Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Sci Immunol. 2022 Apr 29;7(70):eabm8161. doi: 10.1126/sciimmunol.abm8161.
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.
有效的 T 细胞介导的免疫反应需要适当分配代谢资源，以维持生长、增殖和细胞因子产生。基因组的表观遗传控制也控制着 T 细胞转录组和 T 细胞谱系的决定和维持。细胞代谢程序通过为染色质的共价修饰提供底物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，我们揭示了三羧酸 (TCA) 循环通量为生物合成过程提供燃料，同时控制琥珀酸/α-酮戊二酸 (α-KG) 的比例，以调节对驱动 T 细胞炎症至关重要的双加氧酶的活性。与癌细胞不同，琥珀酸脱氢酶 (SDH)/复合物 II 的失活驱动细胞转化和生长，而 T 细胞中的 SDH/复合物 II 缺乏会导致 TCA 循环截断时增殖和存活缺陷，阻止碳通量来支持核苷合成。补充细胞内核苷池部分缓解了 T 细胞对 SDH/复合物 II 增殖和存活的依赖。SDH 缺乏在 T 细胞中诱导促炎基因特征，并促进辅助性 T 细胞 1 和辅助性 T 细胞 17 谱系分化。SDH 缺陷 T 细胞中琥珀酸/α-KG 比例的增加通过改变转录和染色质可及性特征的模式，从而增加转录因子 PR 结构域锌指蛋白 1 的表达，促进炎症。总之，我们的研究揭示了 SDH/复合物 II 在分配碳资源用于 T 细胞增殖和炎症中的合成代谢过程和表观遗传调控中的作用。
