Schlums Heinrich, Cichocki Frank, Tesi Bianca, Theorell Jakob, Beziat Vivien, Holmes Tim D, Han Hongya, Chiang Samuel C C, Foley Bree, Mattsson Kristin, Larsson Stella, Schaffer Marie, Malmberg Karl-Johan, Ljunggren Hans-Gustaf, Miller Jeffrey S, Bryceson Yenan T
Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden; Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Immunity. 2015 Mar 17;42(3):443-56. doi: 10.1016/j.immuni.2015.02.008.
The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.
人类自然杀伤（NK）细胞表型和功能异质性的潜在机制尚不清楚。在此，我们描述了人类巨细胞病毒（HCMV）感染后选择性缺乏信号蛋白表达的多种人类NK细胞亚群的出现。这些NK细胞亚群中B细胞和髓样细胞相关信号蛋白表达的缺失与启动子DNA高甲基化相关。HCMV相关适应性NK细胞与细胞毒性效应T细胞之间的全基因组DNA甲基化模式惊人地相似，但与经典NK细胞不同。功能研究表明，适应性NK细胞中细胞因子反应性改变，这与转录因子PLZF表达降低有关。此外，适应性NK细胞亚群对活化的自体T细胞的功能反应显著降低。目前的结果揭示了一系列表观遗传上独特的适应性NK细胞亚群，它们在病毒感染后多样化，并且与经典NK细胞亚群相比具有不同的功能能力。
