Abstract
Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8+ T cell effector and memory populations. Evaluation of mice with a T cell-specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8+ T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8+ T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8+ T cell effector responses, mTORC2 activity regulated CD8+ T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8+ memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8+ T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adoptive Transfer
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Animals
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CD4-CD8 Ratio
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / transplantation
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Carrier Proteins / genetics
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Cell Line, Tumor
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Deoxyglucose / pharmacology
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Deoxyglucose / therapeutic use
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Female
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Genes, Reporter
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Glycolysis / drug effects
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Immunologic Memory
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Interferon-gamma / biosynthesis
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Lymphocyte Activation
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Lymphopoiesis / physiology*
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Melanoma, Experimental / immunology
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Melanoma, Experimental / therapy
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Mice
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Mice, Congenic
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Mice, Inbred C57BL
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Monomeric GTP-Binding Proteins / deficiency
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Monomeric GTP-Binding Proteins / genetics
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Multiprotein Complexes / deficiency
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Multiprotein Complexes / genetics
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Multiprotein Complexes / physiology*
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Neuropeptides / deficiency
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Neuropeptides / genetics
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Ovalbumin / immunology
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Peptide Fragments / immunology
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Phosphorylation
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins c-akt / metabolism
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Rapamycin-Insensitive Companion of mTOR Protein
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Ras Homolog Enriched in Brain Protein
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Recombinant Fusion Proteins / immunology
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Sirolimus / pharmacology
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Sirolimus / therapeutic use
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TOR Serine-Threonine Kinases / deficiency
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / physiology*
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Thymoma / immunology
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Thymoma / therapy
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Transduction, Genetic
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Carrier Proteins
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Multiprotein Complexes
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Neuropeptides
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OVA-8
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Peptide Fragments
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Rapamycin-Insensitive Companion of mTOR Protein
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Ras Homolog Enriched in Brain Protein
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Recombinant Fusion Proteins
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Rheb protein, mouse
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Tumor Necrosis Factor-alpha
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rictor protein, mouse
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Interferon-gamma
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Ovalbumin
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Deoxyglucose
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Akt1 protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins
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Sirolimus