Henden Camilla, Fjerdingstad Hege B, Bjørnsen Elisabeth G, Thiruchelvam-Kyle Lavanya, Daws Michael R, Inngjerdingen Marit, Glover Joel C, Dissen Erik
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
Norwegian Center for Stem Cell Research, Department of Immunology and Transfusion Medicine, Oslo University Hospital, N-0317 Oslo, Norway.
Stem Cells. 2025 Mar 10;43(3). doi: 10.1093/stmcls/sxae083.
Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK-cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2, and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2, or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS-cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS-cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2-stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS-cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK-cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors.
多能干细胞为治疗损伤和以前无法治愈的疾病提供了机会。一个主要问题是干细胞及其后代的免疫原性。在这里，我们剖析了自然杀伤（NK）细胞对人多能干细胞作出反应的分子机制，研究了多种激活和抑制性NK细胞受体及其配体。表达激活受体NKG2D的报告细胞对胚胎干细胞（ES）系和诱导多能干细胞（iPS）系有强烈反应，而表达激活受体NKp30、NKp46、KIR2DS1、KIR2DS2和KIR2DS4的报告细胞则无反应。人ES细胞和iPS细胞始终表达几种NKG2D的配体。HLA-C和HLA-E的表达缺乏或很低，不足以触发表达抑制性受体KIR2DL1、-2DL2或-2DL3的报告细胞。多能胚胎癌细胞系NTERA-2和2102Ep以及iPS细胞衍生的神经祖细胞也得到了类似的结果。重要的是，神经祖细胞和iPS细胞衍生的运动神经元也表达激活受体NKp30的配体B7H6。与这些观察结果一致，IL-2刺激的NK细胞对ES细胞、iPS细胞以及iPS细胞衍生的运动神经元表现出强大的细胞毒性反应。在NK细胞与多能靶细胞的KIR/HLA匹配和不匹配组合之间，未观察到细胞毒性水平的显著差异。总之，这些数据表明，多能干细胞及其神经后代是NK细胞杀伤的靶标，这是由于它们未能充分表达抑制性受体的配体以及表达了激活受体的配体。
