The interferons (IFNs) are a family of innate immune cytokines that are central in providing a rapid response to pathogens, modulating the immune system, providing cancer protection, and more [1]. They are classified into three distinct families based on their amino acid sequence and receptor usage [2]. Type I and type III IFNs are both comprised of multiple subtypes — in humans, type I IFNs include 12 IFNαs, IFNβ, IFNε, IFNκ, and IFNω and type III IFNs include IFNλ1, IFNλ2, IFNλ3, and IFNλ4. A lone type II IFN has been identified, IFNγ [2]. In this review, we limit the discussion to type I and type III IFNs, which signal through the same components of the JAK/signal transducer and activator of transcription (STAT) pathway (JAK1 and TYK2 kinases activating STAT1 and STAT2). However, while type I IFNs activate all nucleated cells, due to the restricted expression of their receptor, the activity of type III IFNs is mostly restricted to epithelial cells lining mucosal sites [3] and some immune cells including neutrophils [4], B cells, and dendritic cells [5].

Type I and type III IFNs operate via distinct heterodimeric receptor complexes. While type I IFNs bind and signal through the IFNAR1 and IFNAR2 receptor chains, type III IFNs signal through IFNLR1 and IL10R2 receptor chains, where IL10R2 is also a shared receptor of interleukin (IL)-10, IL-22, and IL-26. In both cases, one chain is a high-affinity receptor chain (IFNAR2 and IFNLR1), and one is the low IFN affinity receptor chain (IFNAR1 and IL10R2). However, for type I IFNs, the high- and low-affinity receptors exhibit nM and μM affinity, while for type III IFNs, the affinities are µM and tens of µM, respectively 6, 7. Functional consequences of the much weaker affinities of type III IFNs were discussed elsewhere [2]. Soluble forms of both IFNAR2 and IFNLR1 have been discovered. Soluble IFNAR2 is elevated in the disease [8] and can display intrinsic protective IFN-like activities in human cells [9]. A soluble form of IFNLR1 has also been identified 10, 11, 12, which antagonizes IFNλ3 signaling in human cells [13].

Since the type I and type III IFN receptors both dock TYK2 and JAK1 kinases, ligand engagement of the receptor complexes activate similar canonical JAK/STAT signaling pathways [14], although, as demonstrated using a selective inhibitor, the role of TYK2 is more pronounced for type I IFN activities than for those of the type III IFNs [15]. Noncanonical signaling pathways have also been identified for type I and type III IFNs, including AKT, MAPK/ERK, p38, CrkL-RAP1, and JNK pathways 16, 17. There is also a recent report of the involvement of JAK2 in IFNλ1 signaling in hepatocytes [18].

The overall architecture and structural organization of the ternary IFN receptor complexes of all three IFN families were recently reviewed [2]. We will build on that review delving into the molecular determinants of the ligand–receptor interfaces on the receptor extracellular domains (ECDs), the role of the transmembrane domains (TMD) in signaling, and the organization of the intracellular domains (ICDs) of both the type I and type III IFN systems. We will also discuss the differences between type I and type III IFN systems across species, focusing on the murine and human systems and the characteristics of IFN cross-reactivity across these species.