Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, N-5021 Bergen, Norway.
Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden.
Sci Immunol. 2021 Mar 12;6(57). doi: 10.1126/sciimmunol.abc9801.
Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing and in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in -mutated patients and by ectopic Bcl11b expression. Moreover, was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.
表观遗传景观可以深入了解基因表达和细胞多样性的调控。在这里，我们研究了七种人类血液自然杀伤 (NK) 细胞群体的转录组和表观遗传谱，包括适应性 NK 细胞。编码转录因子 (TF) 的 基因对于 T 细胞的发育和功能至关重要，它的表达在 NK 细胞分化过程中逐渐增加。几个与 T 细胞信号相关的 Bcl11b 调控基因在适应性 NK 细胞亚群中特异性表达。调控网络揭示了 NK 细胞分化不同阶段的相互调控，Bcl11b 分别抑制经典和适应性 NK 细胞中的 和 。在 Bcl11b 基因突变的患者和异位表达 Bcl11b 的情况下，证实了 Bcl11b 在驱动 NK 细胞分化中的关键作用。此外，在小鼠巨细胞病毒模型中， 对于适应性 NK 细胞的反应是必需的，支持这些细胞的扩增。总之，我们定义了人类 NK 细胞的 TF 调控回路，并揭示了 Bcl11b 在促进 NK 细胞分化和功能中的关键作用。
