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Viral infection switches non-plasmacytoid dendritic cells into high interferon producers

Abstract

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.

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Figure 1: Viral infection or cytosolic dsRNA can induce high levels of IFN-α production by non-plasmacytoid splenic dendritic cells.
Figure 2: Cytosolic administration of dsRNA induces IFN-α production by BM-DCs.
Figure 3: IFN-α induction by dsRNA does not require TLR signalling but is largely dependent on PKR.
Figure 4: Infection with ΔNS1 influenza allows IFN-α production by non-plasmacytoid dendritic cells.

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Acknowledgements

This work was funded by Cancer Research UK. We thank T. Muster for the ΔNS1 virus; K. Thielemans for suggestions on the electroporation protocol; M. Edwards for assistance with the LCMV experiments; M. Albert for advice on the influenza experiments; C. Asselin-Paturel for details of the IFN-α ELISA; and B. Strobl for advice on PKR-/- mice. We are grateful to R. Germain, A. O'Garra, G. Schiavo, D. Cantrell, F. Batista and members of the Immunobiology Laboratory, Cancer Research UK, for advice and critical review of the manuscript. S.S.D. is supported by an EMBO fellowship and a Cancer Research UK postdoctoral fellowship. This is publication number 64 from The Edward Jenner Institute for Vaccine Research. R.F. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Caetano Reis e Sousa.

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Diebold, S., Montoya, M., Unger, H. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324–328 (2003). https://doi.org/10.1038/nature01783

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