Interferon signaling in type-2 dendritic cells supports TH2 and T follicular helper fates in response to allergens.

Abstract

Type-2 dendritic cells (DC2s) are essential for the initiation of type-2 immune responses, but the signaling pathways involved in allergen sensing, DC activation and instruction of CD4⁺ T cell differentiation into T_H2 cells remain unclear. Previous studies demonstrated a type-I interferon (IFN-I) signature in skin DC2s following immunization with non-viable larvae of the helminth Nippostrongylus brasiliensis (Nb), house dust mite (HDM) or Schistosoma egg antigen (SEA). Here we show that conditional loss of IFNAR1 signaling in CD11c⁺ DCs significantly impaired T_H2 effector and T follicular helper (TFH) CD4⁺ T cell responses to Nb. In vivo proliferation experiments demonstrated reduced numbers of highly divided CD4⁺ T cells in IFNAR1^∆CD11c mice compared to IFNAR1^WT, with similar proportions of GATA3^hi T_H2 cells within the divided populations indicating that IFNAR1 signaling in DCs was supporting T cell priming and expansion rather than GATA3^hi differentiation. By contrast, TFHs were present in lower frequencies in IFNAR1^∆CD11c mice compared to IFNAR1^WT, suggesting that IFN-I signaling in DCs is necessary for allergen-specific TFH differentiation. Characterization of the DC2 compartment by flow cytometry and bulk RNAseq demonstrated lower numbers of Nb⁺ DC2s in draining lymph nodes (dLN) and reduced expression of genes involved in DC2 motility, focal adhesion, and antigen processing, while expression of costimulatory molecules and cell survival and apoptosis pathway scores were similar. Therefore, IFN-I conditioning of skin DC2s is necessary for their effective priming of CD4⁺ T_H2 responses to allergens and likely acts through the additive effects of multiple IFN-I-regulated pathways in DC2s.