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

While seroclearance of the surface antigen (HBsAg) defines clinical cure and reduces disease-associated risks, HBsAg clearance is rarely observed and remains therapeutically elusive. Here we overcome some of the challenges to studying immune mechanisms of HBsAg clearance in chronic hepatitis B (CHB) using our mouse model of age-dependent HBsAg clearance and persistence, and samples from our BeNEG-DO trial that provided longitudinal PBMCs from patients who either cleared HBsAg or retained stable HBsAg levels after stopping nucleos(t)ide analog therapy.

We show that young mice fail to clear HBsAg and have an impaired ability to efficiently initiate and sustain an HBV-specific CD4+ T cell response. We also demonstrate a role for CD4+ T cells in hepatic leukocyte organization, HBV-specific CD8+ T cell cytotoxicity, and ultimately HBsAg clearance. Upstream of the CD4+ T cell response, we reveal that hepatic dendritic cells, particularly cDC2s, direct effective CD4+ T cell activation and differentiation.