IRF-7 is the master regulator of type-I interferon-dependent immune responses
IRF-7 is the master regulator of type-I interferon-dependent immune responses
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DOI：
10.1038/nature03464
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发表时间：
2005-04-07
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, T
中科院分区：
文献类型：
--
作者：
Honda, K;Yanai, H;Taniguchi, T
I型干扰素（IFN-α/β）应答对于针对病毒的免疫是关键的，并且可以通过病毒感染的胞质检测在许多细胞类型中触发，或者通过Toll样受体9（TLR 9）亚家族在分化的浆细胞样树突细胞中触发，所述TLR 9亚家族经由衔接子MyD 88产生信号以引发稳健的IFN诱导（1-4）。使用Irf 7基因缺陷小鼠（Irf 7（-/-）小鼠），我们表明转录因子IRF-7是通过病毒激活的MyD 88非依赖性途径和TLR激活的MyD 88依赖性途径诱导IFN-α/β基因所必需的。MyD 88非依赖性IFN-α/β基因的病毒诱导在Irf 7（-/-）成纤维细胞中严重受损。一致地，Irf 7（-/-）小鼠比Myd 88（-/-）小鼠更易受病毒感染，并且这与血清IFN水平的显著降低相关，表明IRF-7依赖性诱导全身IFN应答对于先天性抗病毒免疫的重要性。此外，浆细胞样树突状细胞中TLR 9亚家族的激活对IFN产生的强烈诱导完全依赖于IRF-7，并且该MyD 88-IRF-7途径控制CD 8（+）T细胞应答的诱导。因此，IFN应答的所有要素，无论是先天免疫中IFN的全身产生还是适应性免疫中来自浆细胞样树突细胞的IFN的局部作用，都在IRF-7的控制下。
The type-I interferon (IFN-alpha/beta) response is critical to immunity against viruses and can be triggered in many cell types by cytosolic detection of viral infection, or in differentiated plasmacytoid dendritic cells by the Toll-like receptor 9 (TLR9) subfamily, which generates signals via the adaptor MyD88 to elicit robust IFN induction(1-4). Using mice deficient in the Irf7 gene (Irf7(-/-) mice), we show that the transcription factor IRF-7 is essential for the induction of IFN-alpha/beta genes via the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Viral induction of MyD88-independent IFN-alpha/beta genes is severely impaired in Irf7(-/-) fibroblasts. Consistently, Irf7(-/-) mice are more vulnerable than Myd88(-/-) mice to viral infection, and this correlates with a marked decrease in serum IFN levels, indicating the importance of the IRF-7-dependent induction of systemic IFN responses for innate antiviral immunity. Furthermore, robust induction of IFN production by activation of the TLR9 subfamily in plasmacytoid dendritic cells is entirely dependent on IRF-7, and this MyD88-IRF-7 pathway governs the induction of CD8(+) T-cell responses. Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7.