Interferon-Independent Activities of Mammalian STING Mediate Antiviral Response and Tumor Immune Evasion
Interferon-Independent Activities of Mammalian STING Mediate Antiviral Response and Tumor Immune Evasion
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DOI：
10.1016/j.immuni.2020.06.009
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发表时间：
2020-07-14
期刊：
影响因子：
32.4
通讯作者：
Yan, Nan
中科院分区：
文献类型：
--
作者：
Wu, Jianjun;Dobbs, Nicole;Yan, Nan
I型干扰素（IFN）应答通常被认为是STING的主要信号传导活性。在这里，我们产生了Sting 1（S365 A/S365 A）突变小鼠，该小鼠精确地消除了IFN依赖性活性，同时保留了STING的IFN非依赖性活性。Sting（S365 A/S365 A）小鼠保护免受HSV-1感染，尽管缺乏STING介导的IFN应答。这挑战了流行的观点，并表明STING通过IFN非依赖性活动控制HSV-1感染。转录组学分析揭示了STING在巨噬细胞和T细胞中的广泛的IFN非依赖性活性，并且T细胞中的STING活性主要是IFN非依赖性的。在小鼠肿瘤模型中，肿瘤中的T细胞经历部分由STING的IFN非依赖性活性介导的大量细胞死亡。我们发现肿瘤诱导T细胞中STING介导的细胞死亡以逃避免疫控制。我们的数据表明，哺乳动物STING具有广泛的IFN非依赖性活性，这些活性对于限制HSV-1感染、肿瘤免疫逃避以及可能的适应性免疫都很重要。
Type I interferon (IFN) response is commonly recognized as the main signaling activity of STING. Here, we generate the Sting1(S365A/S365A) mutant mouse that precisely ablates IFN-dependent activities while preserving IFN-independent activities of STING. Sting(S365A/S365A) mice protect against HSV-1 infection, despite lacking the STING-mediated IFN response. This challenges the prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis reveals widespread IFN-independent activities of STING in macrophages and T cells, and STING activities in T cells are predominantly IFN independent. In mouse tumor models, T cells in the tumor experience substantial cell death that is in part mediated by IFN-independent activities of STING. We found that the tumor induces STING-mediated cell death in T cells to evade immune control. Our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive immunity.