Glutarate regulates T cell metabolism and anti-tumour immunity

Minogue et al. show that glutarate, a metabolite derived from tryptophan catabolism, has the ability to shape anti-tumour T cell responses by modulating pyruvate handling and alpha-ketoglutarate-dependent dioxygenases. T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of alpha-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 alpha-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.