Type I Interferon Receptors: Biochemistry and Biological Functions*

The type I interferon (IFN)2 receptor (IFNAR) is comprised, as other cytokine receptors, 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 IFN subtypes, , , , , and others in some species. The type I IFN receptors are distinct from those required for the type II IFN (IFNGR1 and IFNGR2) and type III IFNs (IFNLR and IL10R ). Nevertheless, genes encoding a component of each type of IFN receptor, namely IFNAR1, IFNAR2, IFNGR2, and IL10R , are located on human chromosome 21q22.1 in a cytokine receptor gene cluster, as typical of functionally related genes. Although IFNswere identified 50 years ago and the existence of IFN receptors 10 years later, it was in 1990when 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 IFN 8 (1). 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 (2). 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 (3) (Fig. 1A). Subsequently, the functions of the type I IFN receptors have been elucidated with respect to ligand interaction, mechanisms of signal transduction, and biological responses. The pioneering studies that discovered IFNARs and their mechanisms of actions in vitro have been largely validated in vivo using genetargetedmice. This body of work has highlighted the important roles of IFNARs inmediating 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 (4), yet it prolongs the survival of memory T cells (5). Understanding the function of the IFNAR complexwill elucidate how such a diversity of biological outcomes is generated.