Type I interferons (IFNs) (alpha/beta interferon [IFN-␣/␤]) are expressed as a first line of defense against viruses and are known to play a critical role in the antiviral response (38). Type I IFNs combat viruses both directly by inhibiting virus replication in the cells and indirectly by stimulating the innate and adaptive immune responses (38). The direct antiviral activity of type I IFNs is exerted by a number of different mechanisms, e.g., blockage of viral entry into the cell, control of viral transcription, cleavage of RNA, and preventing translation (16,31,37). In addition to the direct effects, type I IFNs play immunoregulatory roles and thereby shape the innate and adaptive immune responses. For instance, IFN-␣/␤ induce natural killer cell cytotoxicity and up-regulate expression of major histocompatibility complex class I on most cells and costimulatory molecules on antigen-presenting cells (9, 37). Furthermore, type I IFNs enhance cross-presentation of exogenous antigen in major histocompatibility complex class I and promote T-cell expansion (14,19,36 (11,15,20,23,32), although they exert their action through a receptor complex distinct from the type I IFNs (20,32). Most of the reports demonstrating antiviral activity of IFN-have addressed the issue in an in vitro experimental setup, but one report has shown that a recombinant IFN--expressing vaccinia virus is attenuated in vivo (4), whereas recombinant IFN-had no antiviral effect in vivo in the transgenic hepatitis B virus mouse model (30). Thus, we still do not have a clear picture of the antiviral potential of IFN-in vivo or of the mechanisms of action.The IFN-s have been demonstrated to be induced after stimulation with several single-stranded RNA (ssRNA) viruses, whereas the information on viruses with other genomes (DNA and double-stranded RNA [dsRNA]) is sparse (11). Virtually all cell types are capable of producing type I IFNs in response to viral infections, with the amount of IFN being virus and cell type dependent (7) and with plasmacytoid dendritic cells (pDCs) being the most potent producers of type I IFNs (3). IFN-s can be produced by a number of cell types, although the pattern of expression has not been elucidated. One report has demonstrated that IFN-s are produced by pDCs to a greater extent than by monocyte-derived DCs after influenza A virus (IAV) infection, suggesting that pDCs are the primary IFN--producing cells (13). However, this needs to be confirmed for other virus infections.Here, we have investigated the expression of type I and III IFNs after infection with DNA and RNA viruses in lymphoid, myeloid, and epithelial cell lines, and we have also examined the ability of type I and III IFNs to cross-induce one another. Subsequently, we investigated the antiviral activity of IFN-in

Type III IFNs (IFN-λ/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-λ 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-28Rα-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-αβ expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-λ expression, whereas IL-28Rα 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-28Rα only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-λ 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.

IFN-functionally resembles type I IFN, inducing antiviral protection in vitro (10,23,27) as well as in vivo (1). Activation of the IFN-receptor leads to the phosphorylation of STAT1, STAT2, and STAT3 and the formation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor (10) and to the induction of typical IFN-induced genes like the OAS and MxA genes. IFN-can reduce cell growth in vitro and possesses antitumor activity in several rodent models (11,25). However, a number of cytokines with very different biological effects activate STAT transcription factors, and pronounced functional differences between type I and type III IFNs exist. The in vivo antiviral activity of IFN-against herpes simplex virus 2 (HSV-2) has been shown to be comparable to that of IFN-␣ in a systemic model. However, a model for the clinically relevant vaginal HSV-2 infection revealed an antiviral activity of IFN-that surpassed that of IFN-␣ (1).The biological effect of the cytokine-receptor system is determined primarily by three factors: the expression profile of the cytokine itself, the expression profile of the receptor, and the set of target genes for regulation. We decided to start our investigation of the function of the IFN-system by asking which genes are regulated by IFN-. A gene array experiment covering the whole human genome revealed that all IFN--induced genes were also induced by type I IFN. Thus, no genes

Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-␣/␤) response is derived from several cell types and induced independently of TLR9. In conventional DCs, the IFN response occurred independently of viral replication but was dependent on viral entry. Moreover, using a HSV-1 UL15 mutant, which fails to package viral DNA into the virion, we found that entry-dependent IFN induction also required the presence of viral genomic DNA. In macrophages and fibroblasts, where the virus was able to replicate, HSV-induced IFN-␣/␤ production was dependent on both viral entry and replication, and ablated in cells unable to signal through the mitochondrial antiviral signaling protein pathway. Thus, during an HSV infection in vivo, multiple mechanisms of pathogen recognition are active, which operate in cell-type-and timedependent manners to trigger expression of type I IFN and coordinate the antiviral response.

The first line of defense against viral infections is mediated by interferons (IFN)s, which are produced rapidly by the infected host. Type I IFNs (IFN-alpha/beta) are known to combat viruses both directly by inhibiting viral replication in the cells and indirectly by stimulating the innate and adaptive immune responses. Recently, a novel class of cytokines was discovered and named IFN-lambda (alternatively type III IFN or interleukin-28/29 [IL- 28/29]), based on IFN-like antiviral activity and induction of typical IFN-inducible genes. Here, we review the literature on IFN-lambda and discuss the current knowledge of the functions and mechanisms of action of IFN-lambda.

Cytokines are small secreted molecules, which mediate cross-talk between cells involved in the immune response. Interferons (IFN)s, constitute a class of cytokines with antiviral activities, and the type I IFNs have been ascribed particularly important roles in the innate antiviral response. Type III IFNs (also known as IFN-lambda or interleukin 28/29) represent a class of novel cytokines with biological activities similar to the type I IFNs, but seem to have a more specialized role in antiviral defense by exerting host-protection primarily at epithelial surfaces. In this review, we describe the current knowledge on the role of type III IFNs in antiviral defense.

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Elimination of viral infections is dependent on rapid recruitment and activation of leukocytes with antiviral activities to infected areas. Chemokines constitute a class of cytokines that have regulatory effects on leukocyte migration and activity. In this study we have studied the role of CC chemokine receptor 1 (CCR1) and CCR5 in host defense during a generalized herpes simplex virus type 2 (HSV-2) infection. Whereas both 4-and 8-week-old CCR1 ؊/؊ mice resembled wild-type mice (C57BL/6) with respect to defense against the infection, significantly higher virus titers were seen in the livers and brains of 4-week-old CCR5 ؊/؊ mice. At the age of 8 weeks, CCR5؊/؊ were indistinguishable from wild-type mice and cleared the infection from liver and spleen. Although 4-week-old CCR5 ؊/؊ mice were able to recruit natural killer (NK) cells to the site of infection, these cells had reduced cytotoxic activity compared to NK cells from wild-type mice. This was not due to lower production of alpha/beta interferon or interleukin-12, two well-described activators of cytotoxic activity in NK cells. We also noted that the spleens of young CCR5 ؊/؊ mice did not increase in size during infection as did the spleens of wild-type and CCR1؊/؊ mice. This observation was accompanied by impaired proliferation of CCR5 ؊/؊ splenocytes (SCs) ex vivo. Moreover, migration of CD8 ؉ T cells to the liver in response to infection was impaired in CCR5 ؊/؊ mice, and adoptive transfer of SCs from CCR5 ؊/؊ mice infected for 6 days into newly infected wild-type mice did not improve antiviral activity in the liver, in contrast to what was seen in mice receiving immune SCs from wild-type mice. Altogether, this study shows that CCR5 plays an age-dependent role in host defense against HSV-2 by supporting both the innate and adaptive immune response.