Effective T cell–mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.

中文翻译：

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琥珀酸脱氢酶/复合物 II 对于 T 细胞增殖和炎症的代谢和表观遗传调控至关重要


有效的 T 细胞介导的免疫反应需要适当分配代谢资源来维持生长、增殖和细胞因子的产生。基因组的表观遗传控制还控制着 T 细胞转录组和 T 细胞谱系的定型和维持。细胞代谢程序通过为染色质共价修饰提供底物来与表观遗传调控相互作用。通过使用互补的遗传、表观遗传和代谢方法，我们发现三羧酸（TCA）循环通量促进生物合成过程，同时控制琥珀酸/α-酮戊二酸（α-KG）的比例来调节双加氧酶的活性，这对于驱动生物合成过程至关重要T细胞炎症。与癌细胞相比，琥珀酸脱氢酶 (SDH)/复合物 II 失活可驱动细胞转化和生长，而当 TCA 循环被截断时，T 细胞中的 SDH/复合物 II 缺陷会导致增殖和生存缺陷，从而阻碍支持核苷生物合成的碳通量。补充细胞内核苷库部分缓解了 T 细胞对 SDH/复合物 II 增殖和存活的依赖。 SDH 缺陷会诱导 T 细胞中的促炎基因特征，并促进辅助性 T 1 和辅助性 T 17 谱系分化。 SDH 缺陷 T 细胞中琥珀酸/α-KG 比率的增加通过改变转录和染色质可及性特征的模式并随后增加转录因子 PR 域锌指蛋白 1 的表达来促进炎症。总的来说，我们的研究揭示了SDH/复合物 II 在 T 细胞增殖和炎症中合成代谢过程和表观遗传调控碳资源分配中的作用。