The Goldilocks Principle conferred by LDH isoenzymes controls murine T cell glycolysis and differentiation

Isoenzyme divergence is a prevalent mechanism governing tissue-specific and developmental stage-specific metabolism in mammals. The isoenzyme pattern (spectrum) of lactate dehydrogenase (LDH) reflects the status of glucose metabolism in different organs such as muscle, liver, and heart. T cells are highly dependent on glucose metabolism for survival, proliferation, and differentiation. However, the LDH isoenzyme spectrum in T cells and its potential impact on T cell-mediated immune response remain unclear. Here, we discovered that the LDH spectrum in murine T cells is characterized by three tetrameric isoenzymes composed of LDHA and LDHB (LDH-3/4/5). Genetic deletion of LDHA or LDHB altered the isoenzyme spectrum by removing all heterotetramers and leaving T cell with LDH-1 (the homotetramer of LDHB) or LDH-5 (the homotetramer of LDHA), respectively. Accordingly, altering the isoenzyme spectrum by deleting LDHA or LDHB compromises T cell metabolic fitness and effector cell differentiation in vivo. Unexpectedly, deleting LDHA suppressed glycolysis, whereas deleting LDHB further enhanced it, indicating that an optimal zone of glycolytic activity is critical to driving effector T cell differentiation. Mechanistically, the LDH isoenzyme spectrum imposed by LDHA and LDHB is required to optimize glycolysis to maintain a balanced NAD+/NADH pool, a hallmark of metabolic fitness. Together, our results suggest that the LDH isoenzyme spectrum enables "Goldilocks levels" of glycolytic and redox activity (i.e., not too high, not too low, but just right) to control T cell differentiation function.