Hepatic T cell suppressors and their inhibition roles in hepatic viral clearance (P6353)

Abstract

Abstract The unique microenvironment of the liver favors T cell inactivation, tolerance, and apoptosis. As such, it is a challenging environment in which to efficiently clear viruses, which may explain why HBV and HCV often establish a chronic viral presence. The principal mechanisms that account for hepatic T cell failure and thus influence the outcome of liver infections, including the identification of inhibitory molecules and their ligands, are beginning to be understood. We recently identified LSECtin from the liver and reported that LSECtin negatively regulates T cell receptor-mediated signaling and T cell Immunity. We then investigate whether LSECtin regulates anti-viral immunity and virus invasiveness in the liver. Using a mouse model infected with a hepatotropic adenovirus, we found that the absence of LSECtin led to a higher frequency of CTL, which produced higher levels of antiviral cytokines and cytotoxic factors and showed increased expression of T-bet and Runx3, thus mediated more efficient virus-specific cytotoxity than WT cells. As a consequence, LSECtin deficiency significantly accelerated liver adenovirus clearance. We further constructed an immunocompetent mouse model of acute hepatitis B viral infection to demonstrate that LSECtin significantly delayed clearance of HBV from blood and infected hepatocytes through limiting the frequency of HBV-specific IFN-γ-producing cells.