The role of IRF7 in interferon production during the innate immune response to viral infection.

摘要

Interferon Regulatory Factors (IRFs) are a family of transcription factors that regulate the expression of diverse genes, including, the Interferon (IFN) gene family. IFNβ is usually generated in response to virus infection. IRF3 and IRF7 are required for mediating the cellular responses to viral infection by controlling the production of these type I IFNs.; IRF7 is not expressed in most cells but is IFN-inducible and critically required for the amplified and sustained induction of IFNα and IFNβ. We showed that IRF7 was constitutively expressed in certain cell lines and primary splenocytes and thymocytes. Constitutive IRF7 expression correlated with the ability to produce large amounts of IFNα, with accelerated kinetics. Furthermore, we demonstrated that splenic cell populations that expressed high levels of constitutive IRF7 were dendritic cells (DCs), specifically, the plasmacytoid DC (PDC). When PDCs were depleted from splenocytes, the ability to produce IFNα following infection decreased dramatically. The PDC was recently described as the long sought-after natural IFN-producing cell (IPC), the source of major IFNα production in the body. In vitro generated PDCs were able to express IRF7 and produce IFNα. Constitutive IRF7 expression provides a potential mechanism to explain the ability of PDCs to generate high levels of IFNα following infection.; To explore the nature of the high IRF7 expression in the PDC, we demonstrated that IRF7 expression could be IFN-independent as PDCs from stat1−/− mice expressed IRF7 and made IFNα following infection. Additionally, we measured the half-life of the IRF7 protein and demonstrated that it was short-lived in the PDC. These results suggested that expression of IRF7 in the PDC was most likely mediated by an IFN-independent transcriptional mechanism and not due to altered protein stability.; Finally, we explored the nature of the DNA binding domain (DBD) of IRF7 and showed that the IRF7 and IRF3 DBDs were quite different. We also examined possible IRF7 inter-domain interactions and proposed a structural model for activation-induced conversion of IRF7 from a closed monomer to an open homodimer.; Thus, IRF7 expression and functionality are critical features of the PDC that allow it to perform the role of the natural IFN-producing cell.