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
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunity. 2014 Jul 17;41(1):75-88. doi: 10.1016/j.immuni.2014.06.005. Epub 2014 Jul 4.
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.
CD8(+) 记忆性T细胞的产生需要代谢重编程，其特征是线粒体脂肪酸氧化（FAO）增强。然而，为这一过程提供燃料的脂肪酸（FA）来源尚不清楚。虽然CD8(+) 记忆性T细胞在更大程度上参与脂肪酸氧化，但我们发现，与CD8(+) 效应T（Teff）细胞相比，它们从外部环境中获取的长链脂肪酸要少得多。记忆性T细胞并非直接使用细胞外脂肪酸，而是利用细胞外葡萄糖来支持脂肪酸氧化和氧化磷酸化（OXPHOS），这表明必须合成脂质以生成脂肪酸氧化所需的底物。我们已经证明，记忆性T细胞依赖溶酶体水解酶LAL（溶酶体酸性脂肪酶）的细胞内源性表达来动员脂肪酸进行脂肪酸氧化和记忆性T细胞发育。我们的观察结果将LAL与淋巴细胞的代谢重编程联系起来，并表明细胞内源性脂解作用对记忆性T细胞命运具有决定性作用。
