López-Montañés María, Alari-Pahissa Elisenda, Sintes Jordi, Martínez-Rodríguez José E, Muntasell Aura, López-Botet Miguel
University Pompeu Fabra, Barcelona 08003, Spain.
Hospital del Mar Medical Research Institute, Barcelona 08003, Spain; and.
J Immunol. 2017 Jul 15;199(2):656-665. doi: 10.4049/jimmunol.1601574. Epub 2017 Jun 19.
NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-γ secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcγR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-γ) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350 particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF-α production but induced minimal IFN-γ secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350 particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350 particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-α but not cytotoxicity or IFN-γ production, potentially favoring the progression of viral infection.
据报道，自然杀伤（NK）细胞在裂解周期中对感染EB病毒的B细胞作出反应，并通过分泌干扰素-γ来控制病毒感染。早期报告提出，通过FcγR-IIIA（CD16）触发的NK细胞抗体依赖性细胞毒性（ADCC）在对EB病毒的反应中发挥作用。在本研究中，我们重新审视了这个问题，结果表明，EB病毒感染者的血清可触发NK细胞对感染EB病毒的细胞进行强烈的脱颗粒和细胞因子产生（即肿瘤坏死因子-α和干扰素-γ），从而增强NK细胞的激活。这种效应优先针对处于裂解期的细胞，并且与gp350/220包膜抗原的表面表达有关。相比之下，EB病毒感染细胞释放的gp350颗粒与B细胞系或自体原代B淋巴细胞的结合，也促进了特异性抗体依赖性NK细胞的脱颗粒和肿瘤坏死因子-α的产生，但诱导的干扰素-γ分泌极少。在这种情况下，与在触发类似NK细胞激活的浓度下的对照抗CD20抗体（利妥昔单抗）的作用相比，靶细胞损伤显得微不足道，这表明细胞相关的gp350颗粒可能会转移溶细胞机制，损害其对质膜的直接作用。这些观察结果支持抗体依赖性NK细胞激活在控制EB病毒中发挥重要作用，增强NK细胞在裂解周期中对受感染B细胞的效应功能。相比之下，数据显示，与旁观者B细胞结合的gp350颗粒触发抗体依赖性NK细胞脱颗粒和肿瘤坏死因子-α的产生，但不触发细胞毒性或干扰素-γ的产生，这可能有利于病毒感染的进展。
