UCSF

Hepatitis B virus (HBV) can cause either an acute infection with self-limiting disease or, instead, a persistent infection resulting in chronic, recurring disease. The major determinant of which disease outcome occurs is the age at which a person is infected with HBV. Greater than 95 percent of adults exposed to HBV will mount an effective immune response resulting in viral clearance, while greater than 90 percent of infants under one year of age and 30-50 percent of young children aged one to five years-old will generate an ineffective immune response that is unable to control the infection. Current therapies targeted at patients living with chronic HBV (CHB) mostly rely on suppression of viral replication, which is ineffective in inducing viral clearance and antibody seroconversion needed to achieve a functional cure. Thus, it is of great interest to characterize and understand the immunological mechanisms that dictate age-dependent disease outcomes of HBV in order to identify potential therapeutic pathways that can help shift the ineffective immune response in CHB patients to an effective response that results in viral control. Using a mouse model that mimics HBV infection in humans and the age-dependent disease outcomes, we were able to identify critical regulators of age-dependent immunity in the liver. Specifically, we identified an essential role for OX40/OX40L interactions in supporting the generation of effective CD4+ T cell responses including the differentiation of Tfh cells and their production of IL-21, as well as the priming of a robust and diverse antigen-specific IFNg T cell response. We also found an age-dependent increase in the number of hepatic ILC3s, which expressed MHC class II, CD69, and cytokines including GM-CSF, IL-22, and IL-17a. A loss of ILC3s either in genetically deficient Rorc(gt)-/- mice or in acutely depleted anti-Thy1.2 antibody-treated mice resulted in significantly impaired HBV antigen clearance and seroconversion. We identified a role for these ILC3s in supporting long-lived CD4+ T cell responses, the appropriate distribution and organization of hepatic immune cell clusters important in immune priming and sustained lymphocyte activation, as well as the early recruitment and effector functions of hepatic CD8+ T cells. Targeting the expansion and functional activities of mature hepatic ILC3s, thus, may represent a previously unidentified pathway that could improve HBV immune outcomes.