Type III IFNs: Beyond antiviral protection

Abstract

The unexpected discovery of a novel family of antiviral mediators, type III IFNs or IFN-λs, challenged the widely accepted primacy of type I IFNs in antiviral immunity, and it is now well recognized that the IFN-λ-based antiviral system plays a major role in antiviral protection of epithelial barriers. The recent characterization of previously unknown IFN-λ-mediated activities has prompted further reassessment of the role of type I IFNs in innate and adaptive immune and inflammatory responses. Since type I and type III IFNs are co-produced in response to a variety of stimuli, it is likely that many physiological processes are simultaneously and coordinately regulated by these cytokines in pathological conditions, and likely at steady state, as baseline expression of both IFN types is maintained by microbiota. In this review, we discuss emerging differences in the production and signaling of type I and type III IFNs, and summarize results of recent studies describing the involvement of type III IFNs in anti-bacterial and anti-fungal, as well as antiviral, defenses.

Keywords: Antiviral protection; Epithelial barrier; Immune response; Interferon; Microbial infection; Neutrophils.

Fig. 1.. Division of labor between type I and type III IFNs in antiviral response.

A. Epithelial (Epith) cells are the main source of type III IFNs. Macrophage (Mac), monocytes (Mo) and dendritic cells (DC) can also produce type III IFNs, but primarily produce IFN-αs. IFN-λs act on epithelial cells and tissue-residing neutrophils (Neut), dendritic cells and macrophages, and B cells and plasmacytoid DCs in blood. Most cell types in tissue and in blood including T, B, NK, dendritic, stromal and endothelial cells, Intraepithelial lymphocytes (IEL), macrophages and neutrophils, but not mucosa-lining epithelial cells respond to type I IFNs. B. IRF3, IRF7 and NF-κB are the key transcription factors regulating IFN expression. IRF1 and MAPK signaling has a stronger regulatory effects on type III IFN then on type I IFN production. All type I and all type III IFNs engage distinct IFN-type-specific receptor complexes, but signal through the JAK-STAT pathway resulting in the activation of the same ISGF3 transcription complex and expression of ISGs many of which encode proteins with antiviral functions. Some activities of type III IFNs are also regulated through MAPK signaling and JAK2 involvement.