Rapid Differentiation of Monocytes into Type I IFN-Producing Myeloid Dendritic Cells as an Antiviral Strategy against Influenza Virus Infection
Rapid Differentiation of Monocytes into Type I IFN-Producing Myeloid Dendritic Cells as an Antiviral Strategy against Influenza Virus Infection
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DOI：
10.4049/jimmunol.1200168
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发表时间：
2012-09-01
影响因子：
4.4
通讯作者：
Sambhara, Suryaprakash
中科院分区：
文献类型：
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作者：
Cao, Weiping;Taylor, Andrew K.;Sambhara, Suryaprakash
髓样树突状细胞（mDC）长期以来被认为是T细胞应答的经典APC。然而，我们证明流感病毒诱导人单核细胞快速分化为mDC。与经典的mDCs不同，病毒诱导的mDCs未能上调DC成熟标志物，并且不能诱导同种异体淋巴细胞增殖。病毒诱导的mDCs分泌很少，如果有的话，促炎细胞因子，但是，他们分泌了大量的单核细胞（MCP-1和IP-10）的化学引诱物。有趣的是，分化的mDC分泌I型IFN并上调IFN刺激的基因（tetherin，IFITM 3和viperin）以及胞质病毒RNA传感器（RIG-I和MDA 5）的表达。此外，来自病毒诱导的mDCs的培养上清液在体外抑制病毒的复制。此外，在流感感染的小鼠模型中单核细胞的消耗引起肺mDC数量的显著减少，以及肺中I型IFN的产生。因此，观察到肺病毒滴度增加和死亡率升高。总之，我们的研究结果表明，宿主对流感病毒感染的反应是通过启动循环单核细胞快速分化为产生IFN的mDC，这有助于先天性抗病毒免疫应答。免疫学杂志，2012，189：2257-2265。
Myeloid dendritic cells (mDCs) have long been thought to function as classical APCs for T cell responses. However, we demonstrate that influenza viruses induce rapid differentiation of human monocytes into mDCs. Unlike the classic mDCs, the virus-induced mDCs failed to upregulate DC maturation markers and were unable to induce allogeneic lymphoproliferation. Virus-induced mDCs secreted little, if any, proinflammatory cytokines; however, they secreted a substantial amount of chemoattractants for monocytes (MCP-1 and IP-10). Interestingly, the differentiated mDCs secreted type I IFN and upregulated the expression of IFN-stimulated genes (tetherin, IFITM3, and viperin), as well as cytosolic viral RNA sensors (RIG-I and MDA5). Additionally, culture supernatants from virus-induced mDCs suppressed the replication of virus in vitro. Furthermore, depletion of monocytes in a mouse model of influenza infection caused significant reduction of lung mDC numbers, as well as type I IFN production in the lung. Consequently, increased lung virus titer and higher mortality were observed. Taken together, our results demonstrate that the host responds to influenza virus infection by initiating rapid differentiation of circulating monocytes into IFN-producing mDCs, which contribute to innate antiviral immune responses. The Journal of Immunology, 2012, 189: 2257-2265.