Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

Maria I. Matias; Carmen S. Yong; Amir Foroushani; Chloe Goldsmith; Cédric Mongellaz; Erdinc Sezgin; Kandice R. Levental; Ali Talebi; Julie Perrault; Anais Rivière; Jonas Dehairs; Océane Delos; Justine Bertand-Michel; Jean Charles Portais; Madeline Wong; Julien C. Marie; Ameeta Kelekar; Sandrina Kinet; Valérie S. Zimmermann; Ilya Levental; Laurent Yvan-Charvet; Johannes V. Swinnen; Stefan A. Muljo; Hector Hernandez-Vargas; Saverio Tardito; Naomi Taylor; Valérie Dardalhon

doi:10.1016/j.celrep.2021.109911

Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

Maria I. Matias, Carmen S. Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R. Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean Charles Portais, Madeline Wong, Julien C. Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S. Zimmermann, Ilya LeventalLaurent Yvan-Charvet, Johannes V. Swinnen, Stefan A. Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon

Laboratory Medicine and Pathology

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

8 Scopus citations

Abstract

Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.

Original language	English (US)
Article number	109911
Journal	Cell reports
Volume	37
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2021.109911
State	Published - Nov 2 2021

Bibliographical note

Funding Information:
We thank all members of our laboratories for discussions and scientific critique. We are indebted to Ünal Coskun, Michal Grzybek, Alessandra Palladini, and Triantafyllos Chavakis for all their expertise and assistance with lipidomics analyses. We are grateful to Myriam Boyer-Clavel and Stéphanie Viala of the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, «Investments for the future»). We are grateful to Amal Makrini of the SERANAD bioinformatics platform for her assistance with analyses. M.I.M. was funded by the French Ministry of Health and a fellowship from ARC and C.S.Y. by an Australian Postgraduate Award, Cancer Therapeutics Australia and ARC. C.G. was supported by the ERICAN program of MSD Avenir (J.C.M.). S.T. is supported by funding from Cancer Research UK (C596/A17196 and A23982). We are grateful to MetaboHUB-MetaToul (Toulouse, France) and MetaboHUB-ANR-11-INBS-0010 for lipid tracing experiments. This research was in part supported by the NIH Intramural Research Program of NIAID (S.A.M.) and NCI (N.T.). This work was supported by generous funding from the ANR research grants (CHIC-20-CE14-0049, NutriDiff, and PolarAttack), FRM, ARC, Sidaction, ANRS, and the French laboratory consortiums EpiGenMed and GR-Ex. M.I.M. C.S.Y. V.D. and N.T. conceived the study; M.I.M. C.S.Y, A.F. C.G. C.M. E.S. K.R.L,. A.T. J.D. O.D, J.B.M. J.C.P. J.C.M. A.K. S.K. V.S.Z. I.L. L.Y.C. J.V.S. S.A.M. H.H.V. S.T. V.D. and N.T. were involved in study design; and M.I.M. C.S.Y. A.F. C.G. C.M. E.S. A.T. J.P. A.R. J.D. O.D. J.B.M. M.W. H.V.V. S.T. and V.D. performed experiments. All authors participated in data analysis. A.F. C.G. C.M. E.S. S.A.M. H.H.V. and S.T. contributed significantly to manuscript writing with important critical input from K.R.L. A.T. J.C.P. S.K. V.S.Z. I.L. L.Y.C. and J.S. M.I.M. C.S.Y. V.D. and N.T. were responsible for writing the manuscript. C.M. S.K. V.D. and N.T. are inventors on patents describing the use of ligands for detection of and modulation of metabolite transporters (N.T. gave up her rights), licensed to METAFORA-biosystems.

