MicroRNA-155 regulates interferon-γ production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection
MicroRNA-155 regulates interferon-γ production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection
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DOI：
10.1111/imm.12463
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发表时间：
2015-08-01
期刊：
影响因子：
6.4
通讯作者：
Yao, Zhi Q.
中科院分区：
文献类型：
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作者：
Cheng, Yong Q.;Ren, Jun P.;Yao, Zhi Q.
宿主的免疫反应必须严格调节的积极和消极的信号之间的复杂平衡，同时打击病原体;持久的病原体可能篡夺这些调节机制，抑制宿主的免疫力，以促进在体内的生存。在这里，我们报告说，Tim-3，一个负信号分子表达的单核细胞和T细胞，上调自然杀伤（NK）细胞在慢性感染丙型肝炎病毒（HCV）的个人。此外，还发现转录因子T-bet在慢性HCV感染期间在NK细胞中上调并与Tim-3表达相关。MicroRNA-155（miR-155）是一种抑制参与免疫应答的信号蛋白的miRNA，在HCV感染的NK细胞中下调。通过将原代NK细胞或NK 92细胞系与表达HCV的Huh-7肝细胞一起孵育，在体外重现了这种Tim-3/T-bet过表达和miR-155抑制。来自HCV感染患者的NK细胞中miR-155的重建导致T-bet/Tim-3表达的降低和干扰素-γ产生的增加。阻断Tim-3信号传导还通过改善信号转导子和转录激活子-5磷酸化来增强NK细胞中干扰素-γ的产生。这些数据表明，HCV诱导的，miR-155调节的Tim-3表达调节NK细胞功能，表明在慢性病毒感染期间平衡免疫清除和免疫损伤的新机制。
Host immune responses must be tightly regulated by an intricate balance between positive and negative signals while fighting pathogens; persistent pathogens may usurp these regulatory mechanisms to dampen host immunity to facilitate survival in vivo. Here we report that Tim-3, a negative signalling molecule expressed on monocytes and T cells, is up-regulated on natural killer (NK) cells in individuals chronically infected with hepatitis C virus (HCV). Additionally, the transcription factor T-bet was also found to be up-regulated and associated with Tim-3 expression in NK cells during chronic HCV infection. MicroRNA-155 (miR-155), an miRNA that inhibits signalling proteins involved in immune responses, was down-regulated in NK cells by HCV infection. This Tim-3/T-bet over-expression and miR-155 inhibition were recapitulated in vitro by incubating primary NK cells or NK92 cell line with Huh-7 hepatocytes expressing HCV. Reconstitution of miR-155 in NK cells from HCV-infected patients led to a decrease in T-bet/Tim-3 expression and an increase in interferon-gamma production. Blocking Tim-3 signalling also enhanced interferon-gamma production in NK cells by improving signal transducer and activator of transcription-5 phosphorylation. These data indicate that HCV-induced, miR-155-regulated Tim-3 expression regulates NK cell function, suggesting a novel mechanism for balancing immune clearance and immune injury during chronic viral infection.