Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. We have assessed the response of immune cells to lactate in the context of chronic inflammation. We recently reported that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Our findings suggest that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of diseases characterised by an inflammatory CD4+ T cell component, such as lymphoid synovitis in rheumatoid arthritis patients, and a potential therapeutic target in chronic inflammatory disorders.