Funding Information:
We thank all members of our laboratories for discussions and scientific critique. We are indebted to Ünal Coskun, Michal Grzybek, Alessandra Palladini, and Triantafyllos Chavakis for all their expertise and assistance with lipidomics analyses. We are grateful to Myriam Boyer-Clavel and Stéphanie Viala of the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency ( ANR-10-INBS-04 , «Investments for the future»). We are grateful to Amal Makrini of the SERANAD bioinformatics platform for her assistance with analyses. M.I.M. was funded by the French Ministry of Health and a fellowship from ARC and C.S.Y. by an Australian Postgraduate Award, Cancer Therapeutics Australia and ARC. C.G. was supported by the ERICAN program of MSD Avenir (J.C.M.). S.T. is supported by funding from Cancer Research UK ( C596/A17196 and A23982 ). We are grateful to MetaboHUB-MetaToul (Toulouse, France) and MetaboHUB-ANR-11-INBS-0010 for lipid tracing experiments. This research was in part supported by the NIH Intramural Research Program of NIAID (S.A.M.) and NCI (N.T.). This work was supported by generous funding from the ANR research grants (CHIC-20-CE14-0049 , NutriDiff, and PolarAttack), FRM, ARC, Sidaction, ANRS, and the French laboratory consortiums EpiGenMed and GR-Ex.

Publisher Copyright:
© 2021

Keywords

CAR T cells
DNA methylation
T cell differentiation
TCA cycle
Th1
Treg
lipidome
mitochondrial metabolism
triacylglyceride synthesis
α-ketoglutarate

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10.1016/j.celrep.2021.109911

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Matias, M. I., Yong, C. S., Foroushani, A., Goldsmith, C., Mongellaz, C., Sezgin, E., Levental, K. R., Talebi, A., Perrault, J., Rivière, A., Dehairs, J., Delos, O., Bertand-Michel, J., Portais, J. C., Wong, M., Marie, J. C., Kelekar, A., Kinet, S., Zimmermann, V. S., ... Dardalhon, V. (2021). Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis. Cell reports, 37(5), [109911]. https://doi.org/10.1016/j.celrep.2021.109911

Matias, MI, Yong, CS, Foroushani, A, Goldsmith, C, Mongellaz, C, Sezgin, E, Levental, KR, Talebi, A, Perrault, J, Rivière, A, Dehairs, J, Delos, O, Bertand-Michel, J, Portais, JC, Wong, M, Marie, JC, Kelekar, A, Kinet, S, Zimmermann, VS, Levental, I, Yvan-Charvet, L, Swinnen, JV, Muljo, SA, Hernandez-Vargas, H, Tardito, S, Taylor, N & Dardalhon, V 2021, 'Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis', Cell reports, vol. 37, no. 5, 109911. https://doi.org/10.1016/j.celrep.2021.109911

@article{26f6713a078943df8fd01535a48c66b8,

title = "Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis",

abstract = "Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.",

keywords = "CAR T cells, DNA methylation, T cell differentiation, TCA cycle, Th1, Treg, lipidome, mitochondrial metabolism, triacylglyceride synthesis, α-ketoglutarate",

author = "Matias, {Maria I.} and Yong, {Carmen S.} and Amir Foroushani and Chloe Goldsmith and C{\'e}dric Mongellaz and Erdinc Sezgin and Levental, {Kandice R.} and Ali Talebi and Julie Perrault and Anais Rivi{\`e}re and Jonas Dehairs and Oc{\'e}ane Delos and Justine Bertand-Michel and Portais, {Jean Charles} and Madeline Wong and Marie, {Julien C.} and Ameeta Kelekar and Sandrina Kinet and Zimmermann, {Val{\'e}rie S.} and Ilya Levental and Laurent Yvan-Charvet and Swinnen, {Johannes V.} and Muljo, {Stefan A.} and Hector Hernandez-Vargas and Saverio Tardito and Naomi Taylor and Val{\'e}rie Dardalhon",

