The Microbial Metabolite, D-lactate, Stimulates Mitochondrial β-oxidation to Enhance CD4+ T cell Effector Function 9312

Abstract Description Microbial production of novel metabolites has been proposed to influence mammalian immune responses. Previous studies have demonstrated that one such metabolite, D-lactate, the stereoisomer of L-lactate, modulates CD8+ cytotoxic T cell function by stimulating mitochondrial electron transport chain activity, enhancing oxidative phosphorylation, and increasing ATP synthesis. To investigate whether D-lactate exerts a similar effect on helper T cells, we examined D-lactate’s effect on cytokine production and effector functions of CD4+ T cells. Our findings revealed a dose-dependent increase in cytokine production in CD4+ T cells treated with D-lactate. The effects of D-lactate are independent of its use as a bioenergetic substrate. Mechanistically, D-lactate treatment promoted β-oxidation. Enhanced cytokine production resulted from increased protein synthesis, dependent on increased oxidative phosphorylation and induction of a phosphate energy shuttle system using creatine phosphate. In a murine adoptive T cell transfer colitis model, D-lactate treatment exacerbated weight loss and increased pro-inflammatory cytokine production. Together, these findings suggest that microbial metabolites such as D-lactate function as signaling molecules to promote inflammation, underscoring the critical yet underappreciated role of ATP production in supporting cytokine translation, release, and cytotoxic granule formation. Funding Sources MSKCC - Craig Thompson Lab Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)