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This hepatic tolerance limits the intrahepatic CD8<jats:sup>+<\/jats:sup> T\u2010cell response for eliminating infections. The tolerant microenvironment in the liver is orchestrated by liver\u2010specific immunoregulatory cells that can be functionally regulated by pathogen\u2010associated molecular patterns (PAMPs). Here, we report that flagellin, a key PAMP of gut bacteria, modulates the intrahepatic CD8<jats:sup>+<\/jats:sup> T\u2010cell response by activating the TLR5 signalling pathway of hepatocytes. We found that mice treated with Salmonella\u2010derived recombinant flagellin (SF) by hydrodynamic injection had a significantly elevated IFN\u2010\u03b3 production by the intrahepatic lymphocytes in 7\u00a0days after injection. This was correlated with a reduced immune suppressive effect of primary mouse hepatocytes (PMHs) in comparison with that of PMHs from mock\u2010injected control mice. In vitro co\u2010culture of SF\u2010treated PMHs with splenocytes revealed that hepatocyte\u2010induced immune suppression is alleviated through activation of the TLR5 but not the NLRC4 signalling pathway, leading to improved activation and function of CD8<jats:sup>+<\/jats:sup> T cells during anti\u2010CD3 stimulation or antigen\u2010specific activation. In an acute HBV replication mouse model established by co\u2010administration of SF together with an HBV\u2010replicating plasmid by hydrodynamic injection, SF significantly enhanced the intrahepatic HBV\u2010specific CD8<jats:sup>+<\/jats:sup> T\u2010cell response against HBV surface antigen. Our results clearly showed that flagellin plays a role in modulating the intrahepatic CD8<jats:sup>+<\/jats:sup> T\u2010cell response by activating the TLR5 pathway in PMHs, which suggests a potential role for gut bacteria in regulating liver immunity.<\/jats:p>","DOI":"10.1111\/imm.13251","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T16:56:44Z","timestamp":1598547404000},"page":"325-344","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8<sup>+<\/sup> T cells"],"prefix":"10.1111","volume":"161","author":[{"given":"Hu","family":"Yan","sequence":"first","affiliation":[{"name":"Mucosal Immunity Research Group State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences Wuhan China"},{"name":"University of Chinese Academy of Sciences Beijing 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