title: Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway.
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.
authors.affiliation: Emory Vaccine Center, Atlanta, GA 30329, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Cao
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: Sudhir Pai
authors.initials: SP
authors.lastname: Kasturi
authors.forename: Ali
authors.initials: A
authors.lastname: Pirani
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran