Department of Medicine, Division of Hematology, Washington University in St Louis, St. Louis, MO 63110, USA.
Center for Pediatric Biomedical Research and Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA.
Dev Cell. 2020 Apr 20;53(2):229-239.e7. doi: 10.1016/j.devcel.2020.02.016. Epub 2020 Mar 19.
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 Hoxa KitCD41CD16/32 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 HOXA 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.
自然杀伤 (NK) 细胞是先天免疫系统的重要组成部分。然而，其发生来源仍不清楚。在这里，我们报告说，NK 细胞潜能首先源自存在于鼠卵黄囊中造血干细胞 (HSC) 独立的红系-髓系祖细胞 (EMPs)。与成年 NK 细胞不同，源自 EMP 的 NK 细胞和原代胎儿 NK 细胞在受到刺激时表现出强烈的脱颗粒反应。使用人类多能干细胞 (hPSC) 的平行研究表明，HOXA CD34 祖细胞产生的 NK 细胞与鼠源性 EMP 衍生的 NK 细胞相似，具有强大的细胞毒性脱颗粒偏向。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 细胞表现出较弱的脱颗粒反应，但可强烈产生炎症细胞因子。总的来说，我们的研究确定了具有强大细胞毒性的 NK 细胞的胚胎外起源，这表明发生来源是设计 hPSC 衍生过继免疫疗法的一个相关因素。
