biostudies-literaturePucella JNDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)NIAID NIH HHSNHLBI NIH HHSNCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of Health1946-1961https://www.ebi.ac.uk/biostudies/studies/S-EPMC12662804biostudies-literatureUnknown26(11)Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small 'IFN-I-naive' subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the Nature immunologyTonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells.PMC12662804AI158808AI128949R01 AI072571U19 AI128949HL145997EI1185/1-1F32 HL145997R37 AI072571T32 CA009161P30 CA016087AI072571CA009161F32 CA232666R01 AI158808CA232666Perez OABandeira Sulczewski FEichinger AIvanova EEsteva ESmibert PStoeckius MReizis BDolgalev IRa ACCadwell KNi HPucella JNSota SSoni CIdoyaga JWeisberg SPFeng JDas AStetson DBZhong JMaqueda-Alfaro RAKhodadadi-Jamayran AFarber DLKoralov SBfalseTonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells.Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small 'IFN-I-naive' subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the 2025-01-01T00:00:00Z2025 Nov2026-06-05T21:43:21.083Z2026-05-22T03:15:52.747ZS-EPMC126628044108772610.1038/s41590-025-02279-4