Fig. 3.

NAD⁺ regulates T cell fates through environmental lactate. SLC5A12-mediated lactate uptake into CD4⁺ T cells in the inflamed tissue reshapes their effector phenotypes, resulting in RORγt activation and subsequent IL-17 transcription via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to these renascent Th17 cell retention in the inflamed tissue as a result of reduced glycolysis and enhanced fatty acid synthesis. On the other hand, the continuous lactate catabolism through lactate dehydrogenase consumes amounts of NAD⁺ contents. The insufficient NAD⁺ pools cannot sustain NAD⁺-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). The dysfunction of GAPDH and PGDH leads to the depletion of post-GAPDH glycolytic intermediates and the 3-phosphoglycerate derivative serine that are important fuels for T cell proliferation. The environmental lactate eventually suppresses effector T cell proliferation.