Identification de mécanismes moléculaires d’induction de la réponse immunitaire de type Th2 par les cellules dendritiques conventionnelles CD11b+ du poumon

摘要

Currently, the activation mechanisms of type 2 helper T cells (Th2) by dendritic cells are not yet fully understood. In recent years, more and more evidences show that there is a functional specialization of the different dendritic cells populations. Therefore, in our laboratory, it was demonstrated that lung CD11b+ conventional dendritic cells (cDC) are the cells responsible for the allergic sensitization after an inhalation of house dust mite extracts in mice. Because this population is responsible for priming Th2 response, we decided to study them in an allergic context as a model in order to identify new mechanisms involve in Th2 induction. So far, few transcription factors required for the pro-Th2 activity of dendritic cells have been identified. Their discovery could considerably improve the understanding of Th2 activation by dendritic cells. Transcriptomic profiling of lung CD11b+ cDCs exposed to HDM in vivo revealed first that HDM triggered an antiviral defence-like response and second that the majority of HDM-induced transcriptional changes depended on the transcription factor Inresterferon 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, mostly known 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.