Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

Leticia Soriano-Baguet; Melanie Grusdat; Henry Kurniawan; Mohaned Benzarti; Carole Binsfeld; Anouk Ewen; Joseph Longworth; Lynn Bonetti; Luana Guerra; Davide G. Franchina; Takumi Kobayashi; Veronika Horkova; Charlène Verschueren; Sergio Helgueta; Deborah Gérard; Tushar H. More; Antonia Henne; Catherine Dostert; Sophie Farinelle; Antoine Lesur; Jean Jacques Gérardy; Christian Jäger; Michel Mittelbronn; Lasse Sinkkonen; Karsten Hiller; Johannes Meiser; Dirk Brenner

doi:10.1016/j.celrep.2023.112153

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

Leticia Soriano-Baguet, Melanie Grusdat, Henry Kurniawan, Mohaned Benzarti, Carole Binsfeld, Anouk Ewen, Joseph Longworth, Lynn Bonetti, Luana Guerra, Davide G. Franchina, Takumi Kobayashi, Veronika Horkova, Charlène Verschueren, Sergio Helgueta, Deborah Gérard, Tushar H. More, Antonia Henne, Catherine Dostert, Sophie Farinelle, Antoine LesurJean Jacques Gérardy, Christian Jäger, Michel Mittelbronn, Lasse Sinkkonen, Karsten Hiller, Johannes Meiser, Dirk Brenner^*

^*Corresponding author for this work

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

11 Citations (Scopus)

Abstract

Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

Original language	English
Article number	112153
Journal	Cell Reports
Volume	42
Issue number	3
Early online date	26 Feb 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.112153
Publication status	Published - 28 Mar 2023

Keywords

acetyl-CoA
citrate
CP: Immunology
CP: Metabolism
epigenetics
experimental autoimmune encephalomyelitis
glucose metabolism
histone acetylation
IL-17
pyruvate dehydrogenase
T cells
Th17 cells

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Soriano-Baguet, L., Grusdat, M., Kurniawan, H., Benzarti, M., Binsfeld, C., Ewen, A., Longworth, J., Bonetti, L., Guerra, L., Franchina, D. G., Kobayashi, T., Horkova, V., Verschueren, C., Helgueta, S., Gérard, D., More, T. H., Henne, A., Dostert, C., Farinelle, S., ... Brenner, D. (2023). Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions. Cell Reports, 42(3), Article 112153. https://doi.org/10.1016/j.celrep.2023.112153

@article{760468f876b649799481d5de85e1cfce,

title = "Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions",

abstract = "Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.",

keywords = "acetyl-CoA, citrate, CP: Immunology, CP: Metabolism, epigenetics, experimental autoimmune encephalomyelitis, glucose metabolism, histone acetylation, IL-17, pyruvate dehydrogenase, T cells, Th17 cells",

author = "Leticia Soriano-Baguet and Melanie Grusdat and Henry Kurniawan and Mohaned Benzarti and Carole Binsfeld and Anouk Ewen and Joseph Longworth and Lynn Bonetti and Luana Guerra and Franchina, {Davide G.} and Takumi Kobayashi and Veronika Horkova and Charl{\`e}ne Verschueren and Sergio Helgueta and Deborah G{\'e}rard and More, {Tushar H.} and Antonia Henne and Catherine Dostert and Sophie Farinelle and Antoine Lesur and G{\'e}rardy, {Jean Jacques} and Christian J{\"a}ger and Michel Mittelbronn and Lasse Sinkkonen and Karsten Hiller and Johannes Meiser and Dirk Brenner",

