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/IL-28) in TLR-Induced Antiviral Activity1
* Institute of Medical Microbiology and Immunology,
Department of Molecular Biology, and
Institute of Human Genetics, University of Aarhus, Aarhus;
Institute of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
¶ Department of Virology, University of Freiburg, Freiburg, Germany; and
|| ZymoGenetics, Seattle, WA 98102
Type III IFNs (IFN-
/IL-28/29) are cytokines with type I IFN-like antiviral activities, which remain poorly characterized. We herein show that most cell types expressed both types I and III IFNs after TLR stimulation or virus infection, whereas the ability of cells to respond to IFN- was restricted to a narrow subset of cells, including plasmacytoid dendritic cells and epithelial cells. To examine the role of type III IFN in antiviral defense, we generated IL-28R
-deficient mice. These mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses, whereas mice lacking the type I IFN receptor (IFNAR–/–) were significantly impaired. However, the strong antiviral activity evoked by treatment of mice with TLR3 or TLR9 agonists was significantly reduced in both IL-28RA–/– and IFNAR–/– mice. The type I IFN receptor system has been shown to mediate positive feedback on IFN-β expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN- expression, whereas IL-28R signaling does not provide feedback on either type I or type III IFN expression in vivo. Finally, using bone-marrow chimeric mice we showed that TLR-activated antiviral defense requires expression of IL-28R only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN- and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research grants from Danish Medical Research Council (Grant 271-06-0438), The Danish Natural Science Research Council (Grant 272-05-0222), The Lundbeck Foundation (Grants 104/04 and 116/06), Kong Chr. IX og Dronning Louises Jubilæumslegat, Aase og Ejnar Danielsens Fond, and the Research Programme in Molecular Medicine, Faculty of Health Science, University of Aarhus. N.A. was supported by fellowships from the Faculty of Health Science, University of Aarhus.
2 Address correspondence and reprint requests to Dr. Søren R. Paludan, Institute of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark. E-mail address: srp{at}microbiology.au.dk
3 Abbreviations used in this paper: MHC-I, MHC class I; BM, bone marrow; cDC, conventional dendritic cell; DC, dendritic cell; EMCV, encephalomyocarditis virus; ES, embryonic stem; IAV, influenza A virus; IFNAR, IFN-β receptor; IL-28R, IL-28 receptor; IRES, internal ribosome entry site; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; LCMV, lymphocytic choriomeningitis virus; MAVS, mitochondrial antiviral signaling protein; MEF, mouse embryonic fibroblast; OAS, 2'-5' oligoadenylate synthetase; pDC, plasmacytoid dendritic cell; p.i., postinfection; TLR, Toll-like receptor; VSV, vesicular stomatitis virus; WT, wild-type.
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