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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Article number109911
JournalCell reports
Volume37
Issue number5
DOIs
StatePublished - 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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