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.

T 细胞的功能和命运可能受到多种代谢物的影响：在某些情况下，通过酶抑制 α-酮戊二酸依赖性双加氧酶发挥作用，在其他情况下，通过重要靶标中赖氨酸的翻译后修饰发挥作用。我们在这里表明，戊二酸是氨基酸分解代谢的产物，具有这两种能力，并且对 T 细胞功能和分化具有强大的影响。我们发现戊二酸通过抑制 α-酮戊二酸依赖性双加氧酶以及通过丙酮酸脱氢酶 E2 亚基的戊二酸化直接调节 T 细胞代谢来发挥这些作用。戊二酸二乙酯（一种可渗透细胞的戊二酸形式）的给药可改变 CD8 ⁺ T 细胞的分化并增加针对靶细胞的细胞毒性。该化合物的体内给药与外周和肿瘤内细胞毒性 CD8 ⁺ T 细胞水平的增加相关。这些结果表明，戊二酸是 T 细胞代谢和分化的重要调节剂，在改善 T 细胞免疫治疗方面具有潜在作用。