Intrahepatic T helper 17 cells recruited by hepatitis B virus X antigen‐activated hepatic stellate cells exacerbate the progression of chronic hepatitis B virus infection
Hongbin Zhang, Yan Xiong, Cheng Yang, Qian Zhan, Yueqiang Fu, Huating Luo, Huating Luo, Hongchun Luo, Hongchun Luo
Abstract
Abstract Immunopathological injury induced by persistent hepatitis B virus (HBV) infection contributes to the progression from chronic hepatitis B (CHB) to hepatic cirrhosis and hepatocellular carcinoma (HCC). Regulatory T cells (Tregs), CD4 + T helper (Th) cells, and hepatic stellate cells (HSCs) are considered to be the pivotal factors during this progression. In this study, our aim was to investigate the molecular mechanisms of liver immunopathological injury associated with Tregs, CD4 + Th cells, and HSCs. Liver tissues were collected to assay the cytokines and distribution and frequencies of CD4 + Th cells and Tregs. The chemotaxis of Th17 cells towards the liver and the interactions between IL‐22, IL‐17A, and HSCs were explored. The data showed the frequencies of Th17 cells, and their effector molecules IL‐22 and IL‐17A were increased along with the severity of chronic liver diseases. However, the frequencies of Tregs were decreased in HBV‐associated cirrhotic tissues compared with those in CHB tissues and HCC tissues. hepatitis B virus X antigen (HBxAg)‐activated HSCs recruited more Th17 cells into the liver and conduced to the secretion of IL‐17A and IL‐22 that could in turn stimulate the proliferation and fibrotic marker secretion of the HSCs. Therefore, we suggest that the interactions between Th17 cells, IL‐17A, IL‐22, and HSCs form a positive feedback loop that aggravated the progression of chronic liver disease with HBV infection through the phosphoinositide‐3‐kinase/protein kinase B (PI3K/AKT) signalling pathway. Our findings indicated the IL‐17A/IL‐22 pathway might become a new treatment target for liver cirrhosis and HCC.