Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells

• Published in: PloS one Vol. 6; no. 5; p. e20107
• Main Authors: He, Shan, Kato, Koji, Jiang, Jiu, Wahl, Daniel R, Mineishi, Shin, Fisher, Erin M, Murasko, Donna M, Glick, Gary D, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2011; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; Apoptosis; Biocompatibility; Biology; Biotechnology; Cancer; Cancer therapies; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Cell growth; Cell Survival - drug effects; Computer memory; Cytokines; Cytotoxicity; Dendritic cells; Deoxyribonucleic acid; DNA; Effector cells; Genomes; Genotype & phenotype; Glucose - deficiency; Glucose - pharmacology; Glycolysis; Glycolysis - drug effects; Growth factors; Hyperpolarization; Immunologic Memory - drug effects; Immunological memory; Immunotherapy; Inhibition; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - pharmacology; Interleukin-2 - deficiency; Interleukin-2 - pharmacology; Internal medicine; Leukemia; Long term memory; Lymphocytes; Lymphocytes T; Medicine; Membrane Potential, Mitochondrial - drug effects; Memory cells; Metabolism; Mice; Mitochondria; Nutrients; Oligomycin; Oligomycins - pharmacology; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Oxygen; Phenotype; Phosphorylation; Rapamycin; Reactive oxygen species; Reactive Oxygen Species - metabolism; Sirolimus - pharmacology; T cell receptors; T-cell receptor; Transgenic mice; Viruses; Ann Arbor Michigan; United States > US; Pennsylvania; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020107

Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized.
Using lymphocytic choriomeningitis virus (LCMV) peptide gp33-specific CD8(+) T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo.
Antigen-activated CD8(+) T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS). These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells.
Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy.