Configuration of the interferon-α/ß receptor complex determines the context of the biological response

Abstract

Constituents of the Type 1 interferon (IFN) receptor (IFNABR) identified to date include the α and β transmembrane subunits and the associated intracellular kinases, Jak 1 and Tyk 2. In this report, we demonstrate that a human cell type that expresses both subunits of IFNABR, together with Jak 1 and Tyk 2, exhibits a limited binding capacity for and is only partially sensitive to the effects of IFN-α/β, despite adequate levels of the cytoplasmic transcription factors Stat1, Stat2, and Stat3. Specifically, a low affinity interaction between IFN-α/β and cell surface receptors results in ISGF3 (Stat1:2) activation and an antiviral response, yet no IFN-inducible growth inhibition. Using a panel of murine cells that are variably configured with respect to the human IFNABR-α/β subunits, we provide evidence that an additional component(s) encoded on human chromosome 21 is required to confer high affinity binding and IFN-inducible growth inhibition to cells that express the α and β subunits of the IFNABR. The data indicate that transcriptional activation that leads to an antiviral response is mediated by IFN-α/β activation of IFNABR-α and IFNABR-β in the context of a low affinity interaction, yet a high affinity interaction is necessary for signal transducing events that mediate growth inhibition. We provide evidence that the extent of ISGF3 activation correlates directly with the magnitude of an antiviral but not a growth inhibitory response.