Inhibition of distinct glycolytic enzymes produces differential effects on CD4 T cell function

Abstract Introduction: When T cells are activated, they upregulate glycolysis and take on a requisite Warburg phenotype. In this study, we evaluated the effect of inhibiting two distinct glycolytic enzymes, GAPDH PGAM, CD4 cell differentiation. Methods/Results: Using inhibitor heptelidic acid, found that inhibition produces potent anti-inflammatory phenotype in Th1 cells, significantly reducing IFNγ expression. We further showed metabolite methylglyoxal, which is necessary for its effect. also produced effects vivo, as acid reduced disease severity altered immune subsets therapeutic treatment paradigm MOG 35–55EAE model multiple sclerosis. Furthermore, enhances Treg polarization, while downstream enzyme, potently blocked polarization. Additionally, PGAM increases serine biosynthesis subsequently alters 1-carbon metabolism. gene expression associated with differentiation response to immunotherapy lung cancer patients. Conclusion: Overall, our vitroand vivoresults indicate targeting enzyme an via methylglyoxal pathway, opposite regulation synthesis. Our findings suggest functional consequences depend specific enzymes targeted, represent promising novel targets immunological disease. This work was supported by NIH/NINDS grant K08NS104266 Conrad N. Hilton Foundation Marilyn Bridging Award Physician Scientists 17316 MDK. WHG NIH MSTP Grant T32 GM136577 American Association Immunologists’ Careers Immunology Fellowship Program.