Investigating The Molecular Mechanisms Of The Metabolic Control Of T Cell Migration and Functions: Lactate controls pro-inflammatory T cell migration and function

Abstract

Lactate has long been considered a "waste"-by-product of cellular metabolism, and it is known to accumulate in inflammatory sites. Recent findings have suggested lactate as signaling metabolite, yet its effects on immune cells during inflammation are largely unexplored. This project hence aimed to examine the effects of extracellular lactate on the function of T cells. I found that the elevated concentration of lactate present in synovia of rheumatoid arthritis (RA) patients inhibits the migration of CD4+ and CD8+ T cells, mediated via the subtype specific transporters Slc5a12 and Slc16a1, respectively. In addition, lactate decreases the cytolytic activity in CD8+ and induces the production of IL-17 in CD4+ T cells. Intracellular, lactate causes a change in redox state, the increase of TCA-cycle metabolites, the production of ROS and a drop in ATP levels. Concomitantly, I found a decrease of glycolysis and oxidative phosphorylation with no effect on fatty acid metabolism. This metabolic inhibition caused an adaptation attempt to rescue the glycolytic flux due to the relocation of HK1 to the mitochondrial membrane. I further show that the lactate-mediated reduction of glycolysis is the cause for the observed migratory inhibition in CD4+ T cells, possibly mediated by the NAD+- dependent enzymes SIRT1 and PARP1. Similarly, I found the lactate-induced IL-17 production to be dependent on NAD metabolism, fatty acid synthesis and FOXO1. Finally, I could causatively link lactate signaling to chronic T cell infiltrates in RA, as I show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of RA patients. Pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in a model of peritonitis. These findings establish lactate as active signaling metabolite that contributes to the perpetuation of chronic inflammation and provide novel therapeutic approaches to combat chronic inflammatory diseases.