Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway.
Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway.
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在浆细胞样树突状细胞（pDC）中I型干扰素（IFN-α/β）的稳健产生对于抗病毒免疫至关重要。在这里，我们表明参与的哺乳动物雷帕霉素靶（mTOR）途径在调节干扰素生产的pDCs。在Toll样受体9（TLR9）激活pDC期间，抑制mTOR或其"下游"介质（p70核糖体S6蛋白激酶p70S6K1和p70S6K2）可阻断TLR9与衔接子MyD88的相互作用以及随后干扰素调节因子IRF7的激活，从而导致IFN-α/β产生受损。微阵列分析证实，免疫抑制药物雷帕霉素对mTOR的抑制抑制了抗病毒和抗炎基因的表达。与此一致，将雷帕霉素包封的微粒靶向体内抗原呈递细胞导致响应于CpG DNA或黄热病疫苗病毒株17 D的IFN-α/β产生减少。因此，mTOR信号传导在TLR介导的pDC的IFN-α/β应答中至关重要。
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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