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Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
- Source :
-
Cell reports [Cell Rep] 2020 Dec 15; Vol. 33 (11), pp. 108500. - Publication Year :
- 2020
-
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 <superscript>+</superscript> ), 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 <superscript>+</superscript> -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.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Proliferation
Humans
Oxidation-Reduction
Lactic Acid metabolism
NAD metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 33
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 33326785
- Full Text :
- https://doi.org/10.1016/j.celrep.2020.108500