Inhibitory B7 Family Members in the Liver

Hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatitis (AIH) and non-alcoholic fatty liver disease (NAFLD), can induce chronic liver disease. Immune-mediated liver damage characterizes the chronic stages of these conditions. Paradoxically, weak immune responses, characterized by CD8+ T cell dysfunction, contribute to the persistence of acute HBV and HCV infections. To study the immune imbalance characteristic of HBV, HCV, AIH and NAFLD we investigated acute and chronic modulation of the B7 family of inhibitory ligands. Increased expression of PD-1 or its ligands, B7-H1 and B7-DC, could contribute to or result from chronic disease. We utilized hepatocyte cell culture and patient biopsies to study acute and chronic disease phases, respectively. Liver biopsies from patients in the chronic stages of HBV, HCV, and AIH contain increased numbers of PD-1 expressing lymphocytes. In vivo, we show that PD-1 ligands are expressed on Kupffer cells, liver sinusoidal endothelial cells (LSECs), and leukocytes. We also detect PD-1 ligands on hepatocytes within biopsies and on primary, cultured cells. All forms of chronic liver inflammation examined (HBV, HCV, and AIH) correlate with increased B7-H1 and B7-DC expression on Kupffer cells, LSECs, and leukocytes. This suggests that inflammation rather than liver damage itself induces expression of B7 family members. Expression of PD-1 and its ligands during Kassel, R iii chronic inflammation may assist the liver in protecting itself from immune-mediated destruction. Huh 7.5 cells (a hepatoma cell line) expressing the complete HCV genome or non-structural region only were utilized to model acute infection. We show that hepatocytes can acutely up-regulate B7-H1 expression in response to IFN-gamma, an inflammatory cytokine present at a high concentration in the liver. HCV does not, however, have the ability to subvert the host immune response by directly up-regulating B7-H1. Further, while PD-1 expressed during acute phases of disease could bind PD-1 ligands expressed on hepatocytes leading to CD8+ T cell dysfunction, we do not detect this mechanism of CD8+ T cell inhibition in vitro.

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