CD163 impairs HBV clearance in mice by regulating intrahepatic T cell immune response via an IL-10-dependent mechanism.

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Chronic hepatitis B (CHB) arises from a persistent hepatitis B virus (HBV) infection, complicating efforts for a functional cure. Kupffer cells (KCs), liver-resident macrophages, are pivotal in mediating immune tolerance to HBV. Although CD163 marks M2-polarized KCs, its precise role in HBV infection remains unclear and warrants further investigation. CD163 expression in liver tissues of patients with CHB was analyzed using the Gene Expression Omnibus (GEO) database. Cd163 knockout mice were utilized to establish HBV-persistent mouse model, and CD163 deficiency effect on HBV viral markers and T cell immune responses were examined in vivo and in vitro. CD163 expression was elevated and correlated with ALT levels in the liver of patients with CHB. In HBV-persistent mouse model, CD163 deficiency facilitated the clearance of HBsAg, HBeAg, HBV DNA, and HBcAg. Additionally, CD163 deficiency promoted the differentiation of naïve T cells into HBV-specific effector T cells. Further, we found that CD163 deficiency reduces KCs-derived IL-10 secretion, and blocking IL-10 further strengthens the enhanced HBV-specific T cell response due to CD163 deficiency. Our findings indicate that CD163 deficiency enhances the HBV-specific T cell response, thereby facilitating HBV clearance through reducing KCs-derived IL-10 secretion. This suggests that CD163 may serve as a potential target for the restoration of exhausted T cell function.