title: mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation.
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.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Pollizzi
authors.forename: Chirag H
authors.initials: CH
authors.lastname: Patel
authors.forename: Im-Hong
authors.initials: IH
authors.lastname: Sun
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Oh
authors.forename: Adam T
authors.initials: AT
authors.lastname: Waickman
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wen
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D017930:Genes, Reporter; D006019:Glycolysis / Q000187:drug effects; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D038041:Lymphopoiesis / Q000502:physiology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics; D046912:Multiprotein Complexes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076205:Ras Homolog Enriched in Brain Protein; D011993:Recombinant Fusion Proteins / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013945:Thymoma / Q000276:immunology / Q000628:therapy; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; C110366:OVA-8; D010446:Peptide Fragments; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076205:Ras Homolog Enriched in Brain Protein; D011993:Recombinant Fusion Proteins; C490213:Rheb protein, mouse; D014409:Tumor Necrosis Factor-alpha; C525637:rictor protein, mouse; D007371:Interferon-gamma; D010047:Ovalbumin; D003847:Deoxyglucose; C514862:Akt1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus