Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development

Immunity. 2014 Jul 17;41(1):75-88. doi: 10.1016/j.immuni.2014.06.005. Epub 2014 Jul 4.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / genetics
  • Fatty Acids / biosynthesis
  • Fatty Acids / metabolism*
  • Glucose / metabolism
  • Immunologic Memory / immunology*
  • Interleukin-15 / immunology
  • Interleukin-2 / immunology
  • Lipolysis / genetics
  • Lipolysis / immunology*
  • Lymphocyte Activation / immunology
  • 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*

Substances

  • 4-methylene-2-octyl-5-oxofuran-3-carboxylic acid
  • Fatty Acids
  • Interleukin-15
  • Interleukin-2
  • RNA, Small Interfering
  • Fatty Acid Synthases
  • Protein Kinases
  • ATP-citrate lyase kinase
  • Sterol Esterase
  • Glucose
  • 4-Butyrolactone
  • Oxygen