An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity.
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 cells and to contribute to the antiviral response evoked by TLRs.
Ank
Nina
N
Institute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark.
Iversen
Marie B
MB
Bartholdy
Christina
C
Staeheli
Peter
P
Hartmann
Rune
R
Jensen
Uffe B
UB
Dagnaes-Hansen
Frederik
F
Thomsen
Allan R
AR
Chen
Zhi
Z
Haugen
Harald
H
Klucher
Kevin
K
Paludan
Søren R
SR
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006558:Herpes Genitalis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011828:Radiation Chimera; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism / Q000502:physiology*; D007378:Interleukins; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016207:Cytokines; D008024:Ligands; D018121:Receptors, Cytokine; D051193:Toll-Like Receptors; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda; C471046:interleukin 28alpha receptor