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International Immunology Advance Access published online on November 13, 2007
International Immunology, doi:10.1093/intimm/dxm119
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Individual plasmacytoid dendritic cells are major contributors to the production of multiple innate cytokines in an organ-specific manner during viral infection

Nicolas Zucchini1,2,3, Gilles Bessou1,2,3, Scott H. Robbins1,2,3, Lionel Chasson1,2,3, Anna Raper4, Paul R. Crocker4 and Marc Dalod1,2,3

1 Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, 13288 Marseille cedex 9, France
2 Institut National de la Santé et de la Recherche Médicale, U631, 13288 Marseille, France
3 Centre National de la Recherche Scientifique, UMR6102, 13288 Marseille, France
4 Division of Cell Biology and Immunology, Wellcome Trust Biocentre WTB2, University of Dundee, Dow Street, Dundee DD1 5EH, UK

Correspondence to: Correspondence to: M. Dalod; E-mail: dalod{at}ciml.univ-mrs.fr.

Plasmacytoid dendritic cells (pDCs) are an important source of IFN-{alpha}/ß in response to a variety of viruses in vivo, including murine cytomegalovirus (MCMV). However, the respective contributions of various infected organs, and within these of pDCs, conventional dendritic cells and other cells, to the systemic production of IFN-{alpha}/ß or other innate cytokines during viral infections in vivo is largely unknown. Whether a specialization of pDC subsets in the production of different patterns of innate cytokines exists in vivo in response to a viral infection has not been investigated. Here, by analyzing for the first time directly ex vivo, at the single-cell level, the simultaneous production of up to three cytokines in pDCs isolated from MCMV-infected mice, we show that (i) pDCs are the quasi-exclusive source of IFN-{alpha}/ß, IL-12 and tumor necrosis factor (TNF)-{alpha}, early during MCMV infection, in two immunocompetent mouse lines and with two viral strains, (ii) pDC activation for IFN-{alpha}/ß production is organ specific and (iii) a significant proportion of pDCs simultaneously produce IFN-{alpha}/ß, TNF-{alpha} and IL-12, although TNF-{alpha} and IFN-{alpha}/ß appear more often co-expressed with one another than each of them with IL-12. Altogether, these results show a broad and non-redundant role of pDCs in early innate detection of, and defense against, viral infection. The data also show differences in the responsiveness of pDCs from different tissues and suggest distinct molecular requirements for pDC production of various cytokines. These observations must be taken into account when designing new antiviral vaccination strategies aimed at harnessing pDC responses.

Keywords: dendritic cells, IFN-{alpha}/ß, IL-12, murine cytomegalovirus, tumor necrosis factor-{alpha}

Transmitting editor: G. Trinchieri

Received 5 April 2007, accepted 15 October 2007.


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