We have previously shown that CD4+ T cells from B6. Sle1Sle2. Sle3 lupus mice and patients present a high cellular metabolism, and a treatment combining 2-deoxy-d-glucose, which inhibits glucose metabolism, and metformin, which inhibits oxygen consumption, normalized lupus T cell functions in vitro and reverted disease in mice. We obtained similar results with B6. lpr mice, another model of lupus, and showed that a continuous treatment is required to maintain the beneficial effect of metabolic inhibitors. Further, we investigated the relative roles of glucose oxidation and pyruvate reduction into lactate in this process. Treatments of B6. Sle1Sle2. Sle3 mice with either 2-deoxy-d-glucose or metformin were sufficient to prevent autoimmune activation, whereas their combination was necessary to reverse the process. Treatment of B6. Sle1Sle2. Sle3 mice with dichloroacetate, an inhibitor of lactate production, failed to effectively prevent or reverse autoimmune pathology. In vitro, CD4+ T cell activation upregulated the expression of genes that favor oxidative phosphorylation. Blocking glucose oxidation inhibited both IFN-γ and IL-17 production, which could not be achieved by blocking pyruvate reduction. Overall, our data show that targeting glucose oxidation is required to prevent or reverse lupus development in mice, which cannot be achieved by simply targeting the pyruvate-lactate conversion.