Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function

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.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…While CD62L expression was significantly higher for all AKT-inhibited T cell conditions compared to DMSO-treated control T cells, no significant finding along different donors in mitochondrial respiration was observed (Figure 4A and Supplementary Figure 4A-B). Although reduced glycolytic metabolism is associated with CD8 + T cell memory, 26,27 we observed a trend towards increased glycolytic function in AKT-inhibited T cells (Figure 4A and B). The increase in glycolysis was most prominent for AktiVIII-treated T cells (Figure 4A and B), while other inhibitors showed only moderate effects.…”

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

“…Moreover, Tsc1-deficient T cells show enhanced glycolytic and oxidative phosphorylation rates in vitro that are closely linked with IL-15-mediated signaling. Although the increased glycolysis upon Tsc1 deletion is in agreement with impaired development of memory cells (11), the effect of the increased oxidative phosphorylation remains to be established. Notably, the IPA analysis indicates that Tsc1 deficiency impinges upon both oxidative phosphorylation and mitochondria function.…”

“…The metabolic programs are dynamically regulated to match the differentiation and function of T cells (4)(5)(6). For the fate decisions between effector and memory CD8 + T cells, the glycolytic and lipid synthetic metabolism promotes effector T-cell generation (7,11), whereas oxidative phosphorylation and mitochondrial activity facilitate memory development (12,13). From the microarray and bioinformatics analyses, we found that Tsc1 −/− antigen-specific CD8 + T cells exhibit elevated expression of metabolic genes involved in glycolysis, lipid synthesis, and oxidative phosphorylation.…”

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

“…BCATc Ϫ/Ϫ T Cells Have Up-regulated Glycolytic MetabolismThe highly energetic process of T cell activation induces a shift to glycolytic metabolism to support rapid cell growth and generation of effector T cells (36,39). We next tested whether loss of BCATc expression in stimulated T cells influences glycolytic function.…”