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.

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