cells promotes allergic Th2 responses by controlling OX40L, IL-10, and IL-33 expression during sensitization

Abstract The specific mechanisms by which DCs initiate Th2 responses are not completely understood. We previously found that mice lacking the transcription factor IRF4 in DCs do not develop type 2 lung inflammation in response to house dust mite extract (HDM). Further, IRF4-deficient DCs had a reduced capacity for restimulating T cells towards a Th2 phenotype ex vivo. We hypothesized that IRF4 is necessary for DCs to perform one or more of the functions required to successfully initiate Th2 responses in vivo. Here we demonstrate that during in vivo HDM sensitization, IRF4 in DCs is required neither for CD11b+ CD24+ cDCs to take up allergen in the lungs, nor for the lung DCs to process antigens. Instead, IRF4-deficient lung DCs display lower levels of the Th2-associated costimulatory molecule OX40L and express less of the Th2-promoting cytokines IL-33 and IL-10 during sensitization. While HDM-bearing DCs lacking IRF4 arrive in the lung-draining lymph nodes at proportions comparable to WT DCs and are capable of processing antigens, reduced numbers migrate to the lung-draining lymph nodes in the absence of IRF4. Following HDM sensitization, mice with IRF4-deficient DCs display impaired CD4+ effector/memory T cell recruitment to the lung parenchyma and reduced T cell expression of CD69. Thus, IRF4 controls a pro-Th2 program in DCs including expression of OX40L, IL-10, and IL-33 as well as migration to the draining lymph nodes, culminating in Th2 priming in response to HDM.