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 - 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 - lipidome
KW - mitochondrial metabolism
KW - T cell differentiation
KW - TCA cycle
KW - Th1
KW - Treg
KW - triacylglyceride synthesis
KW - α-ketoglutarate
UR - http://www.scopus.com/inward/record.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
SN - 2211-1247
VL - 37
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 109911
ER -