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Glutarate regulates T cell metabolism and anti-tumour immunity.

Published version
Peer-reviewed

Repository DOI


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Authors

Cunha, Pedro P 
Wadsworth, Brennan J  ORCID logo  https://orcid.org/0000-0002-9183-227X
Grice, Guinevere L 

Abstract

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.

Description

Keywords

CD8-Positive T-Lymphocytes, Glutarates, Biochemical Phenomena

Journal Title

Nat Metab

Conference Name

Journal ISSN

2522-5812
2522-5812

Volume Title

5

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (215477/Z/19/Z)
Wellcome Trust (214283/Z/18/Z)
Swedish Research Council (2019-01485_VR)