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

Weiping Cao, Santhakumar Manicassamy, Hua Tang, Sudhir Pai Kasturi, Ali Pirani, Niren Murthy, Bali Pulendran

Research output: Contribution to journalArticle

259 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1157-1164
Number of pages8
JournalNature Immunology
Volume9
Issue number10
DOIs
StatePublished - Sep 1 2008
Externally publishedYes

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70-kDa Ribosomal Protein S6 Kinases
Interferon Type I
Toll-Like Receptors
Sirolimus
Dendritic Cells
Interferons
Toll-Like Receptor 9
Antiviral Agents
Yellow Fever Vaccine
Interferon Regulatory Factors
Yellow fever virus
Ribosomal Protein S6 Kinases
Antigen-Presenting Cells
Microarray Analysis
Immunosuppressive Agents
Immunity
Anti-Inflammatory Agents
Gene Expression
DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology

Cite this

Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. / Cao, Weiping; Manicassamy, Santhakumar; Tang, Hua; Kasturi, Sudhir Pai; Pirani, Ali; Murthy, Niren; Pulendran, Bali.

In: Nature Immunology, Vol. 9, No. 10, 01.09.2008, p. 1157-1164.

Research output: Contribution to journalArticle

Cao, Weiping ; Manicassamy, Santhakumar ; Tang, Hua ; Kasturi, Sudhir Pai ; Pirani, Ali ; Murthy, Niren ; Pulendran, Bali. / Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. In: Nature Immunology. 2008 ; Vol. 9, No. 10. pp. 1157-1164.
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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.",
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