Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of the Flaviviridae Suppress Cellular Immune Responses
Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of the Flaviviridae Suppress Cellular Immune Responses
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DOI：
10.4049/jimmunol.1600049
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
E. Reid;N. Juleff;M. Windsor;S. Gubbins;L. Roberts;S. Morgan;G. Meyers;E. Pérez-Martín;E. Tchi
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文献类型：
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作者：
E. Reid;N. Juleff;M. Windsor;S. Gubbins;L. Roberts;S. Morgan;G. Meyers;E. Pérez-Martín;E. Tchi
瘟病毒非细胞病变性牛病毒性腹泻病毒 (BVDV) 可在体外抑制大多数细胞类型中 IFN 的产生。然而，在体内急性感染期间，血清中可检测到 IFN 持续约 5-7 天，这与白细胞减少和免疫抑制时期相关。在这项研究中，我们证明了高度富集的牛浆细胞样树突状细胞 (DC) 群体在体外对 BVDV 产生了 IFN 反应。我们进一步表明，体外和体内感染产生的大部分干扰素都是 III 型干扰素，并且对酸不稳定。此外，我们还表明 IL-28B (IFN-λ3) mRNA 在该细胞群中被体外诱导。用 BVDV 或重组牛 IFN-α 或人 IL-28B 感染后收获的浆细胞样 DC 上清液显着降低了由结核杆菌 Ag 85 刺激的单核细胞来源的 DC 诱导的 CD4+ T 细胞增殖。此外，这些 IFN 主要在单核细胞衍生的 DC 中诱导 IFN 刺激的基因表达。经 IFN 处理的来自鼠骨髓的未成熟 DC 刺激 T 细胞对结核杆菌 Ag 85 增殖反应的能力也降低。来自任一来源的未成熟 DC 在 IFN 处理后吸收 Ag 的能力降低，且呈剂量依赖性。免疫抑制是许多瘟病毒感染的一个特征；我们的研究表明 III 型干扰素的产生在该病毒家族的发病机制中发挥着关键作用。总体而言，在自然宿主中，我们证明了急性病毒感染后 I 型和 III 型 IFN 的诱导与短暂的免疫抑制之间存在联系。
The pestivirus noncytopathic bovine viral diarrhea virus (BVDV) can suppress IFN production in the majority of cell types in vitro. However, IFN is detectable in serum during acute infection in vivo for ∼5–7 d, which correlates with a period of leucopoenia and immunosuppression. In this study, we demonstrate that a highly enriched population of bovine plasmacytoid dendritic cells (DCs) produced IFN in response to BVDV in vitro. We further show that the majority of the IFN produced in response to infection both in vitro and in vivo is type III IFN and acid labile. Further, we show IL-28B (IFN-λ3) mRNA is induced in this cell population in vitro. Supernatant from plasmacytoid DCs harvested postinfection with BVDV or recombinant bovine IFN-α or human IL-28B significantly reduced CD4+ T cell proliferation induced by tubercle bacillus Ag 85–stimulated monocyte-derived DCs. Furthermore, these IFNs induced IFN-stimulated gene expression predominantly in monocyte-derived DCs. IFN-treated immature DCs derived from murine bone marrow also had a reduced capacity to stimulate T cell proliferative responses to tubercle bacillus Ag 85. Immature DCs derived from either source had a reduced capacity for Ag uptake following IFN treatment that is dose dependent. Immunosuppression is a feature of a number of pestivirus infections; our studies suggest type III IFN production plays a key role in the pathogenesis of this family of viruses. Overall, in a natural host, we have demonstrated a link between the induction of type I and III IFN after acute viral infection and transient immunosuppression.