Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
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.
['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|']
nicotinamide adenine dinucleotide 3-phosphoglycerate serine T cell metabolism glycolysis immunometabolism lactate metabolism redox metabolism