IFN‐γ facilitates liver fibrogenesis by CD161(+)CD4(+) T cells through a regenerative IL‐23/IL‐17 axis in chronic hepatitis B virus infection

OBJECTIVES: This study aimed to determine the role of CD161(+)CD4(+) T cells in chronic hepatitis B virus (HBV) infection. METHODS: A total of 94 patients with chronic hepatitis B (CHB), 73 with liver cirrhosis (LC) and 28 healthy controls were enrolled to determine frequency, cytokine production and chemokine receptor expression of circulating CD161(+)CD4(+) T cells. Among these, 50 CHB and 34 LC patients were followed up for a period of 52‐week entecavir monotherapy to assess the association of CD161(+)CD4(+) T cells with seroconversion of HBV e antigen (HBeAg). In addition, 15 patients with hepatocellular carcinoma (HCC) and 15 with hepatic haemangioma (HHA) were enrolled to compare the paired circulating and intrahepatic CD161(+)CD4(+) T cells. RESULTS: CD161(+)CD4(+) T cells were found to accumulate in the circulation of HBV cohorts, which showed a significant correlation with the clinical parameters of disease progression. In addition, higher numbers of circulating CD161(+)CD4(+) T cells were associated with an improved serological response of HBeAg to antiviral treatment. Moreover, CD161(+)CD4(+) T cells as compared to homologous CD161(‐)CD4(+) T cells produced more pro‐inflammatory cytokines including interleukin (IL)‐17 and interferon (IFN)‐γ and expressed higher levels of liver‐homing chemokine receptors including CCR6, CXCR6 and CX3CR1. Notably, a significant enrichment of CD161(+)CD4(+) T cell subsets co‐expressing IFN‐γ and IL‐17 was observed in HBV‐associated cirrhotic livers. During in vitro co‐cultures, circulating CD161(+)CD4(+) T cells in the chronic HBV setting exhibited prominent pro‐fibrogenic effects by regulating primary hepatic stellate cells through a regenerative IFN‐γ/IL‐23/IL‐17 axis. CONCLUSIONS: In chronic HBV infection, CD161(+)CD4(+) T cells play antiviral, pro‐inflammatory and pro‐fibrogenic roles.