mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation

J Clin Invest. 2015 May;125(5):2090-108. doi: 10.1172/JCI77746. Epub 2015 Apr 20.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-CD8 Ratio
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / transplantation
  • Carrier Proteins / genetics
  • Cell Line, Tumor
  • Deoxyglucose / pharmacology
  • Deoxyglucose / therapeutic use
  • Female
  • Genes, Reporter
  • Glycolysis / drug effects
  • Immunologic Memory
  • Interferon-gamma / biosynthesis
  • Lymphocyte Activation
  • Lymphopoiesis / physiology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Monomeric GTP-Binding Proteins / deficiency
  • Monomeric GTP-Binding Proteins / genetics
  • Multiprotein Complexes / deficiency
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / physiology*
  • Neuropeptides / deficiency
  • Neuropeptides / genetics
  • Ovalbumin / immunology
  • Peptide Fragments / immunology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Ras Homolog Enriched in Brain Protein
  • Recombinant Fusion Proteins / immunology
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / deficiency
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / physiology*
  • Thymoma / immunology
  • Thymoma / therapy
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Carrier Proteins
  • Multiprotein Complexes
  • Neuropeptides
  • OVA-8
  • Peptide Fragments
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Ras Homolog Enriched in Brain Protein
  • Recombinant Fusion Proteins
  • Rheb protein, mouse
  • Tumor Necrosis Factor-alpha
  • rictor protein, mouse
  • Interferon-gamma
  • Ovalbumin
  • Deoxyglucose
  • TOR Serine-Threonine Kinases
  • Akt1 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • Monomeric GTP-Binding Proteins
  • Sirolimus