title: Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development.
abstract: Generation of CD8(+) memory T cells requires metabolic reprogramming that is characterized by enhanced mitochondrial fatty-acid oxidation (FAO). However, where the fatty acids (FA) that fuel this process come from remains unclear. While CD8(+) memory T cells engage FAO to a greater extent, we found that they acquired substantially fewer long-chain FA from their external environment than CD8(+) effector T (Teff) cells. Rather than using extracellular FA directly, memory T cells used extracellular glucose to support FAO and oxidative phosphorylation (OXPHOS), suggesting that lipids must be synthesized to generate the substrates needed for FAO. We have demonstrated that memory T cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory T cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory T cell fate.
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David
authors.initials: D
authors.lastname: O'Sullivan
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gerritje J W
authors.initials: GJ
authors.lastname: van der Windt
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Stanley Ching-Cheng
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Curtis
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Buck
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wing Y
authors.initials: WY
authors.lastname: Lam
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DiPlato
authors.affiliation: Mass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: erikapearce@path.wustl.edu.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Pearce
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008066:Lipolysis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D002787:Sterol Esterase / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D005227:Fatty Acids; D019409:Interleukin-15; D007376:Interleukin-2; D034741:RNA, Small Interfering; D064429:Fatty Acid Synthases; D011494:Protein Kinases; C032202:ATP-citrate lyase kinase; D002787:Sterol Esterase; D005947:Glucose; D015107:4-Butyrolactone; D010100:Oxygen