Natural Killer T Cell Activation Inhibits Hepatitis B Virus Replication in Vivo

We have previously reported that hepatitis B virus (HBV)–specific CD8+ cytotoxic T lymphocytes and CD4+ helper T lymphocytes can inhibit HBV replication in the liver of HBV transgenic mice by secreting interferon (IFN)-γ when they recognize viral antigen. To determine whether an activated innate immune system can also inhibit HBV replication, in this study we activated natural killer T (NKT) cells in the liver of HBV transgenic mice by a single injection of α-galactosylceramide (α-GalCer), a glycolipid antigen presented to Vα14+NK1.1+ T cells by the nonclassical major histocompatibility complex class I–like molecule CD1d. Within 24 h of α-GalCer injection, IFN-γ and IFN-α/β were detected in the liver of HBV transgenic mice and HBV replication was abolished. Both of these events were temporally associated with the rapid disappearance of NKT cells from the liver, presumably reflecting activation-induced cell death, and by the recruitment of activated NK cells into the organ. In addition, prior antibody-mediated depletion of CD4+ and CD8+ T cells from the mice did not diminish the ability of α-GalCer to trigger the disappearance of HBV from the liver, indicating that conventional T ce