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

Abstract

Summary Generation of CD8+ memory T (TM) 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. We found that while CD8+ TM cells engaged higher levels of FAO, they acquired substantially fewer long-chain FA from their external environment than CD8+ effector T (TE) cells. Rather than using extracellular FA directly, TM 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 TM cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and TM cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for TM cell fate.

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…This concurrent flux through fatty acid synthesis and oxidation occurs normally in non-hepatic tissue as an adaptive mechanism to promote substrate utilization and increase cellular metabolic rate (Solinas et al 2004, Mottillo et al 2014, O'Sullivan et al 2014. Like in fatty liver, this simultaneous induction of lipogenesis and oxidation is proposed to be dependent upon diminished ACC2-generated malonyl-CoA and submaximal CPT1 inhibition (Yu et al 2002).…”

Tissue-resident memory T cells live off the fat of the land

“…Contraction and memory formation sees a return to metabolic quiescence dominated by OXPHOS [6]. However, unlike naive T cells reliant on glucose, circulating memory T cells utilize endogenously synthesized fatty acids for OXPHOS [7,8]. The metabolic substrates used by T rm cells for OXPHOS were previously unknown.…”

InterFeriNg with Acetγlation: Stress-Levels of Acetate Improve Memory T Cell Function

“…Exactly why cells respond to acetate in this way, however, remains unclear. It has been previously demonstrated that CD8 + memory T cells engage in a futile cycle of fatty acid synthesis and oxidation in order to support quiescence, as well as retain the ability to rapidly mount a reactivation response (O'Sullivan et al, 2014). Whether acetate exposure promotes this phenotype as another way to promote memory cell fate will be an interesting question for future study.…”

“…Increased GAPDH activity might also contribute to enhanced glycolysis that accompanies T cell activation. Although ACSS1 and ACLY were implicated in the production of IFN-g, it is also possible that a second pool of acetate is activated in the cytosol by ACSS2, which could then be used to support fatty acid synthesis (FAS), as well as fatty acid oxidation (FAO), a mechanism that has also been shown to occur in memory T cells (O'Sullivan et al, 2014). CS, citrate synthase; PDH, pyruvate dehydrogenase; FAS, fatty acid synthesis; FAO, fatty acid oxidation; ACSS1, acetyl-CoA synthetase 1; ACSS2, acetyl-CoA synthetase 2; GAPDH, glycerol-3-phosphate dehydrogenase; IFN-g, interferon-g; ACLY, ATP-citrate lyase; OAA, oxaoloacetate.…”