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

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.

Immunometabolism: From basic mechanisms to translation

“…While effector T cells induce aerobic glycolysis, it was shown that memory T cells instead rely on mitochondrial metabolism and lipid oxidation 18,19 but can rapidly revert to glycolysis upon restimulation through endoplasmic reticulummitochondrial direct interactions that serve as metabolic hubs. 20 Unlike effector T cell subsets, regulatory T cells (Tregs) do not require GLUT1 or high levels of glutamine uptake through the amino acid transporter ASCT2 21,22 and instead predominantly rely on mitochondrial lipid, pyruvate, and lactate oxidation. 10,[23][24][25] Tregs can be highly glycolytic, but the primary Treg transcription factor, FoxP3, has also been shown to repress glycolysis and high rates of glucose metabolism can impair Treg suppressive capacity.…”

The metabolic spectrum of memory T cells

“…Initial studies highlighting the importance of the transition from highly anabolic effector T‐cell populations to more quiescent memory T populations, demonstrated that development of memory T‐cell populations in mice were contingent on the limitation of aerobic glycolysis and the engagement of mitochondrial OXPHOS . Robust mitochondrial metabolism has also been linked to rapid recall abilities of memory T cells following antigen restimulation …”

“…2,24 Robust mitochondrial metabolism has also been linked to rapid recall abilities of memory T cells following antigen restimulation. 52,53 Memory T cells have distinct mitochondrial morphology from effector T cells, which can contribute to their metabolism and function. Both T CM and IL-15 derived memory T cells have tighter cristae formation, 54 which has been linked to more efficient OXPHOS.…”

Endoplasmic Reticulum redox pathways: in sickness and in health

“…Bantug et al . have shown that memory CD8+ T cells use mitochondria–ER contact sites as a hub to drive rapid glycolytic remodelling, facilitating the increase in demand for glucose oxidation after IFNγ stimulation in response to an infection . The ER acts as a scaffold in this set‐up: it positions mTORC2‐AKT signalling so that pAKT can phosphorylate and inhibit GSK3β.…”

“…Immunologists have recently turned their attention ERmitochondrial contact sites too, having appreciated that metabolic reprogramming can control the activation of T lymphocytes and influence their development into either regulatory or cytotoxic/helper effector subtypes [57]. Bantug et al have shown that memory CD8+ T cells use mitochondria-ER contact sites as a hub to drive rapid glycolytic remodelling, facilitating the increase in demand for glucose oxidation after IFNc stimulation in response to an infection [58]. The ER acts as a scaffold in this set-up: it positions mTORC2-AKT signalling so that pAKT can phosphorylate and inhibit GSK3b.…”