Surace Laura, Doisne Jean-Marc, Escoll Pedro, Marie Solenne, Dardalhon Valerie, Croft Carys, Thaller Anna, Topazio Davide, Sparaneo Angelo, Cama Antonia, Musumeci Olimpia, d'Ecclesia Aurelio, Buchrieser Carmen, Taylor Naomi, Di Santo James P
INSERM U1223, Paris, France.
Innate Immunity Unit and.
Blood Adv. 2021 Jan 12;5(1):26-38. doi: 10.1182/bloodadvances.2020003458.
Distinct metabolic demands accompany lymphocyte differentiation into short-lived effector and long-lived memory cells. How bioenergetics processes are structured in innate natural killer (NK) cells remains unclear. We demonstrate that circulating human CD56Dim (NKDim) cells have fused mitochondria and enhanced metabolism compared with CD56Br (NKBr) cells. Upon activation, these 2 subsets showed a dichotomous response, with further mitochondrial potentiation in NKBr cells vs paradoxical mitochondrial fission and depolarization in NKDim cells. The latter effect impaired interferon-γ production, but rescue was possible by inhibiting mitochondrial fragmentation, implicating mitochondrial polarization as a central regulator of NK cell function. NKDim cells are heterogeneous, and mitochondrial polarization was associated with enhanced survival and function in mature NKDim cells, including memory-like human cytomegalovirus-dependent CD57+NKG2C+ subsets. In contrast, patients with genetic defects in mitochondrial fusion had a deficiency in adaptive NK cells, which had poor survival in culture. These results support mitochondrial polarization as a central regulator of mature NK cell fitness.
淋巴细胞分化为短命效应细胞和长寿记忆细胞伴随着不同的代谢需求。先天自然杀伤（NK）细胞中的生物能量学过程是如何构建的仍不清楚。我们证明，与CD56Br（NKBr）细胞相比，循环中的人类CD56Dim（NKDim）细胞具有融合的线粒体且代谢增强。激活后，这两个亚群表现出二分反应，NKBr细胞中线粒体进一步增强，而NKDim细胞中则出现矛盾的线粒体裂变和去极化。后一种效应损害了干扰素-γ的产生，但通过抑制线粒体碎片化可以挽救，这表明线粒体极化是NK细胞功能的核心调节因子。NKDim细胞是异质性的，线粒体极化与成熟NKDim细胞（包括记忆样人巨细胞病毒依赖性CD57+NKG2C+亚群）的存活和功能增强有关。相比之下，线粒体融合存在基因缺陷的患者适应性NK细胞缺乏，这些细胞在培养中存活率低。这些结果支持线粒体极化是成熟NK细胞适应性的核心调节因子。
