The pivotal role of infected hepatocytes in determining the outcome of antiviral CD8 T cell immunity in the liver

Lymphocytic choriomeningitis virus (LCMV) and adenoviral infection sensitizes hepatocytes towards efficient CD8 T cell mediated killing. As hepatitis B virus (HBV) infections are a global health problem with 290 million chronic infections, we aimed to analyze, if also HBV renders hepatocytes more susceptible for enhanced cell death induction.

HBV-replicating primary human and murine hepatocytes were co-cultured with HBV-specific CD8 T cells or treated with T cell effector molecules, like Fas-ligand and tumor necrosis factor (TNF). The T cell effector function against infected hepatocytes was analyzed in real-time using impedance measurement. In vivo, we monitored viral clearance using bioluminescence imaging and ALT measurement after transfer of antigen-specific CD8 T cells in mice.

Whereas adenoviral and LCMV infections resulted in higher killing efficiency of virus-specific CD8 T cells, HBV-infected hepatocytes did not display increased susceptibility and were more resistant towards cell death induction. Increasing the number of CD8 T cells or the concentration of effector molecules we could overcome the threshold for cell death induction of HBV-infected hepatocytes. Thereby, killing efficacy of HBV-infected hepatocytes was still comparable to uninfected hepatocytes. Strikingly, co-infection with HBV reversed the virus-induced sensitivity towards immune-mediated cell death induction leading to reduced killing efficacy of HBV-infected hepatocytes.

Here, we demonstrate that HBV infected hepatocytes do not only escape the non-canonical CD8 T cell effector function but are also more resistant towards CD8 T cell mediated killing. Overcoming these immune escape mechanism of HBV bears the promise to boost immune-mediated clearance of HBV-infected hepatocytes.

Publication History

Article published online:
20 January 2025