Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Madhusudhanan Sukumar,Jie Liu,Yun Ji,Murugan Subramanian,Joseph G. Crompton,Zhiya Yu,Rahul Roychoudhuri,Douglas C. Palmer,Pawel Muranski,Edward D. Karoly,Robert P. Mohney,Christopher A. Klebanoff,Ashish Lal,Toren Finkel,Nicholas P. Restifo,Luca Gattinoni +15 more
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TLDR
It is indicated that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+, and the efficacy of T cell-based therapies against chronic infectious diseases and cancer.Abstract:
Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell–based therapies against chronic infectious diseases and cancer.read more
Citations
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AMPK in Lymphocyte Metabolism and Function.
Fabienne Andris,Oberdan Leo +1 more
TL;DR: Recent data about the regulation of T cell metabolism by AMPK is reviewed and its influence on T cell function is discussed.
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Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis
Jared Klarquist,Alisha Chitrakar,Nathan D. Pennock,Augustus M. Kilgore,Trevor J. Blain,Connie Zheng,Thomas Danhorn,Kendra Walton,Li Jiang,Jie Sun,Christopher A. Hunter,Angelo D'Alessandro,Ross M. Kedl +12 more
TL;DR: IL-27 and IL-15 are identified as critical to vaccine-elicited T cell responses because of their capacity to fuel clonal expansion through a mitochondrial metabolic program previously thought only capable of supporting quiescent naïve and memory T cells.
Journal ArticleDOI
Immune effects of glycolysis or oxidative phosphorylation metabolic pathway in protecting against bacterial infection.
Yan Li,Yan Li,Anna Jia,Yuexin Wang,Lin Dong,Yufei Wang,Ying He,Shiyao Wang,Yejin Cao,Hui Yang,Yujing Bi,Guangwei Liu,Guangwei Liu +12 more
TL;DR: The results provide a basis for comprehensively understanding the role of glycolysis and OXPHOS in anti‐infectious immunity and show that hypoxia‐inducible factor 1‐alpha (HIF1α) was an upstream signal in the regulation of gly colysis, but not OX PHOS.
Journal ArticleDOI
Targeting memory T cell metabolism to improve immunity
Mauro Corrado,Erika L. Pearce +1 more
TL;DR: Recent advances in defining memory T cell metabolism are described and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure.
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Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function.
Jessica E. Thaxton,Caroline Wallace,Brian Riesenberg,Yongliang Zhang,Chrystal M. Paulos,Craig Beeson,Bei Liu,Zihai Li +7 more
TL;DR: Data show that ER-modulated cytosolic Ca2+ plays a role in defining CD4+ T-cell phenotype and function, and factors associated with the ER stress response are suitable targets for T cell–based immunotherapies.
References
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Journal ArticleDOI
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Journal ArticleDOI
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Ruoning Wang,Christopher P. Dillon,Lewis Zhichang Shi,Sandra Milasta,Robert Carter,David Finkelstein,Laura L. McCormick,Patrick Fitzgerald,Hongbo Chi,Joshua Munger,Douglas R. Green +10 more
TL;DR: Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines, which may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
Journal ArticleDOI
Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
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TL;DR: Teff and Treg were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation.