Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells
Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells
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DOI：
10.1172/jci42027
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Taniguchi, Masaru
中科院分区：
文献类型：
--
作者：
Watarai, Hiroshi;Fujii, Shin-ichiro;Taniguchi, Masaru
当NKT细胞被负载有α-半乳糖神经酰胺的DC激活以产生Th1细胞因子时，NKT细胞显示出抗肿瘤活性。然而，在这种情况下，大多数患者没有足够数量的NKT细胞来诱导有效的免疫反应，这表明需要一种来源的NKT细胞来补充内源性细胞群。诱导多能干细胞(IPSCs)具有细胞替代治疗的巨大潜力，但是否有可能从IPSCs产生具有功能的NKT细胞还没有得到严格的评估。在这项研究中，我们成功地从胚系中具有功能性NKT细胞特异性重排T细胞受体基因的小鼠的胚胎成纤维细胞和WT成年小鼠的脾NKT细胞中获得了IPSCs。这些IPSCs可在体外分化为NKT细胞，并分泌大量Th1细胞因子干扰素-γ。重要的是，IPSC来源的NKT细胞重复了天然NKT细胞的已知佐剂作用，并在体内抑制了肿瘤生长。这些研究证明了通过IPSC阶段扩增具有功能的NKT细胞的可行性，这种方法可能适用于人类NKT细胞靶向治疗。
NKT cells demonstrate antitumor activity when activated to produce Th1 cytokines by DCs loaded with alpha-galactosylceramide, the prototypic NKT cell-activating glycolipid antigen. However, most patients do not have sufficient numbers of NKT cells to induce an effective immune response in this context, indicating a need for a source of NKT cells that could be used to supplement the endogenous cell population. Induced pluripotent stem cells (iPSCs) hold tremendous potential for cell-replacement therapy, but whether it is possible to generate functionally competent NKT cells from iPSCs has not been rigorously assessed. In this study, we successfully derived iPSCs both from embryonic fibroblasts from mice harboring functional NKT cell-specific rearranged T cell receptor loci in the germline and from splenic NKT cells from WT adult mice. These iPSCs could be differentiated into NKT cells in vitro and secreted large amounts of the Th1 cytokine IFN-gamma. Importantly, iPSC-derived NKT cells recapitulated the known adjuvant effects of natural NKT cells and suppressed tumor growth in vivo. These studies demonstrate the feasibility of expanding functionally competent NKT cells via an iPSC phase, an approach that may be adapted for NKT cell-targeted therapy in humans.