Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway

Nat Immunol. 2008 Oct;9(10):1157-64. doi: 10.1038/ni.1645. Epub 2008 Aug 31.

Abstract

Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • Gene Expression Regulation / immunology
  • Humans
  • Immunoblotting
  • Immunosuppressive Agents / pharmacology
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Mice
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinases / immunology
  • Protein Kinases / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / immunology
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / immunology*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism*
  • Transfection

Substances

  • Immunosuppressive Agents
  • Interferon Type I
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Protein Kinases
  • MTOR protein, human
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Sirolimus