TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8+T cells
TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8+T cells
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肝细胞中 TLR5 的激活减轻了肝内 CD8( )T 细胞的功能抑制
DOI：
10.1111/imm.13251
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发表时间：
2020-10-12
期刊：
影响因子：
6.4
通讯作者：
Yan, Huimin
中科院分区：
文献类型：
--
作者：
Yan, Hu;Zhong, Maohua;Yan, Huimin
肝脏是一个免疫特权器官，具有维持肝脏稳态的耐受性环境。这种肝脏耐受性限制了肝内CD 8（+）T细胞消除感染的反应。肝脏中的耐受性微环境由肝脏特异性免疫调节细胞协调，这些免疫调节细胞可以通过病原体相关分子模式（PAMP）进行功能性调节。在这里，我们报道了鞭毛蛋白，肠道细菌的关键PAMP，通过激活肝细胞的TLR 5信号通路来调节肝内CD 8（+）T细胞反应。我们发现，沙门氏菌衍生的重组鞭毛蛋白（SF）通过流体动力学注射治疗的小鼠在注射后7天内肝内淋巴细胞产生的IFN-γ显著升高。这与原代小鼠肝细胞（PMH）与模拟注射对照小鼠的PMH相比免疫抑制作用降低相关。SF处理的PMH与脾细胞的体外共培养显示，肝细胞诱导的免疫抑制通过TLR 5而不是NLRC 4信号通路的激活而减轻，导致在抗CD 3刺激或抗原特异性激活期间CD 8（+）T细胞的活化和功能改善。在通过流体动力学注射将SF与HBV复制质粒共同给药建立的急性HBV复制小鼠模型中，SF显著增强肝内HBV特异性CD 8（+）T细胞对HBV表面抗原的应答。我们的研究结果清楚地表明，鞭毛蛋白通过激活PMH中的TLR 5途径在调节肝内CD 8（+）T细胞反应中起作用，这表明肠道细菌在调节肝脏免疫中的潜在作用。
The liver is an immune-privileged organ with a tolerogenic environment for maintaining liver homeostasis. This hepatic tolerance limits the intrahepatic CD8(+)T-cell response for eliminating infections. The tolerant microenvironment in the liver is orchestrated by liver-specific immunoregulatory cells that can be functionally regulated by pathogen-associated molecular patterns (PAMPs). Here, we report that flagellin, a key PAMP of gut bacteria, modulates the intrahepatic CD8(+)T-cell response by activating the TLR5 signalling pathway of hepatocytes. We found that mice treated with Salmonella-derived recombinant flagellin (SF) by hydrodynamic injection had a significantly elevated IFN-gamma production by the intrahepatic lymphocytes in 7 days after injection. This was correlated with a reduced immune suppressive effect of primary mouse hepatocytes (PMHs) in comparison with that of PMHs from mock-injected control mice. In vitro co-culture of SF-treated PMHs with splenocytes revealed that hepatocyte-induced immune suppression is alleviated through activation of the TLR5 but not the NLRC4 signalling pathway, leading to improved activation and function of CD8(+)T cells during anti-CD3 stimulation or antigen-specific activation. In an acute HBV replication mouse model established by co-administration of SF together with an HBV-replicating plasmid by hydrodynamic injection, SF significantly enhanced the intrahepatic HBV-specific CD8(+)T-cell response against HBV surface antigen. Our results clearly showed that flagellin plays a role in modulating the intrahepatic CD8(+)T-cell response by activating the TLR5 pathway in PMHs, which suggests a potential role for gut bacteria in regulating liver immunity.