An important role for type III interferon (IFN-λ/IL-28) in TLR-induced antiviral activity
An important role for type III interferon (IFN-λ/IL-28) in TLR-induced antiviral activity
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DOI：
10.4049/jimmunol.180.4.2474
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Paludan, Soren R.
中科院分区：
文献类型：
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作者：
Ank, Nina;Iversen, Marie B.;Paludan, Soren R.
III型IFN（IFN-λ/IL-28/29）是具有I型IFN样抗病毒活性的细胞因子，其特征仍然很差。我们在此表明，大多数细胞类型的TLR刺激或病毒感染后表达I型和III型IFN，而细胞的能力，以响应IFN-λ被限制在一个狭窄的细胞亚群，包括浆细胞样树突状细胞和上皮细胞。为了研究III型IFN在抗病毒防御中的作用，我们产生了IL-28 R α缺陷小鼠。这些小鼠在清除一组不同病毒方面与野生型小鼠无区别，而缺乏I型IFN受体（IFNAR（-/-））的小鼠则明显受损。然而，在IL-28 RA（-/-）和IFNAR（-/-）小鼠中，用TLR 3或TLR 9激动剂治疗小鼠引起的强烈抗病毒活性均显着降低。I型IFN受体系统已显示介导IFN-α β表达的正反馈，并且我们发现I型IFN受体系统也介导IFN-λ表达的正反馈，而IL-28 R α信号传导不提供体内I型或III型IFN表达的反馈。最后，使用骨髓嵌合小鼠，我们发现TLR激活的抗病毒防御只需要在非造血细胞上表达IL-28 Ra。在这个区室中，上皮细胞对IFN-λ作出反应并直接限制病毒复制。我们的数据表明，III型IFN针对特定的细胞亚群，并有助于TLR引起的抗病毒反应。
Type III IFNs (IFN-lambda/IL-28/29) are cytokines with type I IFN-like antiviral activities, which remain poorly characterized. We herein show that most cell types expressed both types I and III IFNs after TLR stimulation or virus infection, whereas the ability of cells to respond to IFN-lambda was restricted to a narrow subset of cells, including plasmacytoid dendritic cells and epithelial cells. To examine the role of type III IFN in antiviral defense, we generated IL-28R alpha-deficient mice. These mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses, whereas mice lacking the type I IFN receptor (IFNAR(-/-)) were significantly impaired. However, the strong antiviral activity evoked by treatment of mice with TLR3 or TLR9 agonists was significantly reduced in both IL-28RA(-/-) and IFNAR(-/-) mice. The type I IFN receptor system has been shown to mediate positive feedback on IFN-alpha beta expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-lambda expression, whereas IL-28R alpha signaling does not provide feedback on either type I or type III IFN expression in vivo. Finally, using bone-marrow chimeric mice we showed that TLR-activated antiviral defense requires expression of IL-28Ra only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-lambda and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs.