Almost 70 years after the discovery of type I interferons (IFNs) in 1957 by Isaacs and Lindenmann 1, 2, and type II IFN in 1965 by Wheelock [3], type III IFNs (IFN-λ1, IFN-λ2, and IFN-λ3 in 2003 and IFN-λ4 in 2013) became the latest type of this fascinating family of secreted molecules named on the basis of their antiviral function to be discovered 4•, 5•, 6. Human IFN-λ1, IFN-λ2, and IFN-λ3 were previously known as IL-29, IL-28A, and IL-28B, respectively, perhaps due to the low level of similarity of their sequences to those of both IL-10 and type I IFNs (∼11–13% amino-acid identity for IL-10, 15–19% amino-acid identity for IFN-α) [5]. The receptor for type III IFNs was identified at the same time as IFN-λ1-3 4•, 7. The amino-acid sequences of human IFN-λ1, IFN-λ2, and IFN-λ3 are 81–96% identical. IFN-λ4 is most closely related to IFN-λ3, but these two molecules display only ∼30% amino-acid sequence identity 8, 9•. Consistently, IFN-λ1, IFN-λ2, and IFN-λ3 have similar antiviral functions via the induction of interferon-stimulated genes (ISGs), with IFN-λ1 being the most potent [5]. IFN-λ4 also has more rapid antiviral activity than the other three IFN-λs, and several studies have suggested that this rapidity may be important for the downregulation of type I IFN responses [9]. Interestingly, the type III IFN receptor has one subunit, IL10RB, in common with the receptor for IL-10 family cytokines, whereas the other subunit, IFNLR1, is specific to the receptor for type III IFNs [10]. In humans, the genomic structure of the genes encoding the three types of IFNs and their receptors further attests to their connection with the IL-10 cytokine family (Figure 1). The genes encoding type I and III IFNs form two separate clusters on chromosomes 9 and 19, whereas the gene encoding the single type II IFN, IFN-γ, clusters with those encoding IL-26 and IL-22 on chromosome 12. The genes for the two subunits of the type III IFN receptor are located close to the genes for the type I and II IFN and IL-10 family cytokine receptors on chromosome 21 (Figure 1) [11]. The receptors for type I, II, and III IFNs, respectively, IFNAR1/2, IFNGR1/2, and IFNLR1/IL10RB, are members of the class II cytokine receptors [12].

Like type I IFNs, human type III IFNs are thought to have antiviral activity. Both type I and III IFNs are induced by viral infection at least through Toll-like receptors (TLRs), retinoic acid-inducible gene 1 (RIG-1)-like receptors (RLRs), and cyclic GMP-AMP synthase-stimulator of interferon genes [13]. Both are monomers that bind to their receptor to activate the interferon-stimulated gene factor 3 (ISGF-3) complex (STAT1-STAT2-IRF9) via Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways [10]. Both trigger the expression of largely overlapping ISGs (Figure 2) [10], and both have antiviral activity in vitro 10, 14•. What differentiates type I IFNs from type III IFNs is their site of action, determined essentially by the expression patterns of their receptors. Type I IFN receptors are widely expressed, whereas type III IFN receptors are restricted to anatomic barriers, including the respiratory epithelium, the fenestrated endothelium of the liver, the gut epithelium, the skin epithelium, and the endothelial junctions of the blood–brain barrier, as well as hematopoietic cells including B lymphocytes, plasmacytoid dendritic cells (pDCs), monocytes, and neutrophils 10, 14•, 15, 16. However, studies of inborn errors and their phenocopies performed since 2003 have shown that human type I IFNs are essential for protective immunity to certain viruses but surprisingly redundant against many more viruses [17], whereas the essential and nonredundant functions of human type III IFNs remain unknown. This is an important issue, as studies of inborn errors of type II IFN and its autoimmune phenocopy have shown that type II IFN is much more a macrophage-activating factor than an antiviral IFN [18]. We provide here an overview of what is currently known about human type III IFNs, focusing in particular on what is known about their nonredundant functions. Mouse type III IFNs have been reviewed elsewhere 10, 13, 14•.