Vogel Karin, Thomann Sabrina, Vogel Benjamin, Schuster Philipp, Schmidt Barbara
Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Immunology. 2014 Dec;143(4):588-600. doi: 10.1111/imm.12337.
Herpes simplex virus type 1 (HSV-1), a member of the herpes virus family, is characterized by a short replication cycle, high cytopathogenicity and distinct neurotropism. Primary infection and reactivation may cause severe diseases in immunocompetent and immunosuppressed individuals. This study investigated the role of human plasmacytoid dendritic cells (pDC) in the activation of natural killer (NK) cells for the control of herpesviral infections. Within peripheral blood mononuclear cells, UV-inactivated HSV-1 and CpG-A induced CD69 up-regulation on NK cells, whereas infectious HSV-1 was particularly active in inducing NK cell effector functions interferon-γ (IFN-γ) secretion and degranulation. The pDC-derived IFN-α significantly contributed to NK cell activation, as evident from neutralization and cell depletion experiments. In addition, monocyte-derived tumour necrosis factor-α (TNF-α) induced after exposure to infectious HSV-1 was found to stimulate IFN-γ secretion. A minority of monocytes was shown to be non-productively infected in experiments using fluorescently labelled viruses and quantitative PCR analyses. HSV-1-exposed monocytes up-regulated classical HLA-ABC and non-classical HLA-E molecules at the cell surface in an IFN-α-dependent manner, whereas stress molecules MICA/B were not induced. Notably, depletion of monocytes reduced NK cell effector functions induced by infectious HSV-1 (P < 0.05). Altogether, our data suggest a model in which HSV-1-stimulated pDC and monocytes activate NK cells via secretion of IFN-α and TNF-α. In addition, infection of monocytes induces NK cell effector functions via TNF-α-dependent and TNF-α-independent mechanisms. Hence, pDC and monocytes, which are among the first cells infiltrating herpetic lesions, appear to have important bystander functions for NK cells to control these viral infections.
1型单纯疱疹病毒（HSV-1）是疱疹病毒家族的成员之一，其特点是复制周期短、细胞致病性高且具有明显的嗜神经性。原发性感染和再激活可能在免疫功能正常和免疫抑制的个体中引发严重疾病。本研究调查了人类浆细胞样树突状细胞（pDC）在激活自然杀伤（NK）细胞以控制疱疹病毒感染中的作用。在外周血单核细胞中，紫外线灭活的HSV-1和CpG-A可诱导NK细胞上CD69上调，而具有感染性的HSV-1在诱导NK细胞效应功能（干扰素-γ（IFN-γ）分泌和脱颗粒）方面特别活跃。从中和和细胞清除实验可以明显看出，pDC衍生的IFN-α对NK细胞激活有显著贡献。此外，发现暴露于具有感染性的HSV-1后诱导产生的单核细胞衍生肿瘤坏死因子-α（TNF-α）可刺激IFN-γ分泌。在使用荧光标记病毒和定量PCR分析的实验中，少数单核细胞显示为非生产性感染。暴露于HSV-1的单核细胞以IFN-α依赖的方式上调细胞表面的经典HLA-ABC和非经典HLA-E分子，而应激分子MICA/B未被诱导。值得注意的是，单核细胞的清除降低了由具有感染性的HSV-1诱导的NK细胞效应功能（P<0.05）。总之，我们的数据表明了一种模型，即HSV-1刺激的pDC和单核细胞通过分泌IFN-α和TNF-α激活NK细胞。此外，单核细胞感染通过TNF-α依赖和TNF-α非依赖机制诱导NK细胞效应功能。因此，pDC和单核细胞作为最早浸润疱疹病变的细胞之一，似乎对NK细胞控制这些病毒感染具有重要的旁观者功能。
