Abstract
BackgroundThe programmed cell death 1 (PD-1)/programmed death-1 ligand 1 (PD-L1) system may play a role in the negative regulation of T cell functions in hepatitis B virus (HBV) infection. Thus, it is important to study its role in the widely used animal model for HBV infection of woodchucks with woodchuck hepatitis virus (WHV).MethodsWoodchuck PD-L1 (wPD-L1) and -L2 (wPD-L2) were cloned and characterized. The levels of wPD-L1 expression in primary woodchuck hepatocytes (PWH), peripheral blood mononuclear cells (PBMCs), and liver tissue of naive and WHV-infected woodchucks were examined by real time reverse transcription (RT)-PCR and flow cytometry. Using antibodies against wPD-L1 and -L2, the effect of blocking PD-1/PD-L1/PD-L2 interaction on the proliferation and degranulation of woodchuck PBMCs was examined.Principal FindingsBoth wPD-L1 and -L2 showed a high homology to their counterparts of other mammalian species and humans. WPD-L1 expression in PWH and PBMCs of naive animals was low but could be stimulated by Toll-like receptor (TLR) ligands and interferons (IFN). WPD-L1 expression in liver tissue was significantly higher than that measured in PWHs and was slightly elevated during acute and chronic WHV infection. However, wPD-1 and wPD-L1 expression on PBMCs was strongly up-regulated during acute and chronic infection. In vitro blockade with antibodies against wPD-L1 and -L2 partially enhanced proliferation and degranulation of PBMCs from WHV-infected woodchucks.ConclusionsOur results demonstrated that wPD-1/wPD-L1 expression in hepatocytes and PBMCs can be induced by different inflammatory stimuli and is up-regulated mainly on PBMCs during WHV infection. A blockade of the woodchuck PD-1/PD-L pathway could partially enhance T cell functions in WHV infection.
Highlights
Hepatitis B virus (HBV) infection is a global health problem due to its high prevalence in the world
Our results demonstrated that wPD-1/Woodchuck PD-L1 (wPD-L1) expression in hepatocytes and peripheral blood mononuclear cells (PBMCs) can be induced by different inflammatory stimuli and is up-regulated mainly on PBMCs during woodchuck hepatitis virus (WHV) infection
The engagement of programmed cell death 1 (PD-1) to its ligands during this period leads to the negative regulation of T cells, which plays an important role in the maintenance of peripheral tolerance against immunopathological tissue damage [3]
Summary
Hepatitis B virus (HBV) infection is a global health problem due to its high prevalence in the world. Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PDL2) belongs to the B7/CD28 family of co-stimulatory molecules and have important functions concerning the regulation of T cell responses. The engagement of PD-1 to its ligands during this period leads to the negative regulation of T cells, which plays an important role in the maintenance of peripheral tolerance against immunopathological tissue damage [3]. PD-1 expression on the virus-specific T cells is negatively correlated with cytokine secretion and cytotoxity and is associated with viral persistence in different chronic virus infections, such as human immunodeficiency virus, HBV, hepatitis C virus, and cytomegalovirus [6,7,8]. The programmed cell death 1 (PD-1)/programmed death-1 ligand 1 (PD-L1) system may play a role in the negative regulation of T cell functions in hepatitis B virus (HBV) infection. It is important to study its role in the widely used animal model for HBV infection of woodchucks with woodchuck hepatitis virus (WHV)
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