The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, and Division of Oral Biology and Medicine, UCLA School of Dentistry, University of California , Los Angeles, CA , USA .
J Immunotoxicol. 2014 Oct;11(4):297-307. doi: 10.3109/1547691X.2013.877104. Epub 2014 Feb 27.
Evidence has previously been demonstrated for the role of NK cells in specific elimination of healthy stem cells (e.g. hMSC, hDPSC, hESC, hiPSC) as well as cancer stem cells, but not their differentiated counterparts. There is also a stage-wise susceptibility to NK cell-mediated cyto-toxicity in tumors, in which case the poorly-differentiated tumors are lysed much more than moderately-differentiated tumors. Well-differentiated tumors were lysed the least compared to either moderately- or poorly-differentiated tumors. It has also been reported that inhibition of differentiation or reversion of cells to a less-differentiated stage by blocking NF-κB or by gene deletion of COX2 significantly augmented NK cell cytotoxicity against both transformed and healthy cells. Additionally, the cytotoxic function of NK cells was severely inhibited against stem cells when they were cultured in the presence of monocytes. Therefore, it is proposed that CD16(+)CD56(dim)CD69(-) NK cells were important for the selection of stem cells, whereas the CD16(dim/-)CD56(dim/+)CD69(+) anergized NK cells were important for differentiation and eventual regeneration of the tissues and the resolution of inflammation, thus potentially serving as regulatory NK (NK(reg)) cells. The concept of 'split anergy' in NK cells and the generation of NK(reg) cells with regard to contributions to cell differentiation, tissue repair and regeneration and in tumor resistance are discussed in this review.
先前已经有证据表明 NK 细胞在特异性清除健康干细胞（例如 hMSC、hDPSC、hESC、hiPSC）和肿瘤干细胞方面发挥了作用，但不会作用于其分化的对应物。肿瘤对 NK 细胞介导的细胞毒性也存在阶段性易感性，在这种情况下，分化不良的肿瘤比中度分化的肿瘤更容易被溶解。与中度或低度分化的肿瘤相比，分化良好的肿瘤被溶解的程度最小。据报道，通过阻断 NF-κB 或通过 COX2 基因缺失抑制细胞分化或使其向低分化阶段逆转，可显著增强 NK 细胞对转化细胞和健康细胞的细胞毒性。此外，当干细胞在单核细胞存在的情况下培养时，NK 细胞对其的细胞毒性功能受到严重抑制。因此，有人提出 CD16(+)CD56(dim)CD69(-)NK 细胞对于干细胞的选择很重要，而 CD16(dim/-)CD56(dim/+)CD69(+)失能 NK 细胞对于分化以及组织的最终再生和炎症的消退很重要，因此可能充当调节性 NK（NK(reg)）细胞。本文就 NK 细胞中的“分裂失能”概念以及 NK(reg)细胞的产生对于细胞分化、组织修复和再生以及肿瘤抵抗的贡献进行了讨论。
