IFN-I signaling in type 2 conventional dendritic cells supports TH2 and T follicular helper differentiation after allergen immunization

Type 2 dendritic cells (DC2s) are essential for T H 2 differentiation, but the signaling pathways involved in allergen sensing, DC activation and instruction of CD4+ T cell priming remain unclear. Previous transcriptomic analyses demonstrated a type-I interferon (IFN-I) signature in skin cDC2s following immunization with non-viable larvae of Nippostrongylus brasiliensis ( Nb ), house dust mite (HDM), and Schistosoma egg antigen (SEA). Blocking IFN-I signaling with anti-IFNAR1 (aIFNAR1) led to reduced T H 2 cytokine responses to these antigens, however, the phenotype of cytokine-producing CD4+ T cells was not further defined. Here we show that conditional loss of IFNAR1 signaling in CD11c+ DCs significantly impaired effector T H 2 and TFH CD4+ T cell responses to Nb . In vivo proliferation experiments demonstrated reduced numbers of highly divided CD4+ T cells in IFNAR1 ΔCD11c mice compared to IFNAR1 WT , with the highly divided population comprising both T H 2 and TFH. Characterization of the cDC2 compartment by flow cytometry and bulk RNAseq demonstrated lower numbers of Nb + cDC2s in the skin-draining LN and a reduced expression of Il15 and Il15Ra in IFNAR1 ΔCD11c mice compared to IFNAR1 WT , while expression of costimulatory molecules including CD80, CD86, Cd40 and Pdcd1lg2 (PD-L2) was not impaired. Therefore, IFN-I conditioning of skin cDC2s is necessary for their effective priming of CD4+ T cell responses to allergens, providing evidence for a role of tissue cytokines in driving cDC2 activation in a T H 2 context.