Type I and type III IFNs bind to different cell-surface receptors but induce identical signal transduction pathways, leading to the expression of antiviral host effector molecules. Despite the fact that type III IFN (IFN-λ) has been shown to predominantly act on mucosal organs, in vivo infection studies have failed to attribute a specific, nonredundant function. Instead, a predominant role of type I IFN was observed, which was explained by the ubiquitous expression of the type I IFN receptor. Here we comparatively analyzed the role of functional IFN-λ and type I IFN receptor signaling in the innate immune response to intestinal rotavirus infection in vivo, and determined viral replication and antiviral gene expression on the cellular level. We observed that both suckling and adult mice lacking functional receptors for IFN-λ were impaired in the control of oral rotavirus infection, whereas animals lacking functional receptors for type I IFN were similar to wild-type mice. Using Mx1 protein accumulation as marker for IFN responsiveness of individual cells, we demonstrate that intestinal epithelial cells, which are the prime target cells of rotavirus, strongly responded to IFN-λ but only marginally to type I IFN in vivo. Systemic treatment of suckling mice with IFN-λ repressed rotavirus replication in the gut, whereas treatment with type I IFN was not effective. These results are unique in identifying a critical role of IFN-λ in the epithelial antiviral host defense. IFNs play a critical role in the antimicrobial host defense. Whereas lymphocyte-derived type II IFN (also called IFN-γ) is associated with resistance against a broad range of intracellular microorganisms, type I and III IFN primarily mediate antiviral protection. IFN-α, IFN-β, and all other type I IFN family members use the same heterodimeric receptor complex (IFNAR) for signaling. Receptor engagement leads to activation of the Jak/STAT signaling pathway and expression of IFN-stimulated genes (ISG), which mediate the antiviral state (1). The type III IFN family consists of three members in humans, IFN-λ1, -λ2, and -λ3 that are also named IL29, IL28A, and IL28B, respectively, whereas mice only express IFN-λ2 and -λ3. Type III IFN are structurally different from type I IFN and bind to a distinct heterodimeric receptor (IL28R), consisting of the IL28Rα, also called IFN-λ receptor 1 (IFN-λR1), and the IL10Rβ chains (2-4). Type I and III IFN are both induced following stimulation of pattern recognition receptors of the innate immune system, such as Toll-like receptors and RIG-like helicases (5-7). IFN-λ-triggered signal transduction events and gene activation profiles are virtually indistinguishable from those of the type I IFN system (2,3,8,9). However, the type I and type III IFN systems differ strikingly with regard to the spectrum of responsive cell types. Whereas receptors for type I IFN seem to be present on most if not all nucleated cells, functional receptors for type III IFN are preferentially expressed on epithelial cells (10).Recent studies inves...

Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon-γ (IFN-γ) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology.

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