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

Arundhoti Das; Gustavo Ulises Martinez-Ruiz; Nicolas Bouladoux; Apollo Stacy; Josquin Moraly; Maria Vega-Sendino; Yongge Zhao; Marieke Lavaert; Yi Ding; Abigail Morales-Sanchez; Christelle Harly; Mina O Seedhom; Raj Chari; Parirokh Awasthi; Tomoko Ikeuchi; Yueqiang Wang; Jinfang Zhu; Niki M Moutsopoulos; WanJun Chen; Jonathan W Yewdell; Virginia Smith Shapiro; Sergio Ruiz; Naomi Taylor; Yasmine Belkaid; Avinash Bhandoola

doi:10.1016/j.immuni.2024.04.001

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

Immunity. 2024 Apr 18:S1074-7613(24)00206-1. doi: 10.1016/j.immuni.2024.04.001. Online ahead of print.

Authors

Arundhoti Das¹, Gustavo Ulises Martinez-Ruiz², Nicolas Bouladoux³, Apollo Stacy⁴, Josquin Moraly⁵, Maria Vega-Sendino¹, Yongge Zhao¹, Marieke Lavaert¹, Yi Ding¹, Abigail Morales-Sanchez⁶, Christelle Harly⁷, Mina O Seedhom⁸, Raj Chari⁹, Parirokh Awasthi¹⁰, Tomoko Ikeuchi¹¹, Yueqiang Wang¹², Jinfang Zhu¹³, Niki M Moutsopoulos¹¹, WanJun Chen¹⁴, Jonathan W Yewdell⁸, Virginia Smith Shapiro¹⁵, Sergio Ruiz¹, Naomi Taylor⁵, Yasmine Belkaid³, Avinash Bhandoola¹⁶

Affiliations

¹ Laboratory of Genome Integrity, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
² 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.
³ Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, NIAID, NIH, Bethesda, MD, USA.
⁴ 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.
⁵ Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
⁶ Laboratory of Genome Integrity, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA; Children's Hospital of Mexico Federico Gomez, Mexico City, Mexico.
⁷ Université de Nantes, CNRS, Inserm, CRCINA, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France.
⁸ Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD, USA.
⁹ Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
¹⁰ Mouse Modeling Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
¹¹ Oral Immunity and Infection Section, NIDCR, NIH, Bethesda, MD, USA.
¹² Shenzhen Typhoon HealthCare, Shenzhen, Guangdong, China.
¹³ Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
¹⁴ Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD, USA.
¹⁵ Department of Immunology, Mayo Clinic, Rochester, MN, USA.
¹⁶ Laboratory of Genome Integrity, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA. Electronic address: avinash.bhandoola@nih.gov.

PMID: 38677292
DOI: 10.1016/j.immuni.2024.04.001

Abstract

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.

Keywords: HIF-1α; IL-17; ILC3; Tox2; glycolysis; metabolic adaptation; tissue residency.

Published by Elsevier Inc.