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.

A Practical Model Evaluating Antiviral Cytokines by Natural Killer Cells in Treatment Naïve Patients with Chronic Hepatitis B Virus Infection

“…Higher IFN-γand TNF-α produced by NK cells has been demonstrated correlated to viral inhibition and HBsAg clearance 48–51 . In addition to direct antiviral effect, these cytokines could further regulate adaptive immune responses by activating T and B cells 22, 52, 53 . Some studies also uncovered that NK cells may play a detrimental role in HBV chronicity thorough killing HBV specific CD8 + cells.…”

Immunogenicity of adenovirus-vector vaccine targeting hepatitis B virus: non-clinical safety assessment in non-human primates

“…The current study has several limitations. First, Natural killer (NK) cells naturally enriched in liver [26], and both of HBV infection [27] and adenovirus vector delivery [28] can affect the function of NK cells. However, we did not properly evaluate the function of NK cells in this study.…”

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