Interferon response factor-3 promotes the pro-Th2 activity of mouse lung CD11b+ conventional dendritic cells in response to house dust mite allergens

Abstract

Very few transcription factors have been identified that are required by antigen-presenting cells (APCs) to induce T helper type 2 (Th2) responses. Because lung CD11b+ conventional dendritic cells (CD11b+ cDCs) are responsible for priming Th2 responses in house-dust mite (HDM)-induced airway allergy, we used them as a model to identify transcriptional events regulating the pro-Th2 activity of cDCs. Transcriptomic profiling of lung CD11b+ cDCs exposed to HDM in vivo revealed first that HDM triggers an antiviral defence-like response, and second that the majority of HDM-induced transcriptional changes depend on the transcription factor Interferon Response Factor-3 (Irf3). Validating the functional relevance of these observations, Irf3-deficient CD11b+ cDCs displayed reduced pro-allergic activity. Indeed, Irf3-deficient CD11b+ cDCs induced less Th2, more regulatory T cell, and similar Th1 differentiation in naïve CD4+ T cells compared to their wild-type counterparts. The altered APC activity of Irf3 CD11b+ cDCs was associated with reduced expression of CD86 and was phenocopied by blocking CD86 activity in wild-type CD11b+ cDCs. Altogether, these results establish Irf3, known mostly for its role in antiviral responses, as a transcription factor involved in the induction of Th2 responses through the promotion of pro-Th2 costimulation in CD11b+ DCs.