State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Hepatology, Huizhou Municipal Central Hospital, Guangzhou, China.
J Infect Dis. 2019 Feb 15;219(5):750-759. doi: 10.1093/infdis/jiy576.
Strategies that target functional recovery of exhausted hepatitis B virus (HBV)-specific CD8+ T cells are beneficial for viral control, but the potential for interleukin 21 (IL-21) to rescue CD8+ T-cell function is not well understood.
We investigated the effect of IL-21 on CD8+ T-cell responses by phenotypic and functional analysis of samples from patients with chronic HBV infection and a mouse model with HBV expression.
IL-21 promoted the proliferative capacity of HBV-specific CD8+ T cells and down-regulated expression of the inhibitory receptors programmed death 1 and T-cell immunoglobulin domain and mucin domain 3. Additionally, IL-21 boosted the production of interferon-γ, granzyme B, and CD107a in HBV-specific CD8+ T cells and enhanced the cytolytic activity of CD8+ T cells against HepG2.2.15 cells. Notably, an HBV mouse model established from IL-21 receptor knockout mice showed significantly decreased frequency of HBV-specific CD8+ T cells and increased levels of serum hepatitis B surface antigen (HBsAg). Meanwhile, administration of recombinant mouse IL-21 in an HBV mouse model established from wild-type mice resulted in enhanced functionality of HBV-specific CD8+ T cells and accelerated HBsAg clearance.
IL-21 enhances the antiviral effect of HBV-specific CD8+ T cells, suggesting that it may contribute to viral clearance in chronic HBV infection.
针对耗尽的乙型肝炎病毒 (HBV)-特异性 CD8+T 细胞的功能恢复的策略有利于病毒控制，但白细胞介素 21 (IL-21) 恢复 CD8+T 细胞功能的潜力尚未得到很好的理解。
我们通过慢性 HBV 感染患者样本和表达 HBV 的小鼠模型的表型和功能分析研究了 IL-21 对 CD8+T 细胞反应的影响。
IL-21 促进了 HBV 特异性 CD8+T 细胞的增殖能力，并下调了程序性死亡 1 和 T 细胞免疫球蛋白域和粘蛋白域 3 的抑制性受体的表达。此外，IL-21 增强了 HBV 特异性 CD8+T 细胞中干扰素-γ、颗粒酶 B 和 CD107a 的产生，并增强了 CD8+T 细胞对 HepG2.2.15 细胞的细胞毒性活性。值得注意的是，从 IL-21 受体敲除小鼠建立的 HBV 小鼠模型显示 HBV 特异性 CD8+T 细胞的频率显著降低，血清乙型肝炎表面抗原 (HBsAg) 水平升高。同时，在从野生型小鼠建立的 HBV 小鼠模型中给予重组小鼠 IL-21 导致 HBV 特异性 CD8+T 细胞的功能增强，并加速 HBsAg 清除。
IL-21 增强了 HBV 特异性 CD8+T 细胞的抗病毒作用，表明它可能有助于慢性 HBV 感染中的病毒清除。
