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

42 Scopus citations


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
Issue number5
StatePublished - Nov 2 2021

Bibliographical note

Publisher Copyright:
© 2021


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


Dive into the research topics of 'Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis'. Together they form a unique fingerprint.

Cite this