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
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
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