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

Summary: 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 cond...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	T cell differentiation Treg α-ketoglutarate lipidome triacylglyceride synthesis CAR T cells Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0c8c5ea249b7400aa1ce379f1a846ac3
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spelling	oai:doaj.org-article:0c8c5ea249b7400aa1ce379f1a846ac32021-11-04T04:28:56ZRegulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis2211-124710.1016/j.celrep.2021.109911https://doaj.org/article/0c8c5ea249b7400aa1ce379f1a846ac32021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S221112472101384Xhttps://doaj.org/toc/2211-1247Summary: 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.Maria I. MatiasCarmen S. YongAmir ForoushaniChloe GoldsmithCédric MongellazErdinc SezginKandice R. LeventalAli TalebiJulie PerraultAnais RivièreJonas DehairsOcéane DelosJustine Bertand-MichelJean-Charles PortaisMadeline WongJulien C. MarieAmeeta KelekarSandrina KinetValérie S. ZimmermannIlya LeventalLaurent Yvan-CharvetJohannes V. SwinnenStefan A. MuljoHector Hernandez-VargasSaverio TarditoNaomi TaylorValérie DardalhonElsevierarticleT cell differentiationTregα-ketoglutaratelipidometriacylglyceride synthesisCAR T cellsBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 5, Pp 109911- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	T cell differentiation Treg α-ketoglutarate lipidome triacylglyceride synthesis CAR T cells Biology (General) QH301-705.5
spellingShingle	T cell differentiation Treg α-ketoglutarate lipidome triacylglyceride synthesis CAR T cells Biology (General) QH301-705.5 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 Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
description	Summary: 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.
format	article
author	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
author_facet	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
author_sort	Maria I. Matias
title	Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
title_short	Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
title_full	Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
title_fullStr	Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
title_full_unstemmed	Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis
title_sort	regulatory t cell differentiation is controlled by αkg-induced alterations in mitochondrial metabolism and lipid homeostasis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/0c8c5ea249b7400aa1ce379f1a846ac3
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Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

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