title: IRF-7 is the master regulator of type-I interferon-dependent immune responses.
abstract: The type-I interferon (IFN-alpha/beta) response is critical to immunity against viruses and can be triggered in many cell types by cytosolic detection of viral infection, or in differentiated plasmacytoid dendritic cells by the Toll-like receptor 9 (TLR9) subfamily, which generates signals via the adaptor MyD88 to elicit robust IFN induction. Using mice deficient in the Irf7 gene (Irf7-/- mice), we show that the transcription factor IRF-7 is essential for the induction of IFN-alpha/beta genes via the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Viral induction of MyD88-independent IFN-alpha/beta genes is severely impaired in Irf7-/- fibroblasts. Consistently, Irf7-/- mice are more vulnerable than Myd88-/- mice to viral infection, and this correlates with a marked decrease in serum IFN levels, indicating the importance of the IRF-7-dependent induction of systemic IFN responses for innate antiviral immunity. Furthermore, robust induction of IFN production by activation of the TLR9 subfamily in plasmacytoid dendritic cells is entirely dependent on IRF-7, and this MyD88-IRF-7 pathway governs the induction of CD8+ T-cell responses. Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Sato
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Mizutani
authors.forename: Naoya
authors.initials: N
authors.lastname: Shimada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000276:immunology; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I / Q000276:immunology*; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051217:Toll-Like Receptor 9; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C084881:flt3 ligand protein