IFN‐γ facilitates liver fibrogenesis by CD161<sup>+</sup>CD4<sup>+</sup> T cells through a regenerative IL‐23/IL‐17 axis in chronic hepatitis B virus infection
Jing Li, Li-Sha Cheng, Haoyu Jia, Chun Liu, Siqi Wang, Yun Liu, Yue Shen, Shengdi Wu, Fanli Meng, Beishi Zheng, Changqing Yang, Wei Jiang
Abstract
Abstract 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.