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Journal Article

An LKB1-mitochondria axis controls TH17 effector function

MPS-Authors

Baixauli,  Francesc
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Piletic,  Klara
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Puleston,  Daniel J
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Villa,  Matteo
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Field,  Cameron S
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Flachsmann,  Lea J
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Quintana,  Andrea
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Rana,  Nisha
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Edwards-Hicks,  Joy
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Matsushita,  Mai
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Stanczak,  Michal A
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Grzes,  Katarzyna M
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kabat,  Agnieszka M
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Fabri,  Mario
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Caputa,  George
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kelly,  Beth
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Corrado,  Mauro
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Musa,  Yaarub
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Duda,  Katarzyna J
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Mittler,  Gerhard
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

O'Sullivan,  David
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons191130

Jenuwein,  Thomas
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons241896

Büscher,  Jörg Martin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce,  Edward Jonathen
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sanin,  David E
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201431

Pearce,  Erika Laine
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

External Resource

https://www.nature.com/articles/s41586-022-05264-1
(Publisher version)

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Fulltext (public)

10.1038_s41586-022-05264-1.pdf
(Publisher version), 22MB

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Citation

Baixauli, F., Piletic, K., Puleston, D. J., Villa, M., Field, C. S., Flachsmann, L. J., et al. (2022). An LKB1-mitochondria axis controls TH17 effector function. Nature, 610, 555-561. doi:10.1038/s41586-022-05264-1.


Cite as: https://hdl.handle.net/21.11116/0000-000D-1323-6
Abstract
CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.