As other cytokine receptors, the type I interferon (IFN) receptor (IFNAR) is comprised of multiple components, in this case designated IFNAR1 and IFNAR2. However it is unique among cytokine receptors in the number of cognate ligands, including 13 IFNα subtypes, β, ω, ϵ, κ, and others in some species. The type I IFN receptors are distinct from those required for the type II IFNγ (IFNGR1 and IFNGR2) and type III IFNs (IFNLR and IL10Rβ). Nevertheless, genes encoding a component of each type of IFN receptor, namely IFNAR1, IFNAR2, IFNGR2, and IL10Rβ, are located on human chromosome 21q22.1 in a cytokine receptor gene cluster, as typical of functionally related genes.
The type I interferon receptor (IFNAR) has important roles in mediating type I IFN responses in hemopoiesis and innate and acquired immunity to infection and cancer. However, IFNs elicit many biological effects that can even be opposite in different cell types. For example, type I IFN inhibits proliferation and is proapoptotic for many cell types, yet it prolongs the survival of memory T cells. Understanding the function of the IFNAR complex will elucidate how such a diversity of biological outcomes is generated.
The IFN-gamma receptor consists of two transmembrane chains, IFNGR1 and IFNGR2, both of which are required for activity. The IFNGR1 chain binds the IFN-gamma ligand, whereas the IFNGR2 chain is required for signal transduction. After ligand binding, Jak1 and Jak2 kinases are activated by phosphorylation and then phosphorylate the IFNGR1 chain, which serves as the recruitment site for Stat1alpha (signal transducers and activators of transcription).
Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Although IFNs were identified 50 years ago and the existence of IFN receptors 10 years later, it was in 1990 when the first type I IFN receptor, now designated IFNAR1, was cloned. This was achieved utilizing human gene libraries expressed in murine cells and rescue of the definitive, species specific antiviral activity of human IFNα8. IFNAR2 cloning was achieved first by identifying a human IFN binding activity in urine, peptide sequencing, and then by gene library screening with derived oligonucleotides. It was subsequently discovered that the original cDNA encoded only one isoform of the IFNAR2 gene, which also encoded a long transmembrane isoform that transduced a signal, a truncated transmembrane isoform, and a soluble/secreted isoform.
IFN-γ is involved in the regulation of the immune and inflammatory responses; in humans, there is only one type of interferon-gamma. It is produced in activated T-cells and natural killer cells. The receptors of type I interferon and type II interferon are IFNAR1 and IFNAR2.
Since the original discovery of the classical JAK (Janus activated kinase) STAT (signal transducer and activator of transcription) pathway of signalling, it has become clear that the coordination and cooperation of multiple distinct signalling cascades-including the mitogen-activated protein kinase p38 cascade and the phosphatidylinositol 3-kinase cascade-are required for the generation of responses to interferons.
The discovery and initial description of the interferon-ambda (IFN-λ) family in early 2003 opened an exciting new chapter in the field of IFN research. There are 3 IFN-λ genes that encode 3 distinct but highly related proteins denoted IFN-λ1, -λ2, and -λ3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Collectively, these 3 cytokines comprise the type III subset of IFNs. Although type I IFNs (IFN-α/β) and type III IFNs (IFN-λ) signal via distinct receptor complexes, they activate the same intracellular signaling pathway and many of the same biological activities, including antiviral activity, in a wide variety of target cells. Consistent with their antiviral activity, expression of the IFN-λ genes and their corresponding proteins is inducible by infection with many types of viruses. Therefore, expression of the type III IFNs (IFN-λs) and their primary biological activity are very similar to the type I IFNs.