The unique regulation and functions of type III interferons in antiviral immunity

Abstract

Type I interferons (IFNs) were long considered to be the sole IFN species produced by virus-infected cells until the discovery of type III IFNs (IFNλs), decades later. Like type I IFNs, type III IFNs are induced by and protect against viral infections, leading to the initial conclusion that the two IFN species are identical in regulation and biological functions. However, the two systems differ in the tissue expression of their receptor, resulting in different roles in vivo. The unique nature of IFNλs has been further demonstrated by recent studies revealing differences in the regulation of type I and III IFN expression, and how these proteins elicit specific cellular responses. This review focuses on the distinctive features of type III IFNs in antiviral innate immunity.

Figure 1. Signaling upstream and downstream of type III interferons (IFNs)

MAVS on peroxisomes mediates type III IFN (IFNλ) signaling downstream of viral RNA detection by RIG-I like receptors (RLRs). IFNλ is expressed by IRF1, IRF3 and NFκB. Type I IFN (IFNβ) is induced by the combined action of IRF3, NFκB and AP-1, downstream of peroxisomal MAVS. Ligation of the type I IFN receptor (IFNAR) activates JAK1 and Tyk2 to induce ISG expression through ISGF3. The type III IFN receptor (IFNλR) probably requires JAK1 and JAK2 to activate STAT phosphorylation.

Figure 2

Bioassays to specifically detect IFNβ and IFNλ in mouse cells. L929 cells do not respond to mouse IFNλ2 but enable the detection of increasing concentrations of mouse IFNβ (a). As IFNλs are able to signal across species but IFNβ is not, human 293T cells are able to detect mouse IFNλ2 but not IFNβ. Units are in μg/ml (IFNλ2) or in units/ml (IFNβ).