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  2. Hepatitis B virus-triggered PTEN/β-catenin/c-Myc signaling enhances PD-L1 expression to promote immune evasion

Hepatitis B virus-triggered PTEN/β-catenin/c-Myc signaling enhances PD-L1 expression to promote immune evasion

  • Am J Physiol Gastrointest Liver Physiol. 2020 Jan 1;318(1):G162-G173. doi: 10.1152/ajpgi.00197.2019.
Yishuang Sun 1 Mengxue Yu 1 Mengmeng Qu 1 Yuhong Ma 1 Dandan Zheng 1 Yanan Yue 1 Shuting Guo 1 Li Tang 1 Guorui Li 1 Weishuai Zheng 1 Min Wang 1 Deyin Guo 2 Changyong Li 1


  • 1 School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China.
  • 2 Laboratory of Medical Virology, School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.

Hepatitis B virus (HBV) exploits multiple strategies to evade host immune surveillance. Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling plays a critical role in regulating T cell homeostasis. However, it remains largely unknown as to how HBV Infection elevates PD-L1 expression in hepatocytes. A mouse model of HBV Infection was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome (pHBV1.3) via the tail vein. Coculture experiments with HBV-expressing hepatoma cells and Jurkat T cells were established in vitro. We observed significant decrease in the expression of Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and increase in β-catenin/PD-L1 expression in liver tissues from patients with chronic hepatitis B and mice subjected to pHBV1.3 hydrodynamic injection. Mechanistically, decrease in PTEN enhanced β-catenin/c-Myc signaling and PD-L1 expression in HBV-expressing hepatoma cells, which in turn augmented PD-1 expression, lowered IL-2 secretion, and induced T cell Apoptosis. However, β-catenin disruption inhibited PTEN-mediated PD-L1 expression, which was accompanied by decreased PD-1 expression, and increased IL-2 production in T cells. Luciferase reporter assays revealed that c-Myc stimulated transcriptional activity of PD-L1. In addition, HBV X protein (HBx) and HBV polymerase (HBp) contributed to PTEN downregulation and β-catenin/PD-L1 upregulation. Strikingly, PTEN overexpression in hepatocytes inhibited β-catenin/PD-L1 signaling and promoted HBV clearance in vivo. Our findings suggest that HBV-triggered PTEN/β-catenin/c-Myc signaling via HBx and HBp enhances PD-L1 expression, leading to inhibition of T cell response, and promotes HBV immune evasion.NEW & NOTEWORTHY This study demonstrates that during HBV Infection, HBV can increase PD-L1 expression via PTEN/β-catenin/c-Myc signaling pathway, which in turn inhibits T cell response and ultimately promotes HBV immune evasion. Targeting this signaling pathway is a potential strategy for immunotherapy of chronic hepatitis B.


HBV; PD-L1; PTEN; immune evasion; β-catenin.