note = "Funding Information: We thank all members of our laboratories for discussions and scientific critique. We are indebted to {\"U}nal Coskun, Michal Grzybek, Alessandra Palladini, and Triantafyllos Chavakis for all their expertise and assistance with lipidomics analyses. We are grateful to Myriam Boyer-Clavel and St{\'e}phanie Viala of the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, «Investments for the future»). We are grateful to Amal Makrini of the SERANAD bioinformatics platform for her assistance with analyses. M.I.M. was funded by the French Ministry of Health and a fellowship from ARC and C.S.Y. by an Australian Postgraduate Award, Cancer Therapeutics Australia and ARC. C.G. was supported by the ERICAN program of MSD Avenir (J.C.M.). S.T. is supported by funding from Cancer Research UK (C596/A17196 and A23982). We are grateful to MetaboHUB-MetaToul (Toulouse, France) and MetaboHUB-ANR-11-INBS-0010 for lipid tracing experiments. This research was in part supported by the NIH Intramural Research Program of NIAID (S.A.M.) and NCI (N.T.). This work was supported by generous funding from the ANR research grants (CHIC-20-CE14-0049, NutriDiff, and PolarAttack), FRM, ARC, Sidaction, ANRS, and the French laboratory consortiums EpiGenMed and GR-Ex. M.I.M. C.S.Y. V.D. and N.T. conceived the study; M.I.M. C.S.Y, A.F. C.G. C.M. E.S. K.R.L,. A.T. J.D. O.D, J.B.M. J.C.P. J.C.M. A.K. S.K. V.S.Z. I.L. L.Y.C. J.V.S. S.A.M. H.H.V. S.T. V.D. and N.T. were involved in study design; and M.I.M. C.S.Y. A.F. C.G. C.M. E.S. A.T. J.P. A.R. J.D. O.D. J.B.M. M.W. H.V.V. S.T. and V.D. performed experiments. All authors participated in data analysis. A.F. C.G. C.M. E.S. S.A.M. H.H.V. and S.T. contributed significantly to manuscript writing with important critical input from K.R.L. A.T. J.C.P. S.K. V.S.Z. I.L. L.Y.C. and J.S. M.I.M. C.S.Y. V.D. and N.T. were responsible for writing the manuscript. C.M. S.K. V.D. and N.T. are inventors on patents describing the use of ligands for detection of and modulation of metabolite transporters (N.T. gave up her rights), licensed to METAFORA-biosystems. Funding Information: We thank all members of our laboratories for discussions and scientific critique. We are indebted to {\"U}nal Coskun, Michal Grzybek, Alessandra Palladini, and Triantafyllos Chavakis for all their expertise and assistance with lipidomics analyses. We are grateful to Myriam Boyer-Clavel and St{\'e}phanie Viala of the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency ( ANR-10-INBS-04 , «Investments for the future»). We are grateful to Amal Makrini of the SERANAD bioinformatics platform for her assistance with analyses. M.I.M. was funded by the French Ministry of Health and a fellowship from ARC and C.S.Y. by an Australian Postgraduate Award, Cancer Therapeutics Australia and ARC. C.G. was supported by the ERICAN program of MSD Avenir (J.C.M.). S.T. is supported by funding from Cancer Research UK ( C596/A17196 and A23982 ). We are grateful to MetaboHUB-MetaToul (Toulouse, France) and MetaboHUB-ANR-11-INBS-0010 for lipid tracing experiments. This research was in part supported by the NIH Intramural Research Program of NIAID (S.A.M.) and NCI (N.T.). This work was supported by generous funding from the ANR research grants (CHIC-20-CE14-0049 , NutriDiff, and PolarAttack), FRM, ARC, Sidaction, ANRS, and the French laboratory consortiums EpiGenMed and GR-Ex. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = nov,

day = "2",

doi = "10.1016/j.celrep.2021.109911",

language = "English (US)",

volume = "37",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

AU - Matias, Maria I.

AU - Yong, Carmen S.

AU - Foroushani, Amir

AU - Goldsmith, Chloe

AU - Mongellaz, Cédric

AU - Sezgin, Erdinc

AU - Levental, Kandice R.

AU - Talebi, Ali

AU - Perrault, Julie

AU - Rivière, Anais

AU - Dehairs, Jonas

AU - Delos, Océane

AU - Bertand-Michel, Justine

AU - Portais, Jean Charles

AU - Wong, Madeline

AU - Marie, Julien C.

AU - Kelekar, Ameeta

AU - Kinet, Sandrina

AU - Zimmermann, Valérie S.

AU - Levental, Ilya

AU - Yvan-Charvet, Laurent

AU - Swinnen, Johannes V.

AU - Muljo, Stefan A.

