Memory CD8+ T Cells Use Cell-Intrinsic Lipolysis to Support the Metabolic Programming Necessary for Development

• Published in: Immunity (Cambridge, Mass.) Vol. 41; no. 1; pp. 75 - 88
• Main Authors: O’Sullivan, David, van der Windt, Gerritje J.W., Huang, Stanley Ching-Cheng, Curtis, Jonathan D., Chang, Chih-Hao, Buck, Michael D., Qiu, Jing, Smith, Amber M., Lam, Wing Y., DiPlato, Lisa M., Hsu, Fong-Fu, Birnbaum, Morris J., Pearce, Edward J., Pearce, Erika L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.07.2014; Elsevier Limited
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; Adoptive Transfer; Animals; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Experiments; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - genetics; Fatty Acids - biosynthesis; Fatty Acids - metabolism; Glucose; Glucose - metabolism; Immunologic Memory - immunology; Interleukin-15 - immunology; Interleukin-2 - immunology; Lipids; Lipolysis - genetics; Lipolysis - immunology; Lymphocyte Activation - immunology; Lymphocytes; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria - metabolism; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen - metabolism; Protein Kinases - genetics; RNA Interference; RNA, Small Interfering; Sterol Esterase - biosynthesis; Sterol Esterase - metabolism
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2014.06.005

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. [Display omitted] •Unlike Teff cells, memory T cells do not acquire substantial amounts of long-chain FA•Glucose supports mitochondrial FAO and OXPHOS in memory T cells•Memory T cells use LAL-mediated cell-intrinsic lipolysis to mobilize FA for FAO•T cell-intrinsic lysosomal lipolysis is important for memory T cell development CD8+ memory T cells engage fatty-acid oxidation (FAO); however, the source of fatty acids that fuel FAO is unclear. O’Sullivan et al. show that memory T cells rely on glucose, and cell-intrinsic lipolysis to mobilize substrates, for FAO.