title: Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs.
abstract: Memory CD8(+) T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8(+) T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8(+) T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen reexposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells while promoting short-lived effector cell differentiation. Transcriptome analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation, and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated glycolytic and oxidative metabolism in response to IL-15 stimulation. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8(+) T-cell development and function.
authors.affiliation: Department of Immunology and Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163.
authors.forename: Sharad
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Department of Immunology and.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Immunology and.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Immunology and.
authors.forename: Peer W F
authors.initials: PW
authors.lastname: Karmaus
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Immunology and Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163 hongbo.chi@stjude.org.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007156:Immunologic Memory / Q000235:genetics*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000941:Antigens; D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: T-cell memory; glycolysis; immune response; oxidative phosphorylation