Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88
Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88
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DOI：
10.1128/jvi.01640-07
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发表时间：
2008-01-01
影响因子：
5.4
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
--
作者：
Jung, Andreas;Kato, Hiroki;Akira, Shizuo
Toll 样受体 (TLR) 和视黄酸诱导基因 I 样解旋酶 (R-LH) 是识别先天免疫细胞的 RNA 病毒感染的两种主要机制。 TLR 和 RLH 的细胞内信号传导由它们的细胞质接头分别介导，即 MyD88 或 TRIF 和 IPS-1。在本研究中，我们使用淋巴细胞样脉络丛脑膜炎病毒（LCMV）作为模型病毒，研究了 TLR 和 RLH 对细胞毒性 T 淋巴细胞（CTL）反应的贡献。病毒特异性细胞毒性 T 淋巴细胞的生成严重依赖于 MyD88，但不依赖于 IPS-1。已知 I 型干扰素 (IFN) 对于 LCW 感染的 CTL 反应的发展非常重要。 I型IFN和促炎细胞因子的血清水平主要取决于MyD88的存在，尽管IPS-1(-/-)小鼠显示IFN-α水平下降，但IFN-β和促炎细胞因子水平没有下降。对Ifna6(+/GFP)报告小鼠的分析表明，浆细胞样树突状细胞(DC)是LCMV感染中IFN-α的主要来源。 MyD88(-/-)小鼠体内对LCMV感染高度敏感。这些结果表明，浆细胞样 DC 通过 TLR 对 LCMV 的识别负责体内 I 型 IFN 的产生。此外，MyD88 依赖性先天机制的激活会诱导 CTL 反应，最终导致病毒消除。
Toll-like receptors (TLRs) and retinoic acid-inducible gene I-like helicases (R-LHs) are two major machineries recognizing RNA virus infection of innate immune cells. Intracellular signaling for TLRs and RLHs is mediated by their cytoplasmic adaptors, i.e., MyD88 or TRIF and IPS-1, respectively. In the present study, we investigated the contributions of TLRs and RLHs to the cytotoxic T-lymphocyte (CTL) response by using lymphocytoid choriomeningitis virus (LCMV) as a model virus. The generation of virus-specific cytotoxic T lymphocytes was critically dependent on MyD88 but not on IPS-1. Type I interferons (IFNs) are known to be important for the development of the CTL response to LCW infection. Serum levels of type I IFNs and proinflammatory cytokines were mainly dependent on the presence of MyD88, although IPS-1(-/-) mice showed a decrease in IFN-alpha levels but not in IFN-beta and proinflammatory cytokine levels. Analysis of Ifna6(+/GFP) reporter mice revealed that plasmacytoid dendritic cells (DCs) are the major source of IFN-alpha in LCMV infection. MyD88(-/-) mice were highly susceptible to LCMV infection in vivo. These results suggest that recognition of LCMV by plasmacytoid DCs via TLRs is responsible for the production of type I IFNs in vivo. Furthermore, the activation of a MyD88-dependent innate mechanism induces a CTL response, which eventually leads to virus elimination.