The role of lactate in CD4+ T cell differentiation and function
In nature, lactate can be found in two different enantiomeric forms, D- and L-lactate. The only difference between both molecules is the rotation angle of one asymmetric carbon atom. However, distinct biological activities and metabolic pathways originate and process one or the other enantiomeric form, respectively. L-lactate is the final metabolite produced from glycolysis, whereas D-lactate arises from methylglyoxal’s detoxification through the glyoxalase system. Although under homeostasis tissular lactate levels are low, during the course of inflammatory processes and cancer development concentrations of both lactates can considerably increase. While L-lactate has been already studied in the context of CD4+ T cells differentiation, nothing was known about the less abundant D- enantiomeric form until now. By supplementing in vitro cultures of Th1 and Th2 cells with exogenous D- or L-lactate, we describe for the first time D-lactate’s enormous potential to enhance Th1 and Th2 functionality. Moreover, addition of either lactate to already differentiated Th1 cells increased expression of several key cytotoxic genes. D-lactate treated Th1 cells greatly upregulated expression of RUNX3, Eomes, GZMB and Perf-1, whereas L-lactate samples showed a more discreet effect. Lactate addition impacted histone acetylation state and metabolic activities like OXPHOS and glycolysis. However, none of these parameters were responsible for D-lactate’s ability to upregulate cytokine production. Differential ROS regulation upon D- or L-lactate treatment was the source of the observed phenotypical differences. D-lactate reduced mitochondrial ROS levels by increasing the activity of the glyoxalase’s pathway. Conversely, L-lactate metabolization increased mitochondrial ROS, thereby impairing cytokine production. Additionally, D-lactate enhanced mTORC1 and ERK signaling, which are both partially responsible for the cytokine burst induced by this enantiomer. mTORC1 increased IFN-g production, whereas ERK was partially responsible for GZMB and Perf-1 upregulation.
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