PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis

B7-H1 (PD-L1) is a B7-family member that binds to programmed death–1 (PD–1). Recently, deficiency of PD-L1 has been demonstrated to result in accelerated hepatocyte damage in experimental autoimmune hepatitis, and PD-L1 was suggested to play a critical role in regulating T-cell homeostasis. Absence of PD–1 enhanced proliferation of T cells in adenovirus-infected livers and resulted in a rapid clearance of the virus.

The aim of this study was to analyze the expression and function of PD-L1 in hepatocytes.

Methods and Results: Constitutive expression of PD-L1 at low levels was detected in primary human hepatocytes (PHH) and 3 different hepatoma cell lines (HepG2, Hep3B and PLC) by real time PCR and FACS analysis. PD-L1 mRNA and protein expression in hepatocytes were markedly increased upon exposure to interferon-α – or -γ. In addition, also activated lymphocytes and viral infection induced significant induction of PD-L1 expression in hepatocytes. FACS analysis revealed apoptosis in Jurkat T cells after coincubation with IFN-g pre-treated hepatoma cells, and this effect could be partially inhibited by a PD-L1 blocking antibody, demonstrating functional relevance of PD-L1 expression in hepatocytes.

Summary and conclusion: We demonstrated for the first time constitutive as well as inducible PD-L1 expression in hepatocytes. Our results suggest a novel bidirectional interaction between hepatocytes and lymphocytes modulated by PD-L1 expression in hepatocytes, which may contribute to the unique immunological properties of the liver.

Key words

PD-L1; hepatocytes; viral infection; T cell apoptosis; Interferon