USP18-Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon alpha Response

Abstract

Type I interferons (IFN) are cytokines that are rapidly secreted upon microbial infections and regulate all aspects of the immune response. In humans 15 type I IFN subtypes exist, of which IFN alpha 2 and IFN beta are used in the clinic for treatment of different pathologies. IFN alpha 2 and IFN beta are non redundant in their expression and in their potency to exert specific bioactivities. The more recently identified type III IFNs (3 IFN lambda or IL-28/IL-29) bind an unrelated cell-type restricted receptor. Downstream of these two receptor complexes is a shared Jak/Stat pathway. Several mechanisms that contribute to the shut down of the IFN-induced signaling have been described at the molecular level. In particular, it has long been known that type I IFN induces the establishment of a desensitized state. In this work we asked how the IFN-induced desensitization integrates into the network built by the multiple type I IFN subtypes and type III IFNs. We show that priming of cells with either type I IFN or type III IFN interferes with the cell's ability to further respond to all IFN alpha subtypes. Importantly, primed cells are differentially desensitized in that they retain sensitivity to IFN beta. We show that USP18 is necessary and sufficient to induce differential desensitization, by impairing the formation of functional binding sites for IFN alpha 2. Our data highlight a new type of differential between IFNs alpha and IFN beta and underline a cross-talk between type I and type III IFN. This cross-talk could shed light on the reported genetic variation in the IFN lambda loci, which has been associated with persistence of hepatitis C virus and patient's response to IFN alpha 2 therapy.