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

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. [Display omitted] •mTORC2, AKT, and GSK3β are present at mitochondria-ER contact sites of CD8+ T cells•mTORC2-activated AKT inhibits GSK3β in nascent activated memory CD8+ T cells•GSK3β inhibition enables binding of HK-I to VDAC, promoting pyruvate oxidation•Pyruvate oxidation is required for rapid generation of IFN-γ in memory T cells How glucose metabolism enables rapid acquisition of effector function in memory CD8+ T cells remains poorly understood. Bantug et al. demonstrate that mitochondria-endoplasmic reticulum contact sites are signaling hubs that enable the metabolic reprogramming required for rapid CD8+ T cell recall responses.