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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Le Bon, A. & Tough, D. F. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Immunol. 14, 432–436 (2002)
Colonna, M., Krug, A. & Cella, M. Interferon-producing cells: on the front line in immune responses against pathogens. Curr. Opin. Immunol. 14, 373–379 (2002)
Jacobs, B. L. & Langland, J. O. When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. Virology 219, 339–349 (1996)
Williams, B. R. Signal integration via PKR. Sci. STKE 2001(89), RE2 (2001); at 〈http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/89/re2〉
Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001)
Garcia-Sastre, A. et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324–330 (1998)
Bergmann, M. et al. Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication. J. Virol. 74, 6203–6206 (2000)
Dalod, M. et al. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J. Exp. Med. 195, 517–528 (2002)
Borrow, P., Evans, C. F. & Oldstone, M. B. Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression. J. Virol. 69, 1059–1070 (1995)
Katze, M. G., He, Y. & Gale, M. Viruses and interferon: A fight for supremacy. Nature Rev. Immunol. 2, 675–687 (2002)
Hochrein, H. et al. Differential production of IL-12, IFN-α, and IFN-γ by mouse dendritic cell subsets. J. Immunol. 166, 5448–5455 (2001)
Edwards, A. D. et al. Microbial recognition via toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering. J. Immunol. 169, 3652–3660 (2002)
Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998)
Horng, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunol. 2, 835–841 (2001)
Balachandran, S. et al. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13, 129–141 (2000)
Marcus, P. I. & Sekellick, M. J. Interferon induction by viruses. XVI. 2-Aminopurine blocks selectively and reversibly an early stage in interferon induction. J. Gen. Virol. 69, 1637–1645 (1988)
Zinn, K., Keller, A., Whittemore, L. A. & Maniatis, T. 2-Aminopurine selectively inhibits the induction of β-interferon, c-fos, and c-myc gene expression. Science 240, 210–213 (1988)
Yang, Y. L. et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14, 6095–6106 (1995)
Smith, E. J., Marie, I., Prakash, A., Garcia-Sastre, A. & Levy, D. E. IRF3 and IRF7 phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or IκB kinase but is blocked by Vaccinia virus E3L protein. J. Biol. Chem. 276, 8951–8957 (2001)
Cousens, L. P., Orange, J. S., Su, H. C. & Biron, C. A. Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection. Proc. Natl Acad. Sci. USA 94, 634–639 (1997)
Cella, M. et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nature Med. 5, 919–923 (1999)
Kadowaki, N., Antonenko, S., Lau, J. Y. & Liu, Y. J. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J. Exp. Med. 192, 219–226 (2000)
Nakano, H., Yanagita, M. & Gunn, M. D. Cd11c(+ )b220(+ )gr-1(+ ) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194, 1171–1178 (2001)
Bruno, L., Seidl, T. & Lanzavecchia, A. Mouse pre-immunocytes as non-proliferating multipotent precursors of macrophages, interferon-producing cells, CD8α(+ ) and CD8α(- ) dendritic cells. Eur. J. Immunol. 31, 3403–3412 (2001)
O'Keeffe, M. et al. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8(+ ) dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307–1319 (2002)
Siegal, F. P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999)
Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nature Immunol. 2, 1144–1150 (2001)
Marie, I., Durbin, J. E. & Levy, D. E. Differential viral induction of distinct interferon-α genes by positive feedback through interferon regulatory factor-7. EMBO J. 17, 6660–6669 (1998)
Edwards, A. D. et al. Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines. Eur. J. Immunol. 33, 827–833 (2003)
van den Hoff, M. J., Christoffels, V. M., Labruyere, W. T., Moorman, A. F. & Lamers, W. H. Electrotransfection with “intracellular” buffer. Methods Mol. Biol. 48, 185–197 (1995)
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature01783
This article is cited by
-
Effects of Vibration Characteristics on the Atomization Performance in the Medical Piezoelectric Atomization Device Induced by Intra-Hole Fluctuation
Chinese Journal of Mechanical Engineering (2021)
-
Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution
Mucosal Immunology (2021)
-
Intratumoural administration and tumour tissue targeting of cancer immunotherapies
Nature Reviews Clinical Oncology (2021)
-
Activation of the PKR/eIF2α signaling cascade inhibits replication of Newcastle disease virus
Virology Journal (2014)
-
Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates
Nature (2014)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.