Reductive carboxylation epigenetically instructs T cell differentiation

Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Jan A. Rath, Alessio Bevilacqua, Jhan-Jie Peng, Anouk Lepez, Christine Gunten, Fabien Franco, Kung-Chi Kao, Nicolas Camviel, Francisco Martín, Bart Ghesquière, Denis Migliorini, Caroline Arber, Pedro Romero (), Ping-Chih Ho () and Mathias Wenes ()
Additional contact information
Alison Jaccard: University of Lausanne
Tania Wyss: University of Lausanne
Noelia Maldonado-Pérez: Centre for Genomics and Oncological Research (GENYO)
Jan A. Rath: University of Lausanne
Alessio Bevilacqua: University of Lausanne
Jhan-Jie Peng: University of Lausanne
Anouk Lepez: AGORA Cancer Research Center
Christine Gunten: University of Lausanne
Fabien Franco: University of Lausanne
Kung-Chi Kao: University of Lausanne
Nicolas Camviel: University of Lausanne
Francisco Martín: Centre for Genomics and Oncological Research (GENYO)
Bart Ghesquière: KU Leuven
Denis Migliorini: AGORA Cancer Research Center
Caroline Arber: University of Lausanne
Pedro Romero: University of Lausanne
Ping-Chih Ho: University of Lausanne
Mathias Wenes: University of Lausanne

Nature, 2023, vol. 621, issue 7980, 849-856

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06546-y

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