Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; and.
J Immunol. 2018 May 15;200(10):3530-3538. doi: 10.4049/jimmunol.1701801. Epub 2018 Apr 11.
Activation of invariant NKT (iNKT) cells manifests antiviral immune responses in vivo. However, clinical trials have failed to show consistent hepatitis B virus (HBV) DNA reduction postadministration of iNKT cell-specific agonist α-galactosylceramide (α-GalCer). In this study, we aimed to investigate HBV infection-related iNKT cell defects and explore iNKT cell-based therapeutic potential for chronic hepatitis B (CHB). Liver specimens from 30 HBV-infected hepatocellular carcinoma patients were collected for CD1d/hepatitis B surface Ag (HBsAg) staining and/or intrahepatic iNKT cell assay. Two hundred and six chronic HBV-infected patients (including 130 CHB patients) were enrolled in the study of circulating iNKT cell frequency and function. We found that liver and hepatoma tissue that positively stained for HBsAg had higher CD1d expression as compared with HBsAg negatively stained counterparts. The elevated CD1d expression in infected tissue is supposed to facilitate the iNKT cell-based antiviral effects locally. However, iNKT cell defects that related with disease progression suggested iNKT cells attenuated their effects during chronic HBV infection. The residual iNKT cells in CHB patients showed aberrant activation and hyporesponsiveness to α-GalCer. Exogenous IL-2 fully rescued α-GalCer-induced expansion of iNKT cells from CHB patients, and synergistic effects of IL-2 and IL-15 helped to recover the CD1d-dependent IFN-γ production. In conclusion, our results highlight the increased CD1d expression in HBV-infected liver and differential iNKT cell defects associated with disease progression during chronic HBV infection. The reversibility of iNKT cell defects suggests protective immune responses could be partially recovered in CHB.
固有自然杀伤 T(iNKT)细胞的激活可在体内表现出抗病毒免疫反应。然而，临床研究表明，在施用 iNKT 细胞特异性激动剂α-半乳糖神经酰胺（α-GalCer）后，并未观察到乙型肝炎病毒（HBV）DNA 的持续减少。在本研究中，我们旨在研究 HBV 感染相关的 iNKT 细胞缺陷，并探索基于 iNKT 细胞的慢性乙型肝炎（CHB）治疗潜力。收集 30 例 HBV 感染的肝细胞癌患者的肝组织标本，进行 CD1d/乙型肝炎表面抗原（HBsAg）染色和/或肝内 iNKT 细胞检测。纳入 206 例慢性 HBV 感染患者（包括 130 例 CHB 患者），研究循环 iNKT 细胞频率和功能。我们发现，与 HBsAg 阴性染色的组织相比，HBsAg 阳性染色的肝和肝癌组织具有更高的 CD1d 表达。感染组织中 CD1d 的上调有助于局部发挥 iNKT 细胞的抗病毒作用。然而，与疾病进展相关的 iNKT 细胞缺陷表明，在慢性 HBV 感染期间，iNKT 细胞的作用减弱。CHB 患者中残留的 iNKT 细胞表现出异常激活和对 α-GalCer 的低反应性。外源性 IL-2 可完全恢复 CHB 患者中 α-GalCer 诱导的 iNKT 细胞扩增，而 IL-2 和 IL-15 的协同作用有助于恢复 CD1d 依赖性 IFN-γ的产生。总之，我们的研究结果突出了 HBV 感染肝脏中 CD1d 表达的增加以及慢性 HBV 感染期间与疾病进展相关的 iNKT 细胞缺陷。iNKT 细胞缺陷的可恢复性表明，CHB 患者的保护性免疫反应可能部分得到恢复。
