title: Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation.
abstract: The asymmetric partitioning of fate-determining proteins has been shown to contribute to the generation of CD8(+) effector and memory T cell precursors. Here we demonstrate the asymmetric partitioning of mTORC1 activity after the activation of naive CD8(+) T cells. This results in the generation of two daughter T cells, one of which shows increased mTORC1 activity, increased glycolytic activity and increased expression of effector molecules. The other daughter T cell has relatively low mTORC1 activity and increased lipid metabolism, expresses increased amounts of anti-apoptotic molecules and subsequently displays enhanced long-term survival. Mechanistically, we demonstrate a link between T cell antigen receptor (TCR)-induced asymmetric expression of amino acid transporters and RagC-mediated translocation of mTOR to the lysosomes. Overall, our data provide important insight into how mTORC1-mediated metabolic reprogramming affects the fate decisions of T cells.
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Pollizzi
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Im-Hong
authors.initials: IH
authors.lastname: Sun
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Chirag H
authors.initials: CH
authors.lastname: Patel
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Lo
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Oh
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Waickman
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ada J
authors.initials: AJ
authors.lastname: Tam
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Blosser
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wen
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002455:Cell Division / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006019:Glycolysis; D007156:Immunologic Memory; D050356:Lipid Metabolism; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011948:Receptors, Antigen, T-Cell; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases