Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control
Joseph Longo, Lisa M. DeCamp, Brandon M. Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S. Dahabieh, Abigail E. Ellis, Michael P. Vincent, Hannah Damico, Kristin L. Gallik, Nicole M Foy, Shelby E. Compton, Colt Capan, Kelsey S. Williams, Corinne R. Esquibel, Zachary Madaj, Hyoungjoo Lee, Dominic G. Roy, Connie M. Krawczyk, Brian B. Haab, Ryan D. Sheldon, Russell G. Jones
Abstract
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 13 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 .