Longo Joseph, DeCamp Lisa M, Oswald Brandon M, Teis Robert, Reyes-Oliveras Alfredo, Dahabieh Michael S, Ellis Abigail E, Vincent Michael P, Damico Hannah, Gallik Kristin L, Compton Shelby E, Capan Colt D, Williams Kelsey S, Esquibel Corinne R, Madaj Zachary B, Lee Hyoungjoo, Roy Dominic G, Krawczyk Connie M, Haab Brian B, Sheldon Ryan D, Jones Russell G
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI, USA.
bioRxiv. 2024 Oct 14:2024.10.10.617261. doi: 10.1101/2024.10.10.617261.
Glucose is essential for T cell proliferation and function, yet its specific metabolic roles remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8 T cell expansion and cytotoxic function . Using C-based stable isotope tracing, we demonstrate that CD8 effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8 T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8 T cells display reduced granzyme expression and tumor control . Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8 T cell responses .
葡萄糖对T细胞增殖和功能至关重要，但其具体的代谢作用仍不清楚。在此，我们确定糖鞘脂（GSL）生物合成是由葡萄糖驱动的关键途径，可促进CD8 T细胞扩增和细胞毒性功能。使用基于碳的稳定同位素示踪，我们证明CD8效应T细胞利用葡萄糖合成尿苷二磷酸葡萄糖（UDP-Glc），这是糖原、聚糖和GSL生物合成的前体。通过靶向酶UGP2或UGCG抑制GSL产生会损害CD8 T细胞扩增和细胞溶解活性，而不影响葡萄糖依赖的能量产生。从机制上讲，我们表明TCR刺激后质膜脂筏完整性和聚集需要葡萄糖依赖的GSL生物合成。此外，缺乏UGCG的CD8 T细胞显示颗粒酶表达降低和肿瘤控制能力下降。总之，我们的数据确定GSL生物合成是葡萄糖的一种关键代谢归宿，它独立于能量产生，是CD8 T细胞反应所必需的。
