NKG2A-Expressing Natural Killer Cells Dominate the Response to Autologous Lymphoblastoid Cells Infected with Epstein-Barr Virus.

Epstein–Barr virus (EBV) is a human γ-herpesvirus that establishes latency and lifelong infection in host B cells while achieving a balance with the host immune response. When the immune system is perturbed through immunosuppression or immunodeficiency, however, these latently infected B cells can give rise to aggressive B cell lymphomas. Natural killer (NK) cells are regarded as critical in the early immune response to viral infection, but their role in controlling expansion of infected B cells is not understood. Here, we report that NK cells from healthy human donors display increased killing of autologous B lymphoblastoid cell lines (LCLs) harboring latent EBV compared to primary B cells. Coculture of NK cells with autologous EBV+ LCL identifies an NK cell population that produces IFNγ and mobilizes the cytotoxic granule protein CD107a. Multi-parameter flow cytometry and Boolean analysis reveal that these functional cells are enriched for expression of the NK cell receptor NKG2A. Further, NKG2A+ NK cells more efficiently lyse autologous LCL than do NKG2A− NK cells. More specifically, NKG2A+2B4+CD16−CD57−NKG2C−NKG2D+ cells constitute the predominant NK cell population that responds to latently infected autologous EBV+ B cells. Thus, a subset of NK cells is enhanced for the ability to recognize and eliminate autologous, EBV-infected transformed cells, laying the groundwork for harnessing this subset for therapeutic use in EBV+ malignancies.

爱泼斯坦 - 巴尔病毒（EBV）是一种人类γ - 疱疹病毒，它在宿主B细胞中建立潜伏感染并终身存在，同时与宿主免疫反应达到平衡。然而，当免疫系统因免疫抑制或免疫缺陷而受到干扰时，这些潜伏感染的B细胞会引发侵袭性B细胞淋巴瘤。自然杀伤（NK）细胞被认为在对病毒感染的早期免疫反应中至关重要，但其在控制感染B细胞扩增方面的作用尚不清楚。在此，我们报道来自健康人类供体的NK细胞对携带潜伏EBV的自体B淋巴母细胞系（LCLs）的杀伤作用相较于原代B细胞有所增强。NK细胞与自体EBV + LCL共培养可鉴定出一个产生干扰素γ并动员细胞毒性颗粒蛋白CD107a的NK细胞群。多参数流式细胞术和布尔分析显示，这些功能性细胞中NK细胞受体NKG2A的表达富集。此外，NKG2A + NK细胞比NKG2A - NK细胞更有效地裂解自体LCL。更具体地说，NKG2A + 2B4 + CD16 - CD57 - NKG2C - NKG2D +细胞构成了对潜伏感染的自体EBV + B细胞作出反应的主要NK细胞群。因此，一部分NK细胞识别和清除自体EBV感染的转化细胞的能力增强，为利用这部分细胞治疗EBV +恶性肿瘤奠定了基础。