Clinical cure of chronic hepatitis B is associated with priming and perpetuation of hepatic CD4 ⁺ T cell responses

Chronic infection with hepatitis B virus (HBV) often leads to immune-mediated progressive liver injury and liver cancer. Seroclearance of the surface antigen (HBsAg) defines clinical cure and reduces disease-associated risks but rarely occurs. Here, we aimed to study the immune mechanisms of HBsAg clearance in chronic hepatitis B (CHB) using a mouse model of age-dependent HBsAg clearance and persistence and longitudinal peripheral blood samples from participants in the BeNEG-DO clinical trial who exhibited either HBsAg clearance or stable HBsAg level retention after stopping nucleos(t)ide analog therapy. Whereas HBsAg clearance in young mice failed and the ability to initiate and sustain HBV-specific CD4 + T cell responses in the liver was impaired, adult mice exhibited a robust HBV-specific CD4 + T cell response and HBsAg clearance. Depletion of CD4 + T cells in adult mice prevented HBsAg seroclearance and hepatocellular injury and disrupted hepatic leukocyte organization and HBV-specific CD8 + T cell cytotoxicity, whereas depletion of CD8 + T cells did not alter HBsAg seroclearance. Upstream of the CD4 + T cell response, hepatic myeloid cells, particularly type 2 conventional dendritic cells, directed CD4 + T cell priming and differentiation. Studies using samples from patients with CHB identified features of HBsAg clearance that overlapped with the mouse model, including T helper 1 and cytotoxic CD4 + T cell activation and augmented CD8 + T cell effector function. These findings identified a role for CD4 + T cell activation in the clinical cure of CHB and suggest that therapeutically enhancing CD4 + T cell responses could improve HBsAg clearance rates.