Tumor Progression Locus 2 Promotes Induction of IFNλ, Interferon Stimulated Genes and Antigen-Specific CD8+ T Cell Responses and Protects against Influenza Virus.
Tumor Progression Locus 2 Promotes Induction of IFNλ, Interferon Stimulated Genes and Antigen-Specific CD8+ T Cell Responses and Protects against Influenza Virus.
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DOI：
10.1371/journal.ppat.1005038
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发表时间：
2015-08
期刊：
影响因子：
6.7
通讯作者：
Watford WT
中科院分区：
文献类型：
--
作者：
Kuriakose T;Tripp RA;Watford WT
丝裂原活化蛋白激酶（MAP）级联通过调节干扰素（IFN）的产生以及病毒的复制在抗病毒免疫中起重要作用。尽管丝氨酸-苏氨酸MAP激酶肿瘤进展基因座2（Tpl 2/MAP 3 K8）已被认为是I型（IFNα/β）和II型（IFNγ）IFN的关键调节因子，但关于Tpl 2如何有助于宿主防御病毒的知之甚少。在此，我们研究了Tpl 2在针对流感病毒的抗病毒免疫应答中的作用。我们证明Tpl 2是多种病毒感应途径的组成部分，以细胞类型特异性方式差异调节IFNα/β和IFNλ的诱导。尽管Tpl 2在IFNα/β和IFNλ的调节中是重要的，但在体外和体内流感病毒感染期间，只有IFNλ需要Tpl 2来诱导。进一步的研究揭示了Tp 12在转导I型IFN信号和促进干扰素刺激基因（ISG）表达中的未预料到的功能。重要的是，非造血细胞中的Tpl 2信号传导对于限制早期病毒复制是必要的。除了早期先天性改变之外，病毒特异性CD 8 + T细胞的扩增受损伴随着在晚期时间点Tp 12-/-小鼠中延迟的病毒清除。与其在促进先天性和适应性抗病毒应答中的关键作用一致，Tp 12是限制与流感病毒感染相关的发病率和死亡率所必需的。总的来说，这些发现确立了Tpl 2在抗病毒宿主防御机制中的重要作用。流感病毒每年感染数百万人，造成严重的发病率、死亡率和社会经济负担。针对流感病毒的宿主免疫应答在病毒被特异性细胞内受体识别后启动。从这些受体传递的信号触发各种信号级联，从而诱导抗病毒免疫应答以控制感染。在此，我们鉴定了丝氨酸-苏氨酸激酶肿瘤进展位点2（Tpl 2）作为病毒传感途径的重要组分，调节干扰素（IFN）的诱导和IFN诱导的限制病毒复制的抗病毒基因。我们还证明Tpl 2对于产生效应CD 8 + T细胞是必需的，所述效应CD 8 + T细胞是从感染的肺清除病毒所需的。与受损的抗病毒应答一致，Tp 12缺陷型小鼠在控制病毒复制方面有缺陷，并且屈服于具有正常低致病性菌株的流感病毒感染。因此，我们的研究将Tpl 2鉴定为整合抗病毒先天性和适应性应答以限制流感病毒感染期间的发病率和死亡率的宿主因子。
Mitogen-activated protein kinase (MAP) cascades are important in antiviral immunity through their regulation of interferon (IFN) production as well as virus replication. Although the serine-threonine MAP kinase tumor progression locus 2 (Tpl2/MAP3K8) has been implicated as a key regulator of Type I (IFNα/β) and Type II (IFNγ) IFNs, remarkably little is known about how Tpl2 might contribute to host defense against viruses. Herein, we investigated the role of Tpl2 in antiviral immune responses against influenza virus. We demonstrate that Tpl2 is an integral component of multiple virus sensing pathways, differentially regulating the induction of IFNα/β and IFNλ in a cell-type specific manner. Although Tpl2 is important in the regulation of both IFNα/β and IFNλ, only IFNλ required Tpl2 for its induction during influenza virus infection both in vitro and in vivo. Further studies revealed an unanticipated function for Tpl2 in transducing Type I IFN signals and promoting expression of interferon-stimulated genes (ISGs). Importantly, Tpl2 signaling in nonhematopoietic cells is necessary to limit early virus replication. In addition to early innate alterations, impaired expansion of virus-specific CD8+ T cells accompanied delayed viral clearance in Tpl2-/- mice at late time points. Consistent with its critical role in facilitating both innate and adaptive antiviral responses, Tpl2 is required for restricting morbidity and mortality associated with influenza virus infection. Collectively, these findings establish an essential role for Tpl2 in antiviral host defense mechanisms. Influenza viruses infect millions of people annually causing significant morbidity, mortality and socio-economic burdens. Host immune responses against influenza virus are initiated upon virus recognition by specific intracellular receptors. Signals relayed from these receptors trigger various signaling cascades, which induce an antiviral immune response to control infection. Herein, we identified the serine-threonine kinase tumor progression locus 2 (Tpl2) as an essential component of virus sensing pathways, regulating induction of interferons (IFNs) and IFN-induced antiviral genes that restrict virus replication. We also demonstrate that Tpl2 is necessary for generation of effector CD8+ T cells, which are required for viral clearance from infected lungs. Consistent with the impaired antiviral responses, Tpl2-deficient mice are defective in controlling virus replication and succumb to influenza virus infection with a normally low pathogenicity strain. Thus, our study identifies Tpl2 as a host factor that integrates antiviral innate and adaptive responses to restrict morbidity and mortality during influenza virus infection.