The Journal of Experimental Medicine
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Published 19 February 2002. doi:10.1084/jem.20011672
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© Rockefeller University Press, 0022-1007/2002/2/517/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 4, February 18, 2002 517-528

Original Article

 Interferon {alpha}/ß and Interleukin 12 Responses to Viral Infections : Pathways Regulating Dendritic Cell Cytokine Expression In Vivo



Marc Dalod1, Thais P. Salazar-Mather1, Lene Malmgaard1, Casey Lewis1, Carine Asselin-Paturel2, Francine Brière2, Giorgio Trinchieri2 and Christine A. Biron1

1 Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912
2 Schering-Plough, Laboratory for Immunological Research, Dardilly F-69571, France

Address correspondence to Christine A. Biron, Dept. of Molecular Microbiology and Immunology, Division of Biology and Medicine, Box G-B629, Brown University, Providence, RI 02912. Phone: 401-863-2921; Fax: 401-863-1971; E-mail: Christine_Biron{at}Brown.edu

Interferon (IFN)-{alpha}/ß and interleukin (IL)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. The studies presented here identified a novel subset of dendritic cells (DCs) as major producers of the cytokines during murine cytomegalovirus (MCMV) but not lymphocytic choriomeningitis virus (LCMV) infections. These DCs differed from those activated by Toxoplasma antigen but were related to plasmacytoid cells, as assessed by their CD8{alpha}+Ly6G/C+CD11b- phenotype. Another DC subset (CD8{alpha}2Ly6G/C-CD11b+) also contributed to IL-12 production in MCMV-infected immunocompetent mice, modestly. However, it dramatically increased IL-12 expression in the absence of IFN-{alpha}/ß functions. Conversely, IFN-{alpha}/ß production was greatly reduced under these conditions. Thus, a cross-regulation of DC subset cytokine responses was defined, whereby secretion of type I IFNs by CD8{alpha}+ DCs resulted in responses limiting IL-12 expression by CD11b+ DCs but enhancing overall IFN-{alpha}/ß production. Taken together, these data indicate that CD8{alpha}+Ly6G/C+CD11b- DCs play important roles in limiting viral replication and regulating immune responses, through cytokine production, in some but not all viral infections. They also illustrate the plasticity of cellular sources for innate cytokines in vivo and provide new insights into the roles of IFNs in shaping immune responses to viruses.

Key Words: DC • IL-12 • IFN-{alpha}/ß • MCMV • LCMV


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