Effector memory (EM) CD4(+) T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain ...bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4(+) T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4(+) T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4(+) T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4(+) T cells in normoxic and hypoxic conditions.
How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial ...infections and that these increased acetate concentrations are required for optimal memory CD8+ T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8+ T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8+ T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8+ T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8+ T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.
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•Serum acetate levels rapidly increase following systemic bacterial infection•Memory CD8+ T cells take up acetate and expand their acetyl-CoA pool•Increased acetyl-CoA levels catalyze functional activity of GAPDH by acetylation•Augmented glycolytic flux rates boost rapid recall responses of memory CD8+ T cells
How systemic metabolic alterations during acute infections impact immune-cell function remains poorly understood. Hess and colleagues demonstrate that acetate rapidly increases during infections, which drives acetylation of GAPDH in memory CD8+ T cells and thereby catalyzes the rapid recall response.
Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated ...human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ T cell effector function.
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•CD46 regulates GLUT1 and LAT1 and enhances glucose and AA uptake in T cells•LAMTOR5 mediates Ragulator-Rag-mTORC1 assembly in activated T cells•Complement drives glycolysis and oxidative phosphorylation critical to Th1 cell induction
The in vivo signals that drive metabolic reprograming of activated T cells remain poorly understood. Kemper and colleagues demonstrate that complement C3b enhances nutrient uptake and sensing in human T cells, enabling increased glycolysis and respiration required for Th1 responses.
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.
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•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.
Glycolysis is linked to the rapid recall capacity of memory CD8
+
T cells, but the pathways that glucose fuels and the molecular and subcellular structural elements enabling enhanced glucose ...metabolism in nascent activated memory CD8
+
T cells are not known. We found that mitochondria–ER contact sites are immunometabolic hubs that integrate mTORC2-initiated signaling with glucose metabolism and mitochondrial respiration in memory CD8
+
T cells. Specifically, in this subcellular compartment, mTORC2, Akt and Gsk-3β were present by default. Rapid activation of Akt by mTORC2 led to inhibition of Gsk-3β at mitochondria–ER junctions, enabling recruitment of hexokinase I (HK-I) to the mitochondrial channel, VDAC. Binding of HK-I to VDAC promoted cellular respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of IFN-γ in memory T cells. Subcellular organization of key signaling events enabling HK-I recruitment to VDAC thus underpins the metabolic reprogramming needed for memory CD8
+
T cells to rapidly acquire effector function.
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