A novel non-MHC-I restricted CTL effector function mediated by TNF and XIAP

Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via the endogenous MHC class I antigen-presentation pathway in infected cells. Cross-priming of viral antigens circumvents such immune escape mechainsms by allowing non-infected dendritic cells to activate virus-specific CTLs. However, activated CTLs remain ineffective as long as viral immune escape is functional in infected target cells and antigen is not presented on MHC class I molecules. Here we show that cross-presentation of antigen from virus-infected hepatocytes by liver sinusoidal endothelial cells stimulates cross-primed CTLs to release TNF, which killed in a caspase and ROS-dependent fashion virally infected hepatocytes. TNF induced killing was highly specific because only infected hepatocytes downregulated the apoptosis inhibitor XIAP allowing full executioner caspase activation and subsequent apoptosis. This identifies a novel antigen-specific CTL effector mechanism that can target virally infected tissue cells whose endogenous MHC class I presentation pathway has been compromised by viral-infection.

LSEC - TNF - XIAP - cross-presentation - viral hepatitis