Résumé
Type I IFNs are potent immunoregulatory cytokines that exert antiviral and antiproliferative activities. They act through a common cell surface receptor made of two subunits, IFNAR2 and IFNAR1. Among the 15 human subtypes, IFNβ is the most potent at least in some bioactivities, eg over 50 fold more potent than IFNα2 in growth inhibition. IFNs α and IFNβ are produced in vivo in response to distinct inducers and their differential potency may have physiological relevance in regulating the immune response.We addressed the long standing question of the molecular basis of the α2/β differential by monitoring early and late readouts in cell models differing in density of surface receptors. We found that, in spite of different receptor assembly competence, IFNα2 and IFNβ are equipotent in activating Stats, in inducing gene expression and cell cycle arrest. The uniqueness of IFNβ resides in its ability to assemble a longer‐lived ligand/receptor ternary complex and to engage IRS‐1/PI3K/p70S6K pathway leading to translational control and higher apoptotic potency. Higher potency of IFNβ is also observed following secondary stimulation of cells primed with type I or type III IFNs (IFN λ). In this context, the IFN‐induced USP18 isopeptidase interacts with IFNAR2 and affects assembly of binding sites, causing higher refractoriness to α IFNs.