NK Cells Help Induce Anti–Hepatitis B Virus CD8+ T Cell Immunity in Mice

Abstract

Although recent clinical studies demonstrate that NK cell function is impaired in hepatitis B virus (HBV)–persistent patients, whether or how NK cells play a role in anti-HBV adaptive immunity remains to be explored. Using a mouse model mimicking acute HBV infection by hydrodynamic injection of an HBV plasmid, we observed that although serum hepatitis B surface Ag and hepatitis B envelope Ag were eliminated within 3 to 4 wk, HBV might persist for >8 wk in CD8−/− mice and that adoptive transfer of anti-HBV CD8+ T cells restored the ability to clear HBV in HBV-carrier Rag1−/− mice. These results indicate that CD8+ T cells are critical in HBV elimination. Furthermore, NK cells increased IFN-γ production after HBV plasmid injection, and NK cell depletion led to significantly increased HBV persistence along with reduced frequency of hepatitis B core Ag–specific CD8+ T cells. Adoptive transfer of IFN-γ–sufficient NK cells restored donor CD8+ T cell function, indicating that NK cells positively regulated CD8+ T cells via secreting IFN-γ. We also observed that NK cell depletion correlated with decreased effector memory CD8+ T cell frequencies. Importantly, adoptive transfer experiments showed that NK cells were involved in anti-HBV CD8+ T cell recall responses. Moreover, DX5+CD49a− conventional, but not DX5−CD49a+ liver-resident, NK cells were involved in improving CD8+ T cell responses against HBV. Overall, the current study reveals that NK cells, especially DX5+CD49a− conventional NK cells, promote the antiviral activity of CD8+ T cell responses via secreting IFN-γ in a mouse model mimicking acute HBV infection.