@article{43b8836b9fd24ccba9f9904f6cda755e,
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-α/β) 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-α/β 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-α/β production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-α/ β responses by pDCs.",
author = "Weiping Cao and Santhakumar Manicassamy and Hua Tang and Kasturi, {Sudhir Pai} and Ali Pirani and Niren Murthy and Bali Pulendran",
note = "Funding Information: We thank S. Aguilar Mertens and L. Bronner for assistance with cell sorting; D. Kalman for assistance with deconvolution microscopy; K. Schaefer-Hales for assistance with confocal microscopy; T. Querec for YF-17D virus preparation; T. Denning for data discussion and technical advice; R. Nair for in vivo experiments; Y. Wang for immunofluorescence staining; J. Jiang for plasmid preparation; T. Taniguchi (University of Tokyo) for cyan fluorescent protein– tagged MyD88 and YFP-tagged IRF7 plasmids; D. Segal (National Cancer Institute) for GFP-tagged TLR9; D. Golenbock (University of Massachusetts) for the YFP-tagged TLR9 plasmid; B. Beutler (The Scripps Research Institute) for the hemagglutinin-tagged MyD88 plasmid; J. Hiscott (McGill University) for constitutively active IRF7; R. Ahmed (Emory University) for YF-17D subpassaged from YF-VAX in SW-480 cells; R.R. Amara (Emory University) for modified vaccinia virus Ankara; T. Van Dyke (Boston University) for highly purified E. coli LPS (strain 25922); S. Zughaier (Emory University) for the RAW264.7 cell line; and S.C. Kozma (Friedrich Miescher Institute for Biomedical Research) and N. Sonenberg (McGill University) for Rps6k1–/– Rps6k2–/– double-knockout mice. Supported by the National Institutes of Health (AI0564499, AI048638, AI05726601, DK057665, AI057157 and AI-50019 to B.P.)",
year = "2008",
doi = "10.1038/ni.1645",
language = "English (US)",
volume = "9",
pages = "1157--1164",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "10",
}