Abstract
BackgroundImmune inhibitory receptors play an important role in chronic infections. However, little is known about their role in hepatitis B virus (HBV) infection. Here, we analyzed the relationship between programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) expression on CD4+ T cells and HBV disease progression.ResultsPD-1 and LAG-3 expression was significantly higher on CD4+ T cells from HBV patients than on those from the HCs. In addition, a significant positive correlation was found between the PD-1 and LAG-3 expression levels and the ALT(alanine aminotransferase) level. CD4+ T cell function was inhibited by high PD-1 and LAG-3 levels, and CD4+ T cells with high PD-1 and LAG-3 expression lost the ability to secrete IFN-γ, IL-2 and TNF-α. Furthermore, blockade of the PD-1 and LAG-3 pathways reversed the damage to CD4+ T cell proliferation and cytokine secretion.ConclusionsCD4+ T cell exhaustion during chronic HBV had high PD-1 and LAG-3 expression and the absence of helper T cell cytokines, including IFN-γ, IL-2 and TNF-α. After blocking PD-L1 and LAG-3, CD4+ T cell function in chronic hepatitis B patients was partially restored.
Highlights
Immune inhibitory receptors play an important role in chronic infections
Patients The frequencies of CD4+ T cells with surface expression of the inhibitory receptors programmed death-1 (PD-1), lymphocyte activation gene-3 (LAG-3), CD160 and CD244 were evaluated in the chronic hepatitis B patients (CHB) patient group (CHB group) and healthy control group (HC group) using flow cytometry
Higher frequencies of PD-1+CD4+ and LAG-3+CD4+ cells were observed in the CHB group than in the Healthy controls (HC) group (P = 0.0014 and P = 0.0104, respectively)
Summary
Immune inhibitory receptors play an important role in chronic infections. little is known about their role in hepatitis B virus (HBV) infection. Recent studies revealed that the sustained combination of exposure to antigens with high viral loads and excessive inhibitory signals in the liver microenvironment could lead to a progressive loss of T cell function and exhaustion of HBV-specific T cells [1, 3] These “exhausted T cells” presented a state dysfunction of T cell and was firstly observed during chronic lymphocytic choriomeningitis virus (LCMV) infection in mice [11, 12] exhibit increased expression of immune inhibitory molecules, including programmed death-1 (PD-1), lymphocyte activation gene-3 (LAG-3 or CD223), T cell immunoglobulin domain and mucin domain 3 (TIM-3), CD244 (2B4) and CD160 [13,14,15,16]. In our previous studies, we demonstrated high PD-1 and LAG-3 expression levels on exhausted CD8+ T cells during chronic HBV infection [17, 18]
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