Interferon‐γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization

Abstract The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon‐α (PEG‐IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG‐IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP‐1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN‐γ + Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8 + T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell‐associated chemokines (C‐X‐C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN‐γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68 + CD86 + macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86 + M1 and CD206 + M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue‐resident memory T cells with increased ALT levels. IFN‐γ + Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.