Interferon-λ in the context of viral infections: production, response and therapeutic implications

Abstract

Interferon (IFN)-λ forms the type III IFN family. Although they signal through distinct receptors, type I (IFN-α/β) and type III IFNs elicit remarkably similar responses in cells. However, in vivo, type III and type I IFN responses are not fully redundant as their respective contribution to the antiviral defense highly depends on virus species. IFN-λ is much more potent than IFN-α/β at controlling rotavirus infection. In contrast, clearance of several other viruses, such as influenza virus, mostly depends on IFN-α/β. The IFN-λ receptor was reported to be preferentially expressed on epithelial cells. Cells responsible for IFN-λ production are still poorly characterized but seem to overlap only partly IFN-α/β-producing cells. Accumulating data suggest that epithelial cells are also important IFN-λ producers. Thus, IFN-λ may primarily act as a protection of mucosal entities, such as the lung, skin or digestive tract. Type I and type III IFN signal transduction pathways largely overlap, and cross talk between these IFN systems occurs. Finally, this review addresses the potential benefit of IFN-λ use for therapeutic purposes and summarizes recent results of genome-wide association studies that identified polymorphisms in the region of the IFN-λ3 gene impacting on the outcome of treatments against hepatitis C virus infection.

Fig. 1

Type I and type III IFN signal transduction pathways. Viral nucleic acids are recognized by transmembrane TLRs, cytoplasmic DNA sensors and RNA helicases, leading to the activation of kinases. These kinases promote the activation of the NF-κB, IRF3 and IRF7 transcription factors and their subsequent translocation to the nucleus where they stimulate IFN gene transcription. IFN-λ1 and IFN-β gene expression largely depends on IRF3 and NF-κB. Expression of IFN-λ2 and IFN-λ3, like that of IFN-α, depends more on IRF7 availability. Type I IFNs use a dimeric receptor composed of IFNAR1 and IFNAR2c. Type III IFNs signal through a different receptor, which is composed of IFNLR1 and IL10RB. Upon binding to their cognate receptors, type I and type III IFNs induce the same Jak/STAT pathway: the transphosphorylation and activation of receptor-associated Jak1 and Tyk2 leads to the phosphorylation of STAT1 and STAT2 transcription factors. Phosphorylated forms of STAT1 and STAT2 further associate with IRF9 to form a heterotrimeric ISG factor 3 (ISGF3) complex. ISGF3 then translocates to the nucleus where it binds to sequences of IFN-stimulated response elements present in the promoter of ISGs to upregulate their transcription. Some ISG products participate themselves in the signaling pathways leading to IFN production and IFN responses thus creating positive (and negative) feedback loops. Given the similarity of type I and type III IFN pathways, IFN-λ is expected to influence both the production of and response to IFN-α/β, and vice versa. cGAS = Cyclic GMP-AMP synthase.

Fig. 2

Relative contributions of type I and type III IFNs in antiviral protection: cartoon illustrating the relative weight of IFN-λ versus IFN-α/β in the control of viral infection. These data were deduced by comparing viral loads in mice deficient for either receptor. HMPV = Human metapneumovirus; RSV = respiratory syncytial virus; SARS-CoV = severe acute respiratory syndrome coronavirus.

Fig. 3

Epithelial specificity of the IFN-λ response in the intestine. Mx1 immunostaining in small-intestine sections of mice treated with IFN. a Response to circulating IFN-α in IFNLR1^0/0 mice; Mx1 is mostly detected in lamina propria cells and little Mx1 expression is detected in epithelial cells. b Response to circulating IFN-λ in IFNAR^0/0 mice; Mx1 expression is restricted to epithelial cells.

Fig. 4

Model of IFN-λ and IFN-α/β responses. By being produced by and acting mostly on epithelial cells, IFN-λ is expected to contribute to an antiviral response that fits anatomical entities such as the gastrointestinal or respiratory mucosae. By acting on most cells, IFN-α/β would act in a rather radial way from the infection focus.