Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs that Orchestrate the Rapid Recall Response of Memory CD8+ T Cells

Immunity. 2018 Mar 20;48(3):542-555.e6. doi: 10.1016/j.immuni.2018.02.012. Epub 2018 Mar 6.

Abstract

Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3β at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8+ T cells to rapidly acquire effector function.

Keywords: Akt; GSK3-beta; IFN-gamma; VDAC; endoplasmic reticulum; glycolysis; hexokinase; mTOR; memory CD8(+) T cells; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Respiration
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Energy Metabolism*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Glycolysis
  • Immunologic Memory*
  • Intracellular Membranes / metabolism
  • Lymphocyte Activation
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Models, Biological
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein / deficiency
  • Signal Transduction*

Substances

  • Rapamycin-Insensitive Companion of mTOR Protein
  • Glycogen Synthase Kinase 3 beta
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt