Judge Chelsey J, Kostadinova Lenche, Sherman Kenneth E, Butt Adeel A, Falck-Ytter Yngve, Funderburg Nicholas T, Landay Alan L, Lederman Michael M, Sieg Scott F, Sandberg Johan K, Anthony Donald D
Department of Pathology, Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Medicine, University Hospitals Case Medical Center and Center for AIDS Research (CFAR), Case Western Reserve University, Cleveland, Ohio, USA.
J Leukoc Biol. 2017 Jul;102(1):171-184. doi: 10.1189/jlb.5A1116-456R. Epub 2017 Apr 11.
Several lines of evidence support the concept that NK cells play an important role in control of hepatitis C virus (HCV) infection via cytokine secretion and cytotoxicity. IL-7 is a homeostatic cytokine with a role in T cell development, activation, proliferation, and cytokine secretion. The IL-7Rα chain [cluster of differentiation (CD)127] is expressed on NK cells, with greatest abundance on the CD56CD16 (CD56) subset. Here, we measured CD127 expression on CD56, CD56CD16 (CD56), or CD56CD16 (CD56) NK cell subsets of 25 uninfected donors (UD); 34 chronic HCV-infected, treatment-naïve; 25 HIV-infected, virally suppressed on antiretroviral therapy (ART); and 42 HCV-HIV-coinfected subjects on ART. Interestingly, CD127 expression on CD56 NK cells negatively correlated with HCV plasma levels in HCV monoinfection and HCV-HIV coinfection. IL-7 induced CD69 expression, as well as IFN-γ production, in CD56 NK cells and also enhanced the IFN-α-induced CD69 expression on these cells. The latter was impaired in HIV infection. Furthermore, IL-7 induced B cell lymphoma 2 (BCL-2) expression and cell cycling of CD56 NK cells, and this effect was impaired in HCV- and HIV-infected subjects. Whereas IL-7-stimulated CD56 NK cell degranulation appeared intact in all cohorts, we observed impaired IL-7-activated NK cell cytolytic function in HCV- and HIV-infected subjects. Finally, IL-7-induced phosphorylation of STAT-5 (pSTAT-5) signaling was impaired in NK cells of subjects with chronic viral infection, and this was reversible upon 6 mo of viral suppression with IFN-free HCV therapy. These results implicate that IL-7-dependent NK cell activation and effector function may be other host immune surveillance mechanisms that are impaired in viral infections.
多条证据支持自然杀伤（NK）细胞通过细胞因子分泌和细胞毒性在丙型肝炎病毒（HCV）感染控制中发挥重要作用这一概念。白细胞介素-7（IL-7）是一种稳态细胞因子，在T细胞发育、激活、增殖和细胞因子分泌中起作用。IL-7受体α链[分化簇（CD）127]在NK细胞上表达，在CD56⁺CD16⁻（CD56⁺）亚群上丰度最高。在此，我们检测了25名未感染供体（UD）、34名未经治疗的慢性HCV感染患者、25名接受抗逆转录病毒治疗（ART）且病毒得到抑制的HIV感染患者以及42名接受ART的HCV-HIV合并感染患者的CD56⁺、CD56⁺CD16⁻（CD56⁺）或CD56⁻CD16⁺（CD56⁻）NK细胞亚群上CD127的表达。有趣的是，在HCV单一感染和HCV-HIV合并感染中，CD56⁺NK细胞上的CD127表达与HCV血浆水平呈负相关。IL-7可诱导CD56⁺NK细胞表达CD69以及产生γ干扰素（IFN-γ），还可增强这些细胞上α干扰素（IFN-α）诱导的CD69表达。后者在HIV感染中受损。此外，IL-7可诱导CD56⁺NK细胞表达B细胞淋巴瘤2（BCL-2）并促进其细胞周期循环，而在HCV和HIV感染患者中这种作用受损。虽然在所有队列中IL-7刺激的CD56⁺NK细胞脱颗粒似乎完整，但我们观察到在HCV和HIV感染患者中IL-7激活的NK细胞溶细胞功能受损。最后，在慢性病毒感染患者的NK细胞中，IL-7诱导的信号转导和转录激活因子5（STAT-5）磷酸化（pSTAT-5）信号受损，而在无干扰素的HCV治疗进行6个月病毒抑制后这种情况是可逆的。这些结果表明，依赖IL-7的NK细胞激活和效应功能可能是病毒感染中受损的其他宿主免疫监视机制。
