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Lactate Limits T Cell Proliferation via the NAD(H) Redox State.

ABSTRACT: Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD⁺), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD⁺-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression.

SUBMITTER: Quinn WJ

PROVIDER: S-EPMC7830708 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Lactate Limits T Cell Proliferation via the NAD(H) Redox State.

Quinn William J WJ Jiao Jing J TeSlaa Tara T Stadanlick Jason J Wang Zhonglin Z Wang Liqing L Akimova Tatiana T Angelin Alessia A Schäfer Patrick M PM Cully Michelle D MD Perry Caroline C Kopinski Piotr K PK Guo Lili L Blair Ian A IA Ghanem Louis R LR Leibowitz Michael S MS Hancock Wayne W WW Moon Edmund K EK Levine Matthew H MH Eruslanov Evgeniy B EB Wallace Douglas C DC Baur Joseph A JA Beier Ulf H UH

Cell reports 20201201 11

Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD<sup>+</sup>), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD<sup>+</sup>-d ...[more]

PMID: 33326785

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Project description:The relationship between the redox state and lactate accumulation in contracting human skeletal muscle was investigated. Ten men performed bicycle exercise for 10 min at 40 and 75% of maximal oxygen uptake [VO2(max.)], and to fatigue (4.8 +/- 0.6 min; mean +/- S.E.M.) at 100% VO2(max.). Biopsies from the quadriceps femoris muscle were analysed for NADH, high-energy phosphates and glycolytic intermediates. Muscle NADH was 0.20 +/- 0.02 mmol/kg dry wt. of muscle at rest, and decreased to 0.12 +/- 0.01 (P less than 0.01) after exercise at 40% VO2(max.), but no change occurred in the [lactate]/[pyruvate] ratio. These data, together with previous results on isolated cyanide-poisoned soleus muscle, where NADH increased while [lactate]/[pyruvate] ratio was unchanged [Sahlin & Katz (1986) Biochem. J. 239, 245-248], suggest that the observed changes in muscle NADH occurred within the mitochondria. After exercise at 75 and 100% VO2(max.), muscle NADH increased above the value at rest to 0.27 +/- 0.03 (P less than 0.05) and 0.32 +/- 0.04 (P less than 0.001) mmol/kg respectively. Muscle lactate was unchanged after exercise at 40% VO2(max.), but increased substantially at the higher work loads. At 40% VO2(max.), phosphocreatine decreased by 11% compared with the values at rest, and decreased further at the higher work loads. The decrease in phosphocreatine reflects increased ADP and Pi. It is concluded that muscle NADH decreases during low-intensity exercise, but increases above the value at rest during high-intensity exercise. The increase in muscle NADH is consistent with the hypothesis that the accelerated lactate production during submaximal exercise is due to a limited availability of O2 in the contracting muscle. It is suggested that the increases in NADH, ADP and Pi are metabolic adaptations, which primarily serve to activate the aerobic ATP production, and that the increased anaerobic energy production (phosphocreatine breakdown and lactate formation) is a consequence of these changes.

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Lactate Limits T Cell Proliferation via the NAD(H) Redox State.

Publications

Lactate Limits T Cell Proliferation via the NAD(H) Redox State.

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