Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Front Immunol. 2022 Dec 5;13:1038821. doi: 10.3389/fimmu.2022.1038821. eCollection 2022.
Natural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes that play an important role in the first line of defense against malignant or virus-infected cells. A better understanding of the transcriptional regulation of human NK cell differentiation is crucial to improve the efficacy of NK cell-mediated immunotherapy for cancer treatment. Here, we studied the role of the transcription factor interferon regulatory factor (IRF) 2 in human NK cell differentiation by stable knockdown or overexpression in cord blood hematopoietic stem cells and investigated its effect on development and function of the NK cell progeny. IRF2 overexpression had limited effects in these processes, indicating that endogenous IRF2 expression levels are sufficient. However, IRF2 knockdown greatly reduced the cell numbers of all early differentiation stages, resulting in decimated NK cell numbers. This was not caused by increased apoptosis, but by decreased proliferation. Expression of IRF2 is also required for functional maturation of NK cells, as the remaining NK cells after silencing of IRF2 had a less mature phenotype and showed decreased cytotoxic potential, as well as a greatly reduced cytokine secretion. Thus, IRF2 plays an important role during development and functional maturation of human NK cells.
自然杀伤 (NK) 细胞是具有细胞毒性和细胞因子产生能力的淋巴细胞，在抵御恶性或病毒感染细胞的第一道防线中发挥着重要作用。更好地理解人类 NK 细胞分化的转录调控对于提高 NK 细胞介导的免疫疗法治疗癌症的疗效至关重要。在这里，我们通过在脐血造血干细胞中稳定敲低或过表达转录因子干扰素调节因子 (IRF) 2 来研究其在人类 NK 细胞分化中的作用，并研究其对 NK 细胞后代发育和功能的影响。IRF2 的过表达在这些过程中几乎没有影响，表明内源性 IRF2 表达水平足够。然而，IRF2 的敲低大大减少了所有早期分化阶段的细胞数量，导致 NK 细胞数量减少。这不是由于细胞凋亡增加引起的，而是由于增殖减少引起的。IRF2 的表达对于 NK 细胞的功能成熟也是必需的，因为沉默 IRF2 后剩余的 NK 细胞具有更不成熟的表型，表现出降低的细胞毒性潜力，以及细胞因子分泌大大减少。因此，IRF2 在人类 NK 细胞的发育和功能成熟过程中起着重要作用。
