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

• Type of Material: Article
• Authors: Weiping Cao, Emory Vaccine Center; Santhakumar Manicassamy, Emory Vaccine Center; Hua Tang, Emory Vaccine Center; Sudhir Kasturi, Emory University; Ali Pirani, Emory University; Niren Murthy, Georgia Institute of Technology; Bali Pulendran, Emory University
• Language: English
• Date: 2008-10
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 Nature Publishing Group
• Final Published Version (URL): http://www.nature.com/ni/journal/v9/n10/full/ni.1645.html
• Title of Journal or Parent Work: Nature Immunology
• ISSN: 1529-2908
• Volume: 9
• Issue: 10
• Start Page: 1157
• End Page: 1164
• Grant/Funding Information: Supported by the National Institutes of Health (AI0564499, AI048638, AI05726601, DK057665, AI057157 and AI-50019 to B.P.)
• Research Categories: Health Sciences, Pathology

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.