Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
Elife. 2021 Oct 28;10:e67476. doi: 10.7554/eLife.67476.
Cellular metabolism has key roles in T cells differentiation and function. CD4 T helper-1 (Th1), Th2, and Th17 subsets are highly glycolytic while regulatory T cells (Tregs) use glucose during expansion but rely on fatty acid oxidation for function. Upon uptake, glucose can enter pentose phosphate pathway (PPP) or be used in glycolysis. Here, we showed that blocking 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP resulted in substantial reduction of Tregs suppressive function and shifts toward Th1, Th2, and Th17 phenotypes which led to the development of fetal inflammatory disorder in mice model. These in turn improved anti-tumor responses and worsened the outcomes of colitis model. Metabolically, 6PGD blocked Tregs showed improved glycolysis and enhanced non-oxidative PPP to support nucleotide biosynthesis. These results uncover critical role of 6PGD in modulating Tregs plasticity and function, which qualifies it as a novel metabolic checkpoint for immunotherapy applications.
细胞代谢在 T 细胞分化和功能中起着关键作用。CD4 T 辅助细胞 1（Th1）、Th2 和 Th17 亚群高度糖酵解，而调节性 T 细胞（Treg）在扩增过程中使用葡萄糖，但依赖于脂肪酸氧化来发挥功能。摄取后，葡萄糖可进入戊糖磷酸途径（PPP）或用于糖酵解。在这里，我们表明，在氧化 PPP 中阻断 6-磷酸葡萄糖酸脱氢酶（6PGD）会导致 Treg 抑制功能显著降低，并向 Th1、Th2 和 Th17 表型转变，从而导致小鼠模型中胎儿炎症障碍的发生。这反过来又改善了抗肿瘤反应，并恶化了结肠炎模型的结果。在代谢方面，被阻断的 6PGD 的 Treg 表现出改善的糖酵解和增强的非氧化 PPP，以支持核苷酸生物合成。这些结果揭示了 6PGD 在调节 Treg 可塑性和功能方面的关键作用，使其成为免疫治疗应用的新型代谢检查点。
