Activity of Hybrid Type I Interferons in Cells Lacking Tyk2: A Common Region of IFN-α8 Induces a Response, but IFN-α2/8 Hybrids Can Behave Like IFN-β

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Abstract
Type I interferons (IFNs) are a family of pleiotropic cytokines with antiviral, antiproliferative, and immunomodulatory properties. The type I IFN family consists of 12 IFN-α subtypes, IFN-β, and IFN-ω. Cells lacking the receptor-associated protein kinase Tyk2 (U1A) are responsive only to IFN-β and partially to IFN-α8. We constructed a series of IFN-α2/α8 hybrids and mutants and identified the region within IFN-α8 responsible for its activity in Tyk2-deficient cells. The same domain mediates the interactions between IFN and IFN-α receptor (IFNAR) in Tyk2-complemented and Tyk2-deficient cells (U1A). The presence or absence of Tyk2 altered the inhibitory effects of anti-IFNAR antibodies, suggesting that the IFN-α binding domain on IFNAR is altered by the presence of Tyk2. The activity of IFN-β was not significantly affected by the deletion of Tyk2, and, surprisingly, one of our IFN-α2/α8 hybrids (IFN-α288) behaved like IFN-β in a number of assays that distinguish IFN-αs from IFN-β. This suggests that this hybrid mimics the interactions of IFN-β with the receptor and also suggests the existence of a distinct binding site(s) on IFNAR for IFN-β and some hybrid IFN-αs.