Shared receptor components but distinct complexes for α and β interferons 1 1Edited by M. Yaniv

The type I interferon family includes 13 α, one ω and one β subtypes recognized by a complex containing the receptor subunits ifnar1 and ifnar2 and their associated Janus tyrosine kinases, Tyk2 and Jak1. To investigate the reported differences in the way that α and β interferons signal through the receptor, we introduced alanine-substitutions in the ifnar2 extracellular domain, and expressed the mutants in U5A cells, lacking endogenous ifnar2. A selection, designed to recover mutants that responded preferentially to α or β interferon yielded three groups: I, neutral; II, sensitive to α interferon, partially resistant to β interferon; III, resistant to α interferon, partially sensitive to β interferon. A mutant clone, TMK, fully resistant to α interferon with good sensitivity to β interferon, was characterized in detail and compared with U5A cells complemented with wild-type ifnar2 and also with Tyk2-deficient 11.1 cells, which exhibit a similar α-unresponsive phenotype with a partial β interferon response. Using anti-receptor antibodies and mutant forms of β interferon, three distinct modes of ligand interaction could be discerned: (i) α interferon with ifnar1 and ifnar2; (ii) β interferon with ifnar1 and ifnar2; (iii) β interferon with ifnar2 alone. We conclude that α and β interferons signal differently through their receptors because the two ligand subtypes interact with the receptor subunits ifnar 1 and ifnar2 in entirely different ways.