AU - Hernandez-Vargas, Hector

AU - Tardito, Saverio

AU - Taylor, Naomi

AU - Dardalhon, Valérie

N1 - Funding Information: We thank all members of our laboratories for discussions and scientific critique. We are indebted to Ünal Coskun, Michal Grzybek, Alessandra Palladini, and Triantafyllos Chavakis for all their expertise and assistance with lipidomics analyses. We are grateful to Myriam Boyer-Clavel and Stéphanie Viala of the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, «Investments for the future»). We are grateful to Amal Makrini of the SERANAD bioinformatics platform for her assistance with analyses. M.I.M. was funded by the French Ministry of Health and a fellowship from ARC and C.S.Y. by an Australian Postgraduate Award, Cancer Therapeutics Australia and ARC. C.G. was supported by the ERICAN program of MSD Avenir (J.C.M.). S.T. is supported by funding from Cancer Research UK (C596/A17196 and A23982). We are grateful to MetaboHUB-MetaToul (Toulouse, France) and MetaboHUB-ANR-11-INBS-0010 for lipid tracing experiments. This research was in part supported by the NIH Intramural Research Program of NIAID (S.A.M.) and NCI (N.T.). This work was supported by generous funding from the ANR research grants (CHIC-20-CE14-0049, NutriDiff, and PolarAttack), FRM, ARC, Sidaction, ANRS, and the French laboratory consortiums EpiGenMed and GR-Ex. M.I.M. C.S.Y. V.D. and N.T. conceived the study; M.I.M. C.S.Y, A.F. C.G. C.M. E.S. K.R.L,. A.T. J.D. O.D, J.B.M. J.C.P. J.C.M. A.K. S.K. V.S.Z. I.L. L.Y.C. J.V.S. S.A.M. H.H.V. S.T. V.D. and N.T. were involved in study design; and M.I.M. C.S.Y. A.F. C.G. C.M. E.S. A.T. J.P. A.R. J.D. O.D. J.B.M. M.W. H.V.V. S.T. and V.D. performed experiments. All authors participated in data analysis. A.F. C.G. C.M. E.S. S.A.M. H.H.V. and S.T. contributed significantly to manuscript writing with important critical input from K.R.L. A.T. J.C.P. S.K. V.S.Z. I.L. L.Y.C. and J.S. M.I.M. C.S.Y. V.D. and N.T. were responsible for writing the manuscript. C.M. S.K. V.D. and N.T. are inventors on patents describing the use of ligands for detection of and modulation of metabolite transporters (N.T. gave up her rights), licensed to METAFORA-biosystems. Funding Information: We thank all members of our laboratories for discussions and scientific critique. We are indebted to Ünal Coskun, Michal Grzybek, Alessandra Palladini, and Triantafyllos Chavakis for all their expertise and assistance with lipidomics analyses. We are grateful to Myriam Boyer-Clavel and Stéphanie Viala of the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency ( ANR-10-INBS-04 , «Investments for the future»). We are grateful to Amal Makrini of the SERANAD bioinformatics platform for her assistance with analyses. M.I.M. was funded by the French Ministry of Health and a fellowship from ARC and C.S.Y. by an Australian Postgraduate Award, Cancer Therapeutics Australia and ARC. C.G. was supported by the ERICAN program of MSD Avenir (J.C.M.). S.T. is supported by funding from Cancer Research UK ( C596/A17196 and A23982 ). We are grateful to MetaboHUB-MetaToul (Toulouse, France) and MetaboHUB-ANR-11-INBS-0010 for lipid tracing experiments. This research was in part supported by the NIH Intramural Research Program of NIAID (S.A.M.) and NCI (N.T.). This work was supported by generous funding from the ANR research grants (CHIC-20-CE14-0049 , NutriDiff, and PolarAttack), FRM, ARC, Sidaction, ANRS, and the French laboratory consortiums EpiGenMed and GR-Ex. Publisher Copyright: © 2021

PY - 2021/11/2

Y1 - 2021/11/2

N2 - Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.

AB - Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.

KW - CAR T cells

KW - DNA methylation

KW - T cell differentiation

KW - TCA cycle

KW - Th1

KW - Treg

KW - lipidome

KW - mitochondrial metabolism

KW - triacylglyceride synthesis

KW - α-ketoglutarate

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UR - http://www.scopus.com/inward/citedby.url?scp=85118509550&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109911

DO - 10.1016/j.celrep.2021.109911

M3 - Article

C2 - 34731632

AN - SCOPUS:85118509550

VL - 37

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 5

M1 - 109911

ER -

Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

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