School of Laboratory Medicine and Biotechnology, Southern Medical University, 510515 Guangzhou City, Guangdong Province, China; General Hospital of Central Theatre Command, 430070 Wuhan City, Hubei Province, China.
General Hospital of Central Theatre Command, 430070 Wuhan City, Hubei Province, China.
Immunobiology. 2022 Nov;227(6):152272. doi: 10.1016/j.imbio.2022.152272. Epub 2022 Sep 7.
Natural killer (NK) cells are key players in the immune system, however, the exact mechanism of NK cell dysfunction during HBV infection remains poorly defined.
Hepatitis B envelope antigen-negative (HBeAg-, n = 19) chronic hepatitis B infection (CHB) patients, HBeAg-positive (HBeAg+, n = 20) CHB patients, HBV-related hepatocellular carcinoma (HBV-HCC, n = 12) patients and healthy blood donors (HD, n = 20), were enrolled in our study. The phenotype and function of the corresponding NK cells of these subjects were then determined. NK cells were cocultured with HBV to assess whether HBV influences the activation of STAT1. Receptors, proliferation, apoptosis rate, and cytotoxicity of NK-92 cells were detected after STAT1 overexpression and knockdown. The relationship between STAT1 and NKG2D promoter was determined by luciferase assay.
The levels of NKG2D and STAT1 were the lowest in the HBV-HCC group compared with the HD group, followed by the HBeAg+ group and then the HBeAg- group, respectively. Interestingly, STAT1 levels were positively correlated with NKG2D expression and HBeAg status. Furthermore, STAT1 directly bound to the NKG2D promoter to regulate the transcription and expression of NKG2D. Finally, the results also suggested that knockdown of STAT1 can inhibit proliferation, increase apoptosis rate of NK-92 cells and impair cytotoxicity of NK-92 cells.
STAT1 is correlated with NK cell dysfunction by downregulating NKG2D transcription in HBV-infected patients. Our findings demonstrate that STAT1 is an important and positive regulator of NK cells, which could provide a potential immunotherapy target for CHB.
自然杀伤 (NK) 细胞是免疫系统的关键参与者，然而，HBV 感染期间 NK 细胞功能障碍的确切机制仍未完全明确。
本研究纳入了 19 名 HBeAg-阴性（HBeAg-，n=19）慢性乙型肝炎（CHB）感染患者、20 名 HBeAg-阳性（HBeAg+，n=20）CHB 感染患者、12 名乙型肝炎病毒相关肝细胞癌（HBV-HCC，n=12）患者和 20 名健康献血者（HD，n=20）。然后测定这些受试者相应 NK 细胞的表型和功能。将 NK 细胞与 HBV 共培养，以评估 HBV 是否影响 STAT1 的激活。在过表达和敲低 STAT1 后，检测 NK-92 细胞的受体、增殖、凋亡率和细胞毒性。通过荧光素酶测定确定 STAT1 与 NKG2D 启动子之间的关系。
与 HD 组相比，HBV-HCC 组的 NKG2D 和 STAT1 水平最低，其次是 HBeAg+组，然后是 HBeAg-组。有趣的是，STAT1 水平与 NKG2D 表达和 HBeAg 状态呈正相关。此外，STAT1 直接与 NKG2D 启动子结合，调节 NKG2D 的转录和表达。最后，结果还表明，STAT1 的敲低可以抑制 NK-92 细胞的增殖，增加其凋亡率，并损害其细胞毒性。
在 HBV 感染患者中，STAT1 通过下调 NKG2D 转录与 NK 细胞功能障碍相关。我们的研究结果表明，STAT1 是 NK 细胞的一个重要的正调控因子，为 CHB 的潜在免疫治疗靶点提供了依据。
