1. Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, UK
2. Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK
3. Institute for Virology, University of Veterinary Medicine, Vienna A-1210, Austria
4. Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut 06520, USA
5. London School of Hygiene & Tropical Medicine, London WC1A 7HT, UK
6. Tenovus Research Laboratory, Cancer Sciences Division, The School of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK

Correspondence to: Caetano Reis e Sousa¹ Email: caetano@cancer.org.uk

Type I interferons (IFN-I) are important cytokines linking innate and adaptive immunity¹. Plasmacytoid dendritic cells make high levels of IFN-I in response to viral infection and are thought to be the major source of the cytokines in vivo². Here, we show that conventional non-plasmacytoid dendritic cells taken from mice infected with a dendritic-cell-tropic strain of lymphocytic choriomeningitis virus make similarly high levels of IFN-I on subsequent culture. Similarly, non-plasmacytoid dendritic cells secrete high levels of IFN-I in response to double-stranded RNA (dsRNA), a major viral signature³, when the latter is introduced into the cytoplasm to mimic direct viral infection. This response is partially dependent on the cytosolic dsRNA-binding enzyme protein kinase R⁴ and does not require signalling through toll-like receptor (TLR) 3, a surface receptor for dsRNA⁵. Furthermore, we show that sequestration of dsRNA by viral NS1 (refs 6, 7) explains the inability of conventional dendritic cells to produce IFN-I on infection with influenza. Our results suggest that multiple dendritic cell types, not just plasmacytoid cells, can act as specialized interferon-producing cells in certain viral infections, and reveal the existence of a TLR-independent pathway for dendritic cell activation that can be the target of viral interference.