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

David O'Sullivan, Gerritje W.J. vanderWindt, Stanley Ching Cheng Huang, Jonathan D. Curtis, Chih Hao Chang, Michae D.L. Buck, Jing Qiu, Amber M. Smith, Wing Y. Lam, Lisa M. DiPlato, Fong Fu Hsu, Morris J. Birnbaum, Edward J. Pearce, Erika L. Pearce

Research output: Contribution to journalArticlepeer-review

442 Scopus citations

Abstract

Generation of CD8+ memory Tcells 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 Tcells 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 Tcells 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 Tcells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory Tcell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory Tcell fate.

Original languageEnglish
Pages (from-to)75-88
Number of pages14
JournalImmunity
Volume41
Issue number1
DOIs
StatePublished - Jul 17 2014

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