IRF-7 is the master regulator of type-I interferon-dependent immune responses

Kenya Honda; Hideyuki Yanai; Hideo Negishi; Masataka Asagiri; Mitsuharu Sato; Tatsuaki Mizutani; Naoya Shimada; Yusuke Ohba; Akinori Takaoka; Nobuaki Yoshida; Tadatsugu Taniguchi

doi:10.1038/nature03464

IRF-7 is the master regulator of type-I interferon-dependent immune responses

Nature. 2005 Apr 7;434(7034):772-7. doi: 10.1038/nature03464. Epub 2005 Mar 30.

Authors

Kenya Honda¹, Hideyuki Yanai, Hideo Negishi, Masataka Asagiri, Mitsuharu Sato, Tatsuaki Mizutani, Naoya Shimada, Yusuke Ohba, Akinori Takaoka, Nobuaki Yoshida, Tadatsugu Taniguchi

Affiliation

¹ Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

PMID: 15800576
DOI: 10.1038/nature03464

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Antigens, Differentiation / genetics
Antigens, Differentiation / metabolism
CD8-Positive T-Lymphocytes / immunology
CpG Islands / genetics
CpG Islands / immunology
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Dendritic Cells / cytology
Dendritic Cells / drug effects
Dendritic Cells / immunology
Dendritic Cells / virology
Fibroblasts
Gene Expression Regulation
Immunity, Innate / immunology
Interferon Regulatory Factor-7
Interferon Type I / immunology*
Membrane Proteins / pharmacology
Mice
Mice, Knockout
Myeloid Differentiation Factor 88
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Cell Surface / metabolism
Receptors, Immunologic / deficiency
Receptors, Immunologic / genetics
Receptors, Immunologic / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Toll-Like Receptor 9
Virus Diseases / genetics
Virus Diseases / immunology*

Substances

Adaptor Proteins, Signal Transducing
Antigens, Differentiation
DNA-Binding Proteins
Interferon Regulatory Factor-7
Interferon Type I
Irf7 protein, mouse
Membrane Proteins
Myd88 protein, mouse
Myeloid Differentiation Factor 88
RNA, Messenger
Receptors, Cell Surface
Receptors, Immunologic
Tlr9 protein, mouse
Toll-Like Receptor 9
flt3 ligand protein