TY - JOUR
T1 - Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
AU - Sukumar, Madhusudhanan
AU - Liu, Jie
AU - Ji, Yun
AU - Subramanian, Murugan
AU - Crompton, Joseph G.
AU - Yu, Zhiya
AU - Roychoudhuri, Rahul
AU - Palmer, Douglas C.
AU - Muranski, Pawel
AU - Karoly, Edward D.
AU - Mohney, Robert P.
AU - Klebanoff, Christopher A.
AU - Lal, Ashish
AU - Finkel, Toren
AU - Restifo, Nicholas P.
AU - Gattinoni, Luca
PY - 2013/10/1
Y1 - 2013/10/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI69589
DO - 10.1172/JCI69589
M3 - Article
C2 - 24091329
AN - SCOPUS:84885055994
SN - 0021-9738
VL - 123
SP - 4479
EP - 4488
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -