初始 T 细胞保持主动维持的静止状态，直到被抗原信号激活，然后它们开始增殖并产生效应细胞以启动功能性免疫反应。代谢重编程对于满足分化过程的生物合成需求至关重要，如果不这样做，可能会促进功能低下、耗竭的T细胞的发育。在这里，我们使用13C代谢组学和转录组学来研究CD8 T细胞在其完整分化过程中的代谢从幼稚的干细胞样记忆到效应细胞，以及在诱导疲劳的条件下。幼稚 T 细胞的静止在葡萄糖氧化的深度抑制和 ENO1 表达的减少中表现得很明显，在其下游没有检测到糖酵解通量。此外，初始 T 细胞中的 TCA 循环活性较低，并且与 SDH 亚基的下调相关。在刺激和退出静止状态后，细胞生长和增殖的开始伴随着代谢酶的差异表达和代谢重编程，以进行有氧糖酵解，并具有高营养吸收、呼吸和乳酸产生的速率。合成代谢途径的高通量对 NADH 稳态造成压力，这与线粒体氧化还原穿梭的脯氨酸循环的参与同时发生。随着效应器功能的获得，细胞越来越依赖糖酵解而不是氧化磷酸化，然而，氧化磷酸化与线粒体丰度的变化无关。在疲惫状态下，效应器功能下降伴随着线粒体代谢、糖酵解和氨基酸输入的减少，以及静止相关基因、TXNIP和KLF2以及T细胞抑制代谢物琥珀酸和衣康酸的上调。总体而言，这些结果确定了多种代谢这些功能不仅调节静止、增殖和效应功能，而且还调节 CD8 T 细胞在分化过程中的耗竭。因此，针对这些代谢检查点可能是预防衰竭和促进抗肿瘤 T 细胞干性的一种有前景的治疗策略。版权所有 © 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler 、 Zippelius、Ghesquière 和 Trajanoski。

Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.Here we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.The quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.Overall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.Copyright © 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski.