TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8+ T cells.

Summary: 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‐γ 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. [ABSTRACT FROM AUTHOR]