MicroRNA-138 Regulates T-Cell Function by Targeting PD-1 in Patients with Hepatitis B Virus-Related Liver Diseases

Abstract

Objective: T-cell exhaustion in hepatitis B virus (HBV) infection, which results from upregulation of programmed cell death-1 (PD-1), leads to persistent HBV infection and related disease progression. Therefore, agents targeting PD-1 may prove beneficial in the treatment of this condition. MicroRNA-138 (miR-138) possesses an anti-tumor ability in that it targets immune checkpoints, including PD-1. However, the function and underlying mechanisms of miR-138 in patients with HBV infection remains unclear.

Methods: Specimens were collected from healthy volunteers (n = 43) and patients with chronic hepatitis B (CHB; n = 52), liver cirrhosis (LC; n = 26), and hepatocellular carcinoma (HCC; n = 31); carriers of HBV who were asymptomatic (n = 51); and patients with CHB receiving antivirus treatment (n = 11). These specimens were then used to study the expression and relationship among miR-138, PD-1, and HBV DNA viral load. To investigate the role of miR-138 in regulating PD-1 expression and determine the effect of miR-138 in regulating T-cell function, a luciferase assay and a transfection assay were each performed with primary CD3+ T cells.

Results: We found that PD-1 was upregulated and miR-138 was downregulated in patients with CHB, LC, and HCC. Correlations analysis revealed that PD-1 expression was positively correlated with HBV DNA viral load whereas miR-138 was negatively correlated. Luciferase assay results showed that miR-138 directly inhibited PD-1 expression by interacting with the 3'-untranslated region of PD-1. As a result of miR-138 overexpression in primary T cells, PD-1 in these T cells was downregulated and antivirus cytokines secreted by T cells were significantly upregulated. In addition, the expression levels of PD-1 and miR-138 were reversed in patients with CHB who received antivirus treatments.

Conclusion: Results showed that miR-138 can promote T-cell responses within patients with HBV infection by inducing a PD-1 blockade. Such an effect suggests that miR-138 may serve as a new therapeutic target for the treatment of HBV infection.

Keywords: HBV-related liver diseases; PD-1; T cells; miR-138.