It is well known that some pathogenic cells have enhanced glycolysis; the regulatory network leading to increased glycolysis are not well characterized. In this study, we show that CNS-infiltrated pathogenic T17 cells from diseased mice specifically upregulate glycolytic pathway genes compared with homeostatic intestinal T17 cells. Bioenergetic assay and metabolomics analyses indicate that in vitro-derived pathogenic T17 cells are highly glycolytic compared with nonpathogenic T17 cells. Chromatin landscape analyses demonstrate T17 cells in vivo that show distinct chromatin states, and pathogenic T17 cells show enhanced chromatin accessibility at glycolytic genes with NF-κB binding sites. Mechanistic studies reveal that targets the E3 ubiquitin ligase -c-Rel pathway to promote glucose metabolism of pathogenic T17 cells. Therapeutic targeting c-Rel-mediated glycolysis in pathogenic T17 cells represses autoimmune diseases. These findings extend our understanding of the regulation T17 cell glycolysis in vivo and provide insights for future therapeutic intervention to T17 cell-mediated autoimmune diseases.