Glutarate regulates T cell metabolism and anti-tumour immunity
© 2023. The Author(s)..
T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Nature metabolism - 5(2023), 10 vom: 22. Okt., Seite 1747-1764 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Minogue, Eleanor [VerfasserIn] |
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| Links: |
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| Themen: |
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| Anmerkungen: |
Date Completed 26.10.2023 Date Revised 16.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s42255-023-00855-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy | ||
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| 700 | 1 | |a Grice, Guinevere L |e verfasserin |4 aut | |
| 700 | 1 | |a Sah-Teli, Shiv K |e verfasserin |4 aut | |
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| 700 | 1 | |a Foskolou, Iosifina P |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Randall S |e verfasserin |4 aut | |
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