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Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development.
Developmental Cell ( IF 10.7 ) Pub Date : 2020-03-19 , DOI: 10.1016/j.devcel.2020.02.016
Carissa Dege 1 , Katherine H Fegan 2 , J Philip Creamer 1 , Melissa M Berrien-Elliott 3 , Stephanie A Luff 1 , Darren Kim 1 , Julia A Wagner 3 , Paul D Kingsley 2 , Kathleen E McGrath 2 , Todd A Fehniger 3 , James Palis 2 , Christopher M Sturgeon 4
Affiliation  

Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from Hoxaneg/low Kit+CD41+CD16/32+ hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXAneg/low CD34+ progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA+ CD34+ progenitors, as well as human cord blood CD34+ cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.

中文翻译:


强效细胞毒性自然杀伤细胞最初是在哺乳动物发育过程中从红骨髓祖细胞中产生的。



自然杀伤 (NK) 细胞是先天免疫系统的重要组成部分。然而,它们的个体起源仍不清楚。在此,我们报告 NK 细胞潜力首先来自小鼠卵黄囊中存在的 Hoxaneg/low Kit+CD41+CD16/32+ 造血干细胞 (HSC) 独立的红髓系祖细胞 (EMP)。 EMP 衍生的 NK 细胞和原代胎儿 NK 细胞与成年的 NK 细胞不同,在刺激后表现出强烈的脱粒作用。使用人类多能干细胞 (hPSC) 的平行研究表明,HOXAneg/低 CD34+ 祖细胞产生的 NK 细胞与鼠 EMP 衍生的 NK 细胞类似,具有强效的细胞毒性脱颗粒倾向。相比之下,hPSC 衍生的 HOXA+ CD34+ 祖细胞以及人脐带血 CD34+ 细胞产生的 NK 细胞表现出减弱的脱颗粒反应,但大量产生炎症细胞因子。总的来说,我们的研究确定了强效细胞毒性 NK 细胞的胚胎外起源,这表明个体起源是设计 hPSC 衍生的过继免疫疗法的相关因素。
更新日期:2020-04-20
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