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, Foy Nicole M, 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.
Cell Metab. 2025 Jul 30. doi: 10.1016/j.cmet.2025.07.006.
Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo 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 in vivo. 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 UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8 T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8 T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-beyond energy production-that is required for CD8 T cell responses in vivo.
葡萄糖对于T细胞增殖和功能至关重要，但其在体内的具体代谢作用仍不清楚。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，它能在体内实现CD8 T细胞扩增和细胞毒性功能。利用基于碳的稳定同位素示踪技术，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。通过靶向尿苷二磷酸葡萄糖焦磷酸化酶2（UGP2）、尿苷二磷酸半乳糖-4-表异构酶（GALE）或尿苷二磷酸葡萄糖神经酰胺葡糖基转移酶（UGCG）来抑制GSL生成，会损害病原体攻击时CD8 T细胞的扩增。从机制上讲，我们表明葡萄糖依赖性GSL生物合成对于质膜脂筏完整性和最佳T细胞受体（TCR）信号传导是必需的。此外，缺乏UGCG的CD8 T细胞在体内表现出颗粒酶表达降低、细胞溶解活性降低和肿瘤控制能力下降。总之，我们的数据确定GSL生物合成是葡萄糖除能量产生之外的关键代谢归宿，这是体内CD8 T细胞反应所必需的。
