Reductive carboxylation epigenetically instructs T cell differentiation.

Details

Serval ID
serval:BIB_D1AE6E79E2FB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Reductive carboxylation epigenetically instructs T cell differentiation.
Journal
Nature
Author(s)
Jaccard A., Wyss T., Maldonado-Pérez N., Rath J.A., Bevilacqua A., Peng J.J., Lepez A., Von Gunten C., Franco F., Kao K.C., Camviel N., Martín F., Ghesquière B., Migliorini D., Arber C., Romero P., Ho P.C., Wenes M.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
09/2023
Peer-reviewed
Oui
Volume
621
Number
7980
Pages
849-856
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules <sup>1-3</sup> . However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8 <sup>+</sup> T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8 <sup>+</sup> T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8 <sup>+</sup> T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8 <sup>+</sup> T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.
Keywords
CD8-Positive T-Lymphocytes, Cell Differentiation/genetics, Lymphocyte Activation, Citric Acid Cycle, Oxidative Phosphorylation, Immunologic Memory/genetics
Pubmed
Web of science
Create date
06/11/2023 15:53
Last modification date
09/12/2023 7:02
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