NK Cells Help Induce Anti-Hepatitis B Virus CD8+ T Cell Immunity in Mice
NK Cells Help Induce Anti-Hepatitis B Virus CD8+ T Cell Immunity in Mice
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DOI：
10.4049/jimmunol.1500846
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发表时间：
2016-05-15
影响因子：
4.4
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
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作者：
Zheng, Meijuan;Sun, Rui;Tian, Zhigang
虽然最近的临床研究表明，NK细胞功能受损的B型肝炎病毒（HBV）持续患者，NK细胞是否或如何发挥作用，抗HBV的适应性免疫仍有待探讨。使用模拟急性HBV感染的小鼠模型，通过流体动力学注射HBV质粒，我们观察到尽管血清B表面Ag和B包膜Ag在3 - 4周内消除，但HBV在CD 8（-/-）小鼠中可能持续>8周，并且过继转移抗HBV CD 8（+）T细胞恢复了HBV携带者Rag 1（-/-）小鼠清除HBV的能力。这些结果表明，CD 8（+）T细胞在HBV清除中至关重要。此外，NK细胞在HBV质粒注射后增加IFN-γ的产生，NK细胞耗竭导致HBV持久性沿着显著增加，同时B型肝炎核心Ag特异性CD 8（+）T细胞的频率降低。IFN-γ-充足的NK细胞的连续转移恢复了供体CD 8（+）T细胞的功能，表明NK细胞通过分泌IFN-γ正向调节CD 8（+）T细胞。我们还观察到NK细胞耗竭与效应记忆CD 8（+）T细胞频率降低相关。重要的是，过继转移实验表明NK细胞参与抗HBV CD 8（+）T细胞回忆应答。此外，DX 5（+）CD 49 a（-）常规NK细胞参与提高CD 8（+）T细胞对HBV的应答，而DX 5（-）CD 49 a（+）肝脏驻留NK细胞则不参与提高CD 8（+）T细胞对HBV的应答。总之，目前的研究表明，NK细胞，特别是DX 5（+）CD 49 a（-）常规NK细胞，通过分泌IFN-γ在模拟急性HBV感染的小鼠模型中促进CD 8（+）T细胞应答的抗病毒活性。
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-gamma 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-gamma-sufficient NK cells restored donor CD8(+) T cell function, indicating that NK cells positively regulated CD8(+) T cells via secreting IFN-gamma. 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-gamma in a mouse model mimicking acute HBV infection.