Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development
Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development
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DOI：
10.1016/j.devcel.2020.02.016
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发表时间：
2020-04-20
影响因子：
11.8
通讯作者：
Sturgeon, Christopher M.
中科院分区：
文献类型：
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作者：
Dege, Carissa;Fegan, Katherine H.;Sturgeon, Christopher M.
自然杀伤（NK）细胞是先天免疫系统的重要组成部分。然而，它们的个体发育起源仍不清楚。在这里，我们报告说，NK细胞的潜力首先来自Hoxa（阴性/低）试剂盒（+）CD 41（+）CD 16/32（+）造血干细胞（HSC）-独立的红骨髓祖细胞（EMP）存在于小鼠卵黄囊。EMP衍生的NK细胞和原代胎儿NK细胞，不像它们的成人对应物，在响应刺激时表现出强烈的脱粒。使用人多能干细胞（hPSC）的平行研究显示，Hoxa（阴性/低）CD 34（+）祖细胞产生NK细胞，与鼠EMP衍生的NK细胞相似，具有强效细胞毒性脱粒偏倚。相比之下，hPSC衍生的HOXA（+）CD 34（+）祖细胞以及人脐带血CD 34（+）细胞产生NK细胞，其表现出减弱的脱粒反应，但强烈产生炎性细胞因子。总的来说，我们的研究确定了胚胎外起源的强效细胞毒性NK细胞，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。
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(neg/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 Hoxa(neg/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.