note = "Funding Information: D.B. is supported by FNR -ATTRACT ( A14/BM/7632103 ) and FNR -CORE grants ( C21/BM/15796788 and C18/BM/12691266 ). D.B., T.K., and C.D. are supported by FNRS -Televie grants 7.4587.20 and/or 7.497.19 ; D.B., L.B., L.G., and L.S.-B. by FNR -PRIDE ( PRIDE/11012546/NEXTIMMUNE ); D.B. and A.E. by PRIDE17/11823097/MicrOH ; D.B. and D.G.F. by FNR -RIKEN ( TregBar/11228353 ); S.H. by FNR -PRIDE ( PRIDE17/12244779/PARK-Q ); D.G. by a postdoctoral fellowship from the Fondation du P{\'e}lican de Mie et Pierre Hippert-Faber ; J.M. by FNR -ATTRACT ( A18/BM/11809970 ); and M.M. by FNR PEARL ( P16/BM/11192868 ). Funding Information: We are grateful to Max L{\"o}hning (Charit{\'e} University Berlin) and Alexander Skupin (University of Luxembourg) for helpful discussions, Dr. Aurelien Ginolhac (University of Luxembourg) for bioinformatic analysis, the Metabolomics Platform of the Luxembourg Center for Systems Biomedicine (LCSB; University of Luxembourg) for metabolomics data, Dr. Rashi Halder of the Sequencing Platform of the LCSB for sequencing data (RRID: SCR_021931), the High-Performance Computing (HPC) platform (University of Luxembourg), and the National Cytometry Platform (LIH; Luxembourg) for support with flow cytometry. We also thank Samantha Storn, Ana{\"i}s Oudin, all Animal Facility staff, and LIH's Animal Welfare Structure for animal services at LIH, Luxembourg, and Djalil Coowar, Jennifer Behm, Marthe Schmit and all Animal Facility staff for animal services at the University of Luxembourg. D.B. is supported by FNR-ATTRACT (A14/BM/7632103) and FNR-CORE grants (C21/BM/15796788 and C18/BM/12691266). D.B. T.K. and C.D. are supported by FNRS-Televie grants 7.4587.20 and/or 7.497.19; D.B. L.B. L.G. and L.S.-B. by FNR-PRIDE (PRIDE/11012546/NEXTIMMUNE); D.B. and A.E. by PRIDE17/11823097/MicrOH; D.B. and D.G.F. by FNR-RIKEN (TregBar/11228353); S.H. by FNR-PRIDE (PRIDE17/12244779/PARK-Q); D.G. by a postdoctoral fellowship from the Fondation du P{\'e}lican de Mie et Pierre Hippert-Faber; J.M. by FNR-ATTRACT (A18/BM/11809970); and M.M. by FNR PEARL (P16/BM/11192868). L.S.-B. performed most experiments, assisted by M.G. H.K. L.B. A.E. L.G. D.G.F. C.B. C.V. and S.F. L.S.-B. M.G. and C.B. isolated brains and spleens from EAE mice. L.S.-B. H.K. A.E. and D.G.F. performed Seahorse flux assays. Isotopic and metabolic tracing experiments were performed by L.S.-B. M.G. and H.K. and analyzed by M.B. and J.M. Histone and palmitate tracing experiments were performed and analyzed by T.H.M. and A.H. Analysis of RNA-seq data was performed by J.L. and S.H. ATAC-seq and data analysis were performed by S.H. D.G. and L.S. T.K. C.D. J.-J.G. C.J. M.M. L.S. K.H. and J.M. provided reagents and expert comments. D.B. supervised the project. L.S.-B. and D.B. conceptualized the work, designed all experiments, analyzed data, and wrote the manuscript. All authors reviewed and edited the final manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = mar,

day = "28",

doi = "10.1016/j.celrep.2023.112153",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

Soriano-Baguet, L, Grusdat, M, Kurniawan, H, Benzarti, M , Binsfeld, C , Ewen, A , Longworth, J, Bonetti, L, Guerra, L, Franchina, DG, Kobayashi, T , Horkova, V , Verschueren, C, Helgueta, S, Gérard, D, More, TH, Henne, A, Dostert, C, Farinelle, S, Lesur, A, Gérardy, JJ, Jäger, C, Mittelbronn, M, Sinkkonen, L, Hiller, K, Meiser, J & Brenner, D 2023, 'Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions', Cell Reports, vol. 42, no. 3, 112153. https://doi.org/10.1016/j.celrep.2023.112153

TY - JOUR

T1 - Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

AU - Soriano-Baguet, Leticia

AU - Grusdat, Melanie

AU - Kurniawan, Henry

AU - Benzarti, Mohaned

AU - Binsfeld, Carole

AU - Ewen, Anouk

AU - Longworth, Joseph

AU - Bonetti, Lynn

AU - Guerra, Luana

AU - Franchina, Davide G.

AU - Kobayashi, Takumi

AU - Horkova, Veronika

AU - Verschueren, Charlène

AU - Helgueta, Sergio

AU - Gérard, Deborah

AU - More, Tushar H.

