Glutarate regulates T cell function and metabolism
Minogue, E. A.; Cunha, P. P.; Quaranta, A.; Zurita, J.; Sah-Teli, S. K.; Wadsworth, B.; Hughes, R.; Grice, G.; Velica, P.; Bargiela, D.; Barbieri, L.; Wheelock, C.; Nathan, J. A.; Karppinen, P.; Foskolou, I. P.; Johnson, R. S.
Show abstract
T cell function is influenced by several metabolites; some acting through enzymatic inhibition of -KG-dependent dioxygenases (KGDDs), 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, with effects on T cell function and differentiation. Glutarate exerts those effects through KGDD inhibition and through direct regulation of T cell metabolism via post-translational modification of the pyruvate dehydrogenase E2 subunit. 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 reduces tumor growth and is correlated with increased levels of both peripheral and intratumoral cytotoxic CD8+ T cells. These results demonstrate that glutarate regulates both T cell metabolism and differentiation, with a potential role in the improvement of T cell immunotherapy.
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