Glutarate regulates T cell metabolism and anti-tumour immunity
Eleanor Minogue, Pedro P. Cunha, Brennan J. Wadsworth, Guinevere L. Grice, Shiv K. Sah‐Teli, R. J. F. Hughes, David Bargiela, Alessandro Quaranta, Javier Zurita, Robin Antrobus, Pedro Veliça, Laura Barbieri, Craig E. Wheelock, Peppi Koivunen, James A. Nathan, Iosifina P. Foskolou, Randall S. Johnson
Abstract
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.