Lund Research Center for Stem Cell Biology and Cell Therapy, Lund University, 221 84 Lund, Sweden.
Division of Molecular Hematology, Department of Laboratory Medicine, Lund University, 221 84 Lund, Sweden.
J Immunol. 2018 Dec 1;201(11):3307-3319. doi: 10.4049/jimmunol.1701675. Epub 2018 Oct 26.
Within the hematopoietic system, the Notch pathway is critical for promoting thymic T cell development and suppressing the B and myeloid lineage fates; however, its impact on NK lymphopoiesis is less understood. To study the role of Notch during NK cell development in vivo, we investigated different NK cell compartments and function in Rbp-JkVav-Cre mice, in which , the major transcriptional effector of canonical Notch signaling, was specifically deleted in all hematopoietic cells. Peripheral conventional cytotoxic NK cells in -deleted mice were significantly reduced and had an activated phenotype. Furthermore, the pool of early NK cell progenitors in the bone marrow was decreased, whereas immature NK cells were increased, leading to a block in NK cell maturation. These changes were cell intrinsic as the hematopoietic chimeras generated after transplantation of -deficient bone marrow cells had the same NK cell phenotype as the -deleted donor mice, whereas the wild-type competitors did not. The expression of several crucial NK cell regulatory pathways was significantly altered after deletion. Together, these results demonstrate the involvement of canonical Notch signaling in regulation of multiple stages of NK cell development.
在造血系统中，Notch 通路对于促进胸腺 T 细胞发育和抑制 B 细胞和髓样谱系命运至关重要；然而，其对 NK 淋巴样细胞发生的影响知之甚少。为了研究 Notch 在体内 NK 细胞发育中的作用，我们在 Rbp-JkVav-Cre 小鼠中研究了不同的 NK 细胞区室和功能，其中 Notch 信号的主要转录效应因子在所有造血细胞中特异性缺失。-缺失小鼠的外周常规细胞毒性 NK 细胞显著减少，且具有激活表型。此外，骨髓中的早期 NK 细胞祖细胞池减少，而未成熟 NK 细胞增加，导致 NK 细胞成熟受阻。这些变化是细胞内在的，因为移植 -缺陷骨髓细胞后生成的造血嵌合体与 -缺失供体小鼠具有相同的 NK 细胞表型，而野生型竞争细胞则没有。删除后几个关键的 NK 细胞调节途径的表达显著改变。总之，这些结果表明，经典 Notch 信号转导参与了 NK 细胞发育的多个阶段的调节。
