CD8 T cell mediated immune response against cross-presenting liver sinusoidal endothelial cells leads to hepatitis

HBV-specific CD8 T cells responses are considered to be targeted directly against HBV-infected hepatocytes leading to development of hepatitis. However, previous work by Schirmbeck et al revealed that CD8 T cells recognizing a peptide in the context of H2Kb, which is exclusively presented by cross-presenting cells, leads to elevated ALT levels. This supported the hypothessis that recognition of antigen on non-hepatocytes leads to CTL-mediated liver disease. To directly investigate the role of non-parenchymal liver cells in initiating of hepatitis, we employed transgenic mouse lines with cell-type specific expression of the MHC I molecule H2Kb. After adenoviral transfer of Ovalbumin (AdOVA)into hepatocytes and adoptive transfer of OVA-specific CTLS we observed that the OVA-specific CTL-response caused strong ALT elevation. Importantly, using a tie2-H2Kb transgenic mouse, where antigen is presented on liver sinusoidal endothelial cells (LSEC) but not on hepatocytes, we also detected liver damage within 48 hrs after infection with AdOVA and adoptive transfer of OVA-specific CTLs. In contrast, presentation of antigen exclusively on hepatocytes in CRP-H2Kb-transgenic mice did not lead to significant ALT elevation. Antigen-presentation by LSEC in vivo to CTLs was followed by rapid elimination as demonstrated by ultrastructural analysis. Although sinusoidal platelet accumulation was observed, sinusoidal thrombosis was not responsible for liver damage. Expression of cytokines from effector T cells stimulated by LSEC in situ caused hepatocytes damage. Our results indicate that cross-presentation by LSEC represents the first step in virus-induced liver damage and shed light on the early steps of T cell-mediated pathophysiology in viral hepatitis.

hepatitis