An LKB1–mitochondria axis controls TH17 effector function

Francesc Baixauli, Klara Piletic, Daniel J. Puleston, Matteo Villa, Cameron S. Field, Lea J. Flachsmann, Andrea Quintana, Nisha Rana, Joy Edwards-Hicks, Mai Matsushita, Michal A. Stanczak, Katarzyna M. Grzes, Agnieszka M. Kabat, Mario Fabri, George Caputa, Beth Kelly, Mauro Corrado, Yaarub Musa, Katarzyna J. Duda, Gerhard Mittler, David O’Sullivan, Hiromi Sesaki, Thomas Jenuwein, Joerg M. Buescher, Edward J. Pearce, David E. Sanin and Erika L. Pearce ()
Additional contact information
Francesc Baixauli: Max Planck Institute for Immunobiology and Epigenetics
Klara Piletic: Max Planck Institute for Immunobiology and Epigenetics
Daniel J. Puleston: Max Planck Institute for Immunobiology and Epigenetics
Matteo Villa: Max Planck Institute for Immunobiology and Epigenetics
Cameron S. Field: Max Planck Institute for Immunobiology and Epigenetics
Lea J. Flachsmann: Max Planck Institute for Immunobiology and Epigenetics
Andrea Quintana: Max Planck Institute for Immunobiology and Epigenetics
Nisha Rana: Max Planck Institute for Immunobiology and Epigenetics
Joy Edwards-Hicks: Max Planck Institute for Immunobiology and Epigenetics
Mai Matsushita: Max Planck Institute for Immunobiology and Epigenetics
Michal A. Stanczak: Max Planck Institute for Immunobiology and Epigenetics
Katarzyna M. Grzes: Max Planck Institute for Immunobiology and Epigenetics
Agnieszka M. Kabat: Max Planck Institute for Immunobiology and Epigenetics
Mario Fabri: Max Planck Institute for Immunobiology and Epigenetics
George Caputa: Max Planck Institute for Immunobiology and Epigenetics
Beth Kelly: Max Planck Institute for Immunobiology and Epigenetics
Mauro Corrado: Max Planck Institute for Immunobiology and Epigenetics
Yaarub Musa: Max Planck Institute for Immunobiology and Epigenetics
Katarzyna J. Duda: Max Planck Institute for Immunobiology and Epigenetics
Gerhard Mittler: Max Planck Institute for Immunobiology and Epigenetics
David O’Sullivan: Max Planck Institute for Immunobiology and Epigenetics
Hiromi Sesaki: Johns Hopkins University School of Medicine
Thomas Jenuwein: Max Planck Institute for Immunobiology and Epigenetics
Joerg M. Buescher: Max Planck Institute for Immunobiology and Epigenetics
Edward J. Pearce: Max Planck Institute for Immunobiology and Epigenetics
David E. Sanin: Max Planck Institute for Immunobiology and Epigenetics
Erika L. Pearce: Max Planck Institute for Immunobiology and Epigenetics

Nature, 2022, vol. 610, issue 7932, 555-561

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05264-1

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