Tonic 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 '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.
Authors
- Boris Reizis (ORCID: https://orcid.org/0000-0003-1140-7853)
- Joseph N. Pucella (ORCID: https://orcid.org/0000-0003-0875-8046)
- Chetna Soni (ORCID: https://orcid.org/0000-0001-7800-2338)
- Oriana A. Perez (ORCID: https://orcid.org/0000-0002-4093-1147)
- Igor Dolgalev (ORCID: https://orcid.org/0000-0003-4451-126X)
- Eduardo Esteva (ORCID: https://orcid.org/0000-0002-7223-6632)
- Annesa Das (ORCID: https://orcid.org/0000-0001-8633-0702)
- Stela Sota
- Peter Smibert (ORCID: https://orcid.org/0000-0003-0772-1647)
- Raul A. Maqueda‐Alfaro (ORCID: https://orcid.org/0000-0003-3538-1176)
- Ellie Ivanova (ORCID: https://orcid.org/0000-0002-1850-9505)
- Ken Cadwell (ORCID: https://orcid.org/0000-0002-5860-0661)
- Stuart P. Weisberg (ORCID: https://orcid.org/0000-0002-8698-5976)
- Daniel B. Stetson (ORCID: https://orcid.org/0000-0002-5936-1113)
- Fernando Bandeira Sulczewski (ORCID: https://orcid.org/0000-0001-5611-6967)
- Donna L. Färber (ORCID: https://orcid.org/0000-0001-8236-9183)
- Jue Feng (ORCID: https://orcid.org/0000-0002-2506-1294)
- Juliana Idoyaga (ORCID: https://orcid.org/0000-0002-4430-8862)
- Sergei B. Koralov (ORCID: https://orcid.org/0000-0002-4843-3791)
- Marlon Stoeckius (ORCID: https://orcid.org/0000-0002-5658-029X)
- Anna Eichinger (ORCID: https://orcid.org/0000-0002-2256-6633)
- Alireza Khodadadi‐Jamayran (ORCID: https://orcid.org/0000-0003-2495-7504)
- Judy Zhong (ORCID: https://orcid.org/0000-0002-2163-8447)
- Hai Ni (ORCID: https://orcid.org/0009-0004-0156-1704)
- Aldona Dembińska-Kie ́c
Institutions
- University of San Diego (US)
- University of Washington (US)
- Cornell University (US)
- Columbia University Irving Medical Center (US)
- UC San Diego Health System (US)
- University of California San Diego (US)
- New York Genome Center (US)
- Weill Cornell Medicine (US)
- New York University (US)
- University of Pennsylvania (US)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1038/s41590-025-02279-4
- Citations
- 2
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 1.59