Laboratory of Genome Integrity, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
Laboratory of Genome Integrity, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA; Faculty of Medicine, Research Division, National Autonomous University of Mexico, Mexico City, Mexico; Children's Hospital of Mexico Federico Gomez, Mexico City, Mexico.
Immunity. 2024 May 14;57(5):1019-1036.e9. doi: 10.1016/j.immuni.2024.04.001. Epub 2024 Apr 26.
Group 3 innate lymphoid cells (ILC3) are the major subset of gut-resident ILC with essential roles in infections and tissue repair, but how they adapt to the gut environment to maintain tissue residency is unclear. We report that Tox2 is critical for gut ILC3 maintenance and function. Gut ILC3 highly expressed Tox2, and depletion of Tox2 markedly decreased ILC3 in gut but not at central sites, resulting in defective control of Citrobacter rodentium infection. Single-cell transcriptional profiling revealed decreased expression of Hexokinase-2 in Tox2-deficient gut ILC3. Consistent with the requirement for hexokinases in glycolysis, Tox2 ILC3 displayed decreased ability to utilize glycolysis for protein translation. Ectopic expression of Hexokinase-2 rescued Tox2 gut ILC3 defects. Hypoxia and interleukin (IL)-17A each induced Tox2 expression in ILC3, suggesting a mechanism by which ILC3 adjusts to fluctuating environments by programming glycolytic metabolism. Our results reveal the requirement for Tox2 to support the metabolic adaptation of ILC3 within the gastrointestinal tract.
3 组固有淋巴细胞 (ILC3) 是肠道驻留 ILC 的主要亚群，在感染和组织修复中具有重要作用，但它们如何适应肠道环境以维持组织驻留尚不清楚。我们报告说，Tox2 对肠道 ILC3 的维持和功能至关重要。肠道 ILC3 高度表达 Tox2，Tox2 的耗竭显著减少了肠道中的 ILC3，但在中枢部位没有减少，导致对柠檬酸杆菌感染的控制缺陷。单细胞转录谱分析显示，Tox2 缺陷肠道 ILC3 中己糖激酶-2 的表达降低。与糖酵解中己糖激酶的要求一致，Tox2 ILC3 显示出降低的利用糖酵解进行蛋白质翻译的能力。Hexokinase-2 的异位表达挽救了 Tox2 肠道 ILC3 的缺陷。缺氧和白细胞介素 (IL)-17A 均可诱导 ILC3 中 Tox2 的表达，这表明 ILC3 通过编程糖酵解代谢来适应不断变化的环境的一种机制。我们的研究结果揭示了 Tox2 支持 ILC3 在胃肠道内代谢适应的必要性。
