Joseph N. Pucella, Raul A. Maqueda‐Alfaro, Hai Ni, Fernando Bandeira Sulczewski, Anna Eichinger, Eduardo Esteva, Aldona Dembińska-Kie ́c, Annesa Das, Oriana A. Perez, Jue Feng, Marlon Stoeckius, Peter Smibert, Alireza Khodadadi‐Jamayran, Igor Dolgalev, Ellie Ivanova, Stela Sota, Ken Cadwell, Sergei B. Koralov, Judy Zhong, Chetna Soni, Daniel B. Stetson, Stuart P. Weisberg, Donna L. Färber, Juliana Idoyaga, Boris Reizis
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 'IFN-I-primed' subsets (pDC-B/C) that showed lower IFN-I responses and poor survival, but did not support virus replication. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity and survival of pDCs but increases their virus resistance, facilitating optimal antiviral responses.