Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Italy.
Department of Pharmacy, University of Pisa, Italy.
J Hepatol. 2017 Jun;66(6):1130-1137. doi: 10.1016/j.jhep.2017.01.032. Epub 2017 Feb 10.
BACKGROUND & AIMS: The Fc receptor family for immunoglobulin (Ig)G type III (FcγRIII, CD16) is an activating receptor on natural killer (NK) cells and an essential mediator of antibody-dependent cellular cytotoxicity (ADCC). There is only limited information on its role during chronic hepatitis C virus (HCV) infection. We studied CD16 expression in relation to NK cell functional activity in HCV-infected patients and sought mechanistic insights into virus-induced modulation.
NK cell CD16 expression and activation status were evaluated ex vivo by flow cytometry in HCV-infected patients and healthy controls (HC) as well as in vitro after co-culture with HCV-infected HuH7.5 cells. Rituximab-mediated ADCC was assessed in HC and HCV-infected patients using Daudi cells as a target. The role of metzincins in CD16 down-modulation was assessed using specific inhibitory molecules and by evaluating intracellular mRNA levels.
HCV-infected patients exhibited increased frequencies of ex vivo activated NK cells and a concomitantly decreased NK CD16 expression, which resulted in impaired ADCC activity. Moreover, exposure of NK cells to culture-derived HCV recapitulated the ex vivo findings of decreased CD16 expression and increased NK cell activation. Importantly, blockade of metzincin-mediated shedding activity, including selective a disintegrin and metalloproteinase 17 (ADAM-17) inhibition, restored NK CD16 expression. Successful treatment with direct-acting antivirals partially improved NK ADCC function despite delayed CD16 reconstitution.
Chronic HCV infection induces NK cell activation resulting in ADAM-17-dependent CD16 shedding and consequent impaired ADCC function. Altered ADCC may contribute to failure to eradicate HCV-infected hepatocytes.
We show here that hepatitis C virus (HCV) activates natural killer (NK) lymphocytes which, as a consequence, loose their Fc receptor for IgG (CD16), an essential molecule for antibody binding. We show that this occurs through the action of enzymes named metzincins, resulting in altered NK-mediated antibody-dependent killing (ADCC) of target cells. This mechanism may contribute to HCV persistence and may represent a general phenomenon whereby some viruses can escape host's immune responses.
免疫球蛋白（IgG）III 型（FcγRIII，CD16）Fc 受体家族是自然杀伤（NK）细胞上的一种激活受体，也是抗体依赖性细胞毒性（ADCC）的重要介质。关于其在慢性丙型肝炎病毒（HCV）感染中的作用，仅有有限的信息。我们研究了 HCV 感染患者中 NK 细胞 CD16 表达与 NK 细胞功能活性的关系，并寻求对病毒诱导的调节的机制见解。
通过流式细胞术检测 HCV 感染患者和健康对照者（HC）NK 细胞 CD16 表达和激活状态，以及与 HCV 感染的 HuH7.5 细胞共培养后的体外状态。使用 Daudi 细胞作为靶标，通过利妥昔单抗介导的 ADCC 在 HC 和 HCV 感染患者中进行评估。使用特异性抑制分子和评估细胞内 mRNA 水平来评估金属蛋白酶在 CD16 下调中的作用。
HCV 感染患者表现出体外激活 NK 细胞的频率增加，同时 NK CD16 表达降低，导致 ADCC 活性受损。此外，NK 细胞暴露于培养衍生的 HCV 可再现 CD16 表达降低和 NK 细胞激活增加的体外发现。重要的是，金属蛋白酶介导的脱落活性的阻断，包括选择性解整合素和金属蛋白酶 17（ADAM-17）抑制，可恢复 NK CD16 表达。直接作用抗病毒治疗的成功部分改善了 NK ADCC 功能，尽管 CD16 重建延迟。
慢性 HCV 感染诱导 NK 细胞激活，导致 ADAM-17 依赖性 CD16 脱落，继而导致 ADCC 功能受损。改变的 ADCC 可能有助于未能清除 HCV 感染的肝细胞。
在这里，我们展示了丙型肝炎病毒（HCV）激活自然杀伤（NK）淋巴细胞，导致其失去 IgG（CD16）的 Fc 受体，这是抗体结合的必需分子。我们表明，这是通过称为金属蛋白酶的酶的作用发生的，导致 NK 介导的靶细胞抗体依赖性杀伤（ADCC）改变。这种机制可能有助于 HCV 的持续存在，并且可能代表一种普遍现象，即某些病毒可以逃避宿主的免疫反应。
