IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo

Abstract

Interferons (IFN) exert antiviral, immunomodulatory and cytostatic activities. IFN-α/β (type I IFN) and IFN-λ (type III IFN) bind distinct receptors, but regulate similar sets of genes and exhibit strikingly similar biological activities. We analyzed to what extent the IFN-α/β and IFN-λ systems overlap in vivo in terms of expression and response. We observed a certain degree of tissue specificity in the production of IFN-λ. In the brain, IFN-α/β was readily produced after infection with various RNA viruses, whereas expression of IFN-λ was low in this organ. In the liver, virus infection induced the expression of both IFN-α/β and IFN-λ genes. Plasmid electrotransfer-mediated in vivo expression of individual IFN genes allowed the tissue and cell specificities of the responses to systemic IFN-α/β and IFN-λ to be compared. The response to IFN-λ correlated with expression of the α subunit of the IFN-λ receptor (IL-28Rα). The IFN-λ response was prominent in the stomach, intestine and lungs, but very low in the central nervous system and spleen. At the cellular level, the response to IFN-λ in kidney and brain was restricted to epithelial cells. In contrast, the response to IFN-α/β was observed in various cell types in these organs, and was most prominent in endothelial cells. Thus, the IFN-λ system probably evolved to specifically protect epithelia. IFN-λ might contribute to the prevention of viral invasion through skin and mucosal surfaces.

Author Summary

Virus-infected cells can secrete interferons (IFNs), cytokines that induce an infection-resistant state in neighboring cells. IFNs are critical to slow down early multiplication of pathogens in the body. Two IFN families exhibiting strikingly similar properties were described: type I IFNs (or IFN-α/β) and type III IFNs (or IFN-λ). Our work addressed the question of the redundancy of these two IFN systems in vivo. First, we found that the relative expression of IFN-λ over that of IFN-α/β exhibited some extent of tissue specificity and was low in the brain. Next, we used a strategy based on in vivo expression of cloned IFN genes to compare the responses of different tissues to IFN-α and IFN-λ. As was suggested by previous in vitro work, response to IFN-λ appeared to be restricted to epithelial cells, unlike response to IFN-α which occurred in most cell types. Tissues with a high epithelial content such as intestine, skin or lungs were the most responsive to IFN-λ and expressed the higher amounts of IFN-λ receptor. Our data suggest that the IFN-λ system evolved as a specific protection of epithelia and that it might contribute to prevent viral invasion through skin and mucosal surfaces.