Interferon at 50: new molecules, new potential, new (and old) questions

Type I interferons (IFNs) are a family of cytokines defined by their antiviral activity but with a broad spectrum of biological activities, including antiproliferative, antitumor, and immunomodulatory effects. Mirroring these activities are diverse therapeutic applications to viral infections, antitumor therapy, and multiple sclerosis. The type I IFNs all signal through a common heterodimeric receptor. The existence of such a large family of cytokines (17 human IFNs) activating a common receptor is unusual. Moreover, the IFNs vary in their relative potency in different assays and are not functionally equivalent. How this functional variation is mediated through a common receptor has not been understood. Reports have now highlighted the interaction of IFNs with the low-affinity receptor subunit IFNAR-1 as a surprising key to their differential activity, particularly regarding antiproliferative and antitumor activities. Two groups have used contrasting approaches to produce variant IFN-alpha proteins with novel activity profiles. These advances portend enhanced therapeutic possibilities based on the better understanding of IFN-receptor interactions, while raising interesting mechanistic questions.