Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.

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

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

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-gamma. 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 (DeltaPsim) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved DeltaPsim and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on DeltaPsim, 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 DeltaPsim 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

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

Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function.

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

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

Vascular kinin B(1) and B(2) receptor-mediated effects in the rat isolated perfused kidney–differential regulations

1. Bradykinin (BK) and analogs acting preferentially at kinin B(1) or B(2) receptors were tested on the rat isolated perfused kidney. Kidneys were perfused in an open circuit with Tyrode's solution. Kidneys preconstricted with prostaglandin F(2α) were used for the analysis of vasodilator responses. 2. BK induced a concentration-dependent renal relaxation (pD(2)=8.9±0.4); this vasodilator response was reproduced by a selective B(2) receptor agonist, Tyr(Me)(8)-BK (pD(2)=9.0±0.1) with a higher maximum effect (E(max)=78.9±6.6 and 55.8±4.3% of ACh-induced relaxation respectively, n=6 and 19, P<0.02). Icatibant (10 nM), a selective B(2) receptor antagonist, abolished BK-elicited relaxation. Tachyphylaxis of kinin B(2) receptors appeared when repeatedly stimulated at 10 min intervals. 3. Des-Arg(9)-BK, a selective B(1) receptor agonist, induced concentration-dependent vasoconstriction at micromolar concentration. Maximum response was enhanced in the presence of lisinopril (1 μM) and inhibited by R 715 (8 μM), a selective B(1) receptor antagonist. Des-Arg(9)-[Leu(8)]-BK behaved as an agonist. 4. A contractile response to des-Arg(9)-BK occurred after 1 h of perfusion and increased with time by a factor of about three over a 3 h perfusion. This post-isolation sensitization to des-Arg(9)-BK was abolished by dexamethasone (DEX, 30 mg kg(−1) i.p., 3 h before the start of the experiment and 10 μM in perfusate) and actinomycin D (2 μM). Acute exposure to DEX (10 μM) had no effect on sensitized des-Arg(9)-BK response, in contrast to indomethacin (30 μM) that abolished it. DEX pretreatment however had no effect on BK-induced renal vasodilation. 5. Present results indicate that the main renal vascular response to BK consists of relaxation linked to the activation of kinin B(2) receptors which rapidly desensitize. Renal B(1) receptors are also present and are time-dependently sensitized during the in vitro perfusion of the rat kidneys