An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

作者：Nina Ank, Marie Beck Iversen, Christina Bartholdy, Peter Staeheli, Rune Hartmann, Uffe Birk Jensen, Frederik Dagnæs‐Hansen, Allan Randrup Thomsen, Zhi Jane Chen, Harald S. Haugen, Kevin M. Klucher, Søren R. Paludan · 发表于：The Journal of Immunology · 年份：2008 · DOI：10.4049/jimmunol.180.4.2474 · 被引用次数：428 · 研究领域：Cytokine Signaling Pathways and Interactions、interferon and immune responses、Immune Response and Inflammation

Type III IFNs (IFN-lambda/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-lambda 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-28Ralpha-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-alphabeta expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-lambda expression, whereas IL-28Ralpha 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-28Ralpha only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-lambda and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of...