AU - Henne, Antonia

AU - Dostert, Catherine

AU - Farinelle, Sophie

AU - Lesur, Antoine

AU - Gérardy, Jean Jacques

AU - Jäger, Christian

AU - Mittelbronn, Michel

AU - Sinkkonen, Lasse

AU - Hiller, Karsten

AU - Meiser, Johannes

AU - Brenner, Dirk

N1 - Funding Information: D.B. is supported by FNR -ATTRACT ( A14/BM/7632103 ) and FNR -CORE grants ( C21/BM/15796788 and C18/BM/12691266 ). D.B., T.K., and C.D. are supported by FNRS -Televie grants 7.4587.20 and/or 7.497.19 ; D.B., L.B., L.G., and L.S.-B. by FNR -PRIDE ( PRIDE/11012546/NEXTIMMUNE ); D.B. and A.E. by PRIDE17/11823097/MicrOH ; D.B. and D.G.F. by FNR -RIKEN ( TregBar/11228353 ); S.H. by FNR -PRIDE ( PRIDE17/12244779/PARK-Q ); D.G. by a postdoctoral fellowship from the Fondation du Pélican de Mie et Pierre Hippert-Faber ; J.M. by FNR -ATTRACT ( A18/BM/11809970 ); and M.M. by FNR PEARL ( P16/BM/11192868 ). Funding Information: We are grateful to Max Löhning (Charité University Berlin) and Alexander Skupin (University of Luxembourg) for helpful discussions, Dr. Aurelien Ginolhac (University of Luxembourg) for bioinformatic analysis, the Metabolomics Platform of the Luxembourg Center for Systems Biomedicine (LCSB; University of Luxembourg) for metabolomics data, Dr. Rashi Halder of the Sequencing Platform of the LCSB for sequencing data (RRID: SCR_021931), the High-Performance Computing (HPC) platform (University of Luxembourg), and the National Cytometry Platform (LIH; Luxembourg) for support with flow cytometry. We also thank Samantha Storn, Anaïs Oudin, all Animal Facility staff, and LIH's Animal Welfare Structure for animal services at LIH, Luxembourg, and Djalil Coowar, Jennifer Behm, Marthe Schmit and all Animal Facility staff for animal services at the University of Luxembourg. D.B. is supported by FNR-ATTRACT (A14/BM/7632103) and FNR-CORE grants (C21/BM/15796788 and C18/BM/12691266). D.B. T.K. and C.D. are supported by FNRS-Televie grants 7.4587.20 and/or 7.497.19; D.B. L.B. L.G. and L.S.-B. by FNR-PRIDE (PRIDE/11012546/NEXTIMMUNE); D.B. and A.E. by PRIDE17/11823097/MicrOH; D.B. and D.G.F. by FNR-RIKEN (TregBar/11228353); S.H. by FNR-PRIDE (PRIDE17/12244779/PARK-Q); D.G. by a postdoctoral fellowship from the Fondation du Pélican de Mie et Pierre Hippert-Faber; J.M. by FNR-ATTRACT (A18/BM/11809970); and M.M. by FNR PEARL (P16/BM/11192868). L.S.-B. performed most experiments, assisted by M.G. H.K. L.B. A.E. L.G. D.G.F. C.B. C.V. and S.F. L.S.-B. M.G. and C.B. isolated brains and spleens from EAE mice. L.S.-B. H.K. A.E. and D.G.F. performed Seahorse flux assays. Isotopic and metabolic tracing experiments were performed by L.S.-B. M.G. and H.K. and analyzed by M.B. and J.M. Histone and palmitate tracing experiments were performed and analyzed by T.H.M. and A.H. Analysis of RNA-seq data was performed by J.L. and S.H. ATAC-seq and data analysis were performed by S.H. D.G. and L.S. T.K. C.D. J.-J.G. C.J. M.M. L.S. K.H. and J.M. provided reagents and expert comments. D.B. supervised the project. L.S.-B. and D.B. conceptualized the work, designed all experiments, analyzed data, and wrote the manuscript. All authors reviewed and edited the final manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2023 The Author(s)

PY - 2023/3/28

Y1 - 2023/3/28

N2 - Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

AB - Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

KW - acetyl-CoA

KW - citrate

KW - CP: Immunology

KW - CP: Metabolism

KW - epigenetics

KW - experimental autoimmune encephalomyelitis

KW - glucose metabolism

KW - histone acetylation

KW - IL-17

KW - pyruvate dehydrogenase

KW - T cells

KW - Th17 cells

UR - http://www.scopus.com/inward/record.url?scp=85148681484&partnerID=8YFLogxK

UR - https://pubmed.ncbi.nlm.nih.gov/36848289

U2 - 10.1016/j.celrep.2023.112153

DO - 10.1016/j.celrep.2023.112153

M3 - Article

C2 - 36848289

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 112153

ER -

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

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