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; Wan Jun 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

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, Wan Jun Chen, Jonathan W. YewdellVirginia Smith Shapiro, Sergio Ruiz, Naomi Taylor, Yasmine Belkaid, Avinash Bhandoola

Immunology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1019-1036.e9
Journal	Immunity
Volume	57
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2024.04.001
State	Published - May 14 2024

Keywords

HIF-1α
IL-17
ILC3
Tox2
glycolysis
metabolic adaptation
tissue residency

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2024.04.001

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Das, A., Martinez-Ruiz, G. U., Bouladoux, N., Stacy, A., Moraly, J., Vega-Sendino, M., Zhao, Y., Lavaert, M., Ding, Y., Morales-Sanchez, A., Harly, C., Seedhom, M. O., Chari, R., Awasthi, P., Ikeuchi, T., Wang, Y., Zhu, J., Moutsopoulos, N. M., Chen, W. J., ... Bhandoola, A. (2024). Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut. Immunity, 57(5), 1019-1036.e9. https://doi.org/10.1016/j.immuni.2024.04.001

Das, A, Martinez-Ruiz, GU, Bouladoux, N, Stacy, A, Moraly, J, Vega-Sendino, M, Zhao, Y, Lavaert, M, Ding, Y, Morales-Sanchez, A, Harly, C, Seedhom, MO, Chari, R, Awasthi, P, Ikeuchi, T, Wang, Y, Zhu, J, Moutsopoulos, NM, Chen, WJ, Yewdell, JW, Shapiro, VS, Ruiz, S, Taylor, N, Belkaid, Y & Bhandoola, A 2024, 'Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut', Immunity, vol. 57, no. 5, pp. 1019-1036.e9. https://doi.org/10.1016/j.immuni.2024.04.001

@article{728b76b2ed4145728d195f553bc0ede3,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = may,

day = "14",

doi = "10.1016/j.immuni.2024.04.001",

language = "English (US)",

volume = "57",

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T1 - Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut

AU - Das, Arundhoti

AU - Martinez-Ruiz, Gustavo Ulises

AU - Bouladoux, Nicolas

AU - Stacy, Apollo

AU - Moraly, Josquin

AU - Vega-Sendino, Maria

AU - Zhao, Yongge

AU - Lavaert, Marieke

AU - Ding, Yi

AU - Morales-Sanchez, Abigail

AU - Harly, Christelle

AU - Seedhom, Mina O.

AU - Chari, Raj

AU - Awasthi, Parirokh

AU - Ikeuchi, Tomoko

AU - Wang, Yueqiang

AU - Zhu, Jinfang

AU - Moutsopoulos, Niki M.

AU - Chen, Wan Jun

AU - Yewdell, Jonathan W.

AU - Shapiro, Virginia Smith

AU - Ruiz, Sergio

AU - Taylor, Naomi

AU - Belkaid, Yasmine

AU - Bhandoola, Avinash

PY - 2024/5/14

Y1 - 2024/5/14

N2 - 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.

AB - 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.

KW - HIF-1α

KW - IL-17

KW - ILC3

KW - Tox2

KW - glycolysis

KW - metabolic adaptation

KW - tissue residency

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DO - 10.1016/j.immuni.2024.04.001

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C2 - 38677292

AN - SCOPUS:85192315875

SN - 1074-7613

VL - 57

SP - 1019-1036.e9

JO - Immunity

JF - Immunity

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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