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Scientific article
English

Reductive carboxylation epigenetically instructs T cell differentiation

Published inNature, vol. 621, no. 7980, p. 849-856
Publication date2023-09-28
First online date2023-09-20
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 molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ 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+ 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+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ 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.

eng
Keywords
  • CD8-Positive T-Lymphocytes
  • Cell Differentiation / genetics
  • Citric Acid Cycle
  • Immunologic Memory / genetics
  • Lymphocyte Activation
  • Oxidative Phosphorylation
Funding
Citation (ISO format)
JACCARD, Alison et al. Reductive carboxylation epigenetically instructs T cell differentiation. In: Nature, 2023, vol. 621, n° 7980, p. 849–856. doi: 10.1038/s41586-023-06546-y
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ISSN of the journal0028-0836
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