Microbial Metabolite D-Lactate Enhances CD4+ T Cell Effector Function by Rewiring Metabolism Independently of Its Catabolism 2255554

Abstract Introduction Lactate profoundly influences immune cell metabolism and function by stimulating mitochondrial oxidative phosphorylation and enhancing ATP production. The effects of D-lactate on CD4+ T helper cells remain largely unexplored. Since D-lactate is produced not only in trace amounts by mammalian cells but also by gut microbiota, elucidating how it modulates T helper cell responses may reveal fundamental mechanisms of immune regulation and provide insight into disease processes such as cancer. Methods In Vitro T Cell Activation and Treatment. Metabolic Assays. Genetic Mouse Model. In Vivo Tumor Control Studies. Functional and Phenotypic Analyses. Gene Perturbation Studies. Results D-lactate enhances CD4+ T cell cytokine production in vitro and improves tumor control in vivo, which depends on mitochondrial oxidative phosphorylation and preferential fatty acid utilization. The creatine kinase energy shuttle is essential for ATP delivery in D-lactate-treated cells, and disruption of this pathway markedly diminishes D-lactate—induced effects. Using a conditional knockout mouse model of its cognate enzyme, Lactate Dehydrogenase D (LDHD), we show that LDHD is dispensable, demonstrating that the effects are a direct consequence of D-lactate and not a downstream metabolite. Finally, a surprising finding is that D-lactate-treated CD4+ T cells display a cytotoxic phenotype, producing significantly higher levels of perforin and granzyme B, and exhibit enhanced antigen-specific killing in vitro. This enhanced cytotoxicity depends on oxidative phosphorylation and the creatine kinase system and can be inhibited by blocking another strongly induced gene, fascin. Conclusion Together, these findings demonstrate that the microbial metabolite D-lactate enhances CD4+ T cell cytokine production and effector function by rewiring cellular metabolism. Both of these effects enhance the ability of CD4+ T cells to mount an efficient immune response at sites of D-lactate accumulation. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)