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.

• Authors: William J Quinn 3rd, Jing Jiao, Tara TeSlaa, Jason Stadanlick, Zhonglin Wang, Liqing Wang, Tatiana Akimova, Alessia Angelin, Patrick M Schäfer, Michelle D Cully, Caroline Perry, Piotr K Kopinski, Lili Guo, Ian A Blair, Louis R Ghanem, Michael S Leibowitz, Wayne W Hancock, Edmund K Moon, Matthew H Levine, Evgeniy B Eruslanov, Douglas C Wallace, Joseph A Baur, Ulf H Beier
• Journal: Cell reports (Cell Rep) Vol. 33 Issue 11 Pg. 108500 (12 15 2020) ISSN: 2211-1247 [Electronic] United States
• PMID: 33326785 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• NAD
• Lactic Acid

Topics

• Cell Proliferation
• Humans
• Lactic Acid (metabolism)
• NAD (metabolism)
• Oxidation-Reduction