Glucose-dependent glycosphingolipid biosynthesis fuels CD8 + T cell function and tumor control.

Autor:	Longo J; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., DeCamp LM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Oswald BM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Teis R; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Reyes-Oliveras A; Department of Cell Biology, Van Andel Institute, Grand Rapids, MI, USA., Dahabieh MS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Ellis AE; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Vincent MP; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Damico H; Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA., Gallik KL; Optical Imaging Core, Van Andel Institute, Grand Rapids, MI, USA., Compton SE; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Capan CD; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Williams KS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition Program, Van Andel Institute, Grand Rapids, MI, USA., Esquibel CR; Optical Imaging Core, Van Andel Institute, Grand Rapids, MI, USA., Madaj ZB; Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA., Lee H; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Roy DG; Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Canada.; Institut du Cancer de Montréal, Montréal, Canada., Krawczyk CM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Haab BB; Department of Cell Biology, Van Andel Institute, Grand Rapids, MI, USA., Sheldon RD; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Jones RG; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Metabolism and Nutrition Program, Van Andel Institute, Grand Rapids, MI, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 14. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1101/2024.10.10.617261
Abstrakt:	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 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 in vivo . Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8 + T cell responses in vivo . Competing Interests: DECLARATION OF INTERESTS R.G.J. is a scientific advisor to Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics.
Databáze:	MEDLINE
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