Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut,Immunity

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Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut
Immunity ( IF 25.5 ) Pub Date : 2024-04-26 , DOI: 10.1016/j.immuni.2024.04.001
Arundhoti Das ₁ , Gustavo Ulises Martinez-Ruiz ₂ , Nicolas Bouladoux ₃ , Apollo Stacy ₄ , Josquin Moraly ₅ , Maria Vega-Sendino ₁ , Yongge Zhao ₁ , Marieke Lavaert ₁ , Yi Ding ₁ , Abigail Morales-Sanchez ₆ , Christelle Harly ₇ , Mina O Seedhom ₈ , Raj Chari ₉ , Parirokh Awasthi ₁₀ , Tomoko Ikeuchi ₁₁ , Yueqiang Wang ₁₂ , Jinfang Zhu ₁₃ , Niki M Moutsopoulos ₁₁ , WanJun Chen ₁₄ , Jonathan W Yewdell ₈ , Virginia Smith Shapiro ₁₅ , Sergio Ruiz ₁ , Naomi Taylor ₅ , Yasmine Belkaid ₃ , Avinash Bhandoola ₁

Affiliation

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.
Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, NIAID, NIH, Bethesda, MD, USA.
Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, NIAID, NIH, Bethesda, MD, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
Laboratory of Genome Integrity, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA; Children's Hospital of Mexico Federico Gomez, Mexico City, Mexico.
Université de Nantes, CNRS, Inserm, CRCINA, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France.
Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD, USA.
Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Mouse Modeling Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Oral Immunity and Infection Section, NIDCR, NIH, Bethesda, MD, USA.
Shenzhen Typhoon HealthCare, Shenzhen, Guangdong, China.
Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD, USA.
Department of Immunology, Mayo Clinic, Rochester, MN, USA.

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.

中文翻译：

转录因子 Tox2 是 ILC3 在肠道中的代谢适应和组织驻留所必需的

第 3 组先天淋巴细胞（ILC3）是肠道驻留 ILC 的主要亚群，在感染和组织修复中起着重要作用，但它们如何适应肠道环境以维持组织驻留尚不清楚。我们报道 Tox2 对肠道 ILC3 的维持和功能至关重要。肠道 ILC3 高度表达 Tox2，Tox2 的耗竭显着降低了肠道中的 ILC3，但中央部位没有降低，导致柠檬酸杆菌啮齿动物感染控制缺陷。单细胞转录分析显示己糖激酶-2 在 Tox2 缺陷型肠道 ILC3 中的表达降低。与糖酵解中对己糖激酶的要求一致，Tox2-/-ILC3 显示出利用糖酵解进行蛋白质翻译的能力降低。己糖激酶-2 的异位表达挽救了 Tox2 - / - 肠道 ILC3 缺陷。缺氧和白细胞介素（IL）-17A 分别诱导 ILC3 中的 Tox2 表达，表明 ILC3 通过编程糖酵解代谢来适应波动环境的一种机制。我们的结果揭示了 Tox2 需要支持 ILC3 在胃肠道内的代谢适应。

更新日期：2024-04-26

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