Kupffer Cells Interact With Hepatitis B Surface Antigen In Vivo and In Vitro, Leading to Proinflammatory Cytokine Production and Natural Killer Cell Function

Background. Based on their localization, Kupffer cells (KCs) likely interact with hepatitis B virus (HBV). However, the role of KCs in inducing immunity toward HBV is poorly understood. Therefore, the interaction of hepatitis B surface antigen (HBsAg) and KCs, and possible functional consequences, were assessed. Methods. KCs in liver tissue from patients with chronic HBV were analyzed for presence of HBsAg and their phenotype, and compared with KCs in control liver tissue. Liver graft perfusate-derived KCs and in vitro-generated monocyte-derived macrophages were investigated for functional interaction with patient-derived HBsAg. Results. Intrahepatic KCs were HBsAg positive and more activated than those from control livers. KCs internalized HBsAg in vitro, which did not change their phenotype, but strongly induced proinflammatory cytokine production. Additionally, monocyte-derived macrophages also interacted with HBsAg, leading to activation and cytokine production. Furthermore, HBsAg-exposed macrophages and KC activated natural killer (NK) cells, resulting in increased CD69 expression and interferon-gamma production. Conclusions. KCs directly interact with HBsAg in vivo and in vitro. HBsAg-induced cytokine production by KCs and monocyte-derived macrophages and subsequent NK cell activation may be an early event in viral containment and may support induction of HBV-specific immunity upon HBV infection, but may also contribute to liver pathology.