Immunity 48, 542–55 (2018)

Mitochondria–endoplasmic reticulum (ER) interactions are known to modulate mitochondrial respiration in non-immune cells. In Immunity, Bantug et al. show that mitochondria–ER junctions in effector memory (EM) CD8+ T cells represent a signaling hub in which mTORC2–AKT–GSK3β signaling induces the oxidation of glucose to drive rapid production of the cytokine IFN-γ. More mitochondria–ER contacts are found in EM CD8+ T cells than in naive CD8+ T cells. Inhibition of GSK3β by mTORC2–AKT at these junctions allows recruitment of the kinase HK-I to the ion channel VDAC on the outer membrane of the mitochondria and the influx of substrates important for mitochondrial respiration. Destabilization of mitochondria–ER contracts or inhibition of the HK-1–VDAC interaction interferes with the rapid production of IFN-γ in activated EM CD8+ T cells through inhibition of glycolysis and, possibly, of glycolysis-dependent histone acetylation at the Ifng promoter.