Dichotomous metabolic networks govern human ILC2 proliferation and function

Group 2 innate lymphoid cells (ILC2) represent innate homologues of Th2 cells that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited and its key regulators are unknown. Here we show that circulating “naïve” ILC2 have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than NK cells. Accordingly, ILC2 are severely reduced in patients with mitochondrial disease and impaired OXPHOS. Metabolomic and nutrient receptors analysis reveals ILC2 uptake amino acids to sustain OXPHOS at steady-state. Upon activation with interleukin 33 (IL-33), ILC2 become highly proliferative relying on glycolysis and mTOR to produce IL-13, while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2, offering new strategies to target ILC2 in disease settings. Overall design: CRTh2+ ILC2 and CD56Dim NK cells were freshly isolated by FACS from peripheral blood of three healthy adult individuals. In total, 6 samples were analyzed and comparing between two cell populations.

2型先天淋巴细胞（Group 2 innate lymphoid cells, ILC2）是2型辅助T细胞（Th2 cells）的先天同源类群，可通过分泌2型细胞因子参与免疫防御与组织稳态维持。相较于代谢适应微环境变化的T淋巴细胞，目前学界对人类ILC2代谢的认知仍较为有限，其关键调控因子亦尚未明确。本研究发现，循环型“未致敏”ILC2具备出乎意料的代谢特征：其氧化磷酸化（oxidative phosphorylation, OXPHOS）水平高于自然杀伤细胞（natural killer cells, NK）。相应地，线粒体疾病患者体内的ILC2会显著减少，且氧化磷酸化功能受损。代谢组学与营养受体分析显示，静息状态下ILC2通过摄取氨基酸以维持氧化磷酸化功能。当经白细胞介素33（interleukin 33, IL-33）激活后，ILC2会高度增殖：其依赖糖酵解与雷帕霉素靶蛋白（mTOR）分泌白细胞介素13（IL-13），同时仍以氨基酸为氧化磷酸化供能，以维持细胞存活与增殖能力。本研究结果表明，人类ILC2的增殖与功能在代谢层面存在解偶联现象，这为疾病状态下靶向ILC2的治疗策略提供了全新思路。实验整体设计：从3名健康成年个体的外周血中，通过荧光激活细胞分选（Fluorescence-Activated Cell Sorting, FACS）新鲜分离得到CRTh2阳性ILC2与CD56Dim自然杀伤细胞，共获得6份样本并对两组细胞群体进行对比分析。