Systemic Lupus Erythematosus (SLE) is a complex rheumatic disease driven in part through inappropriate CD4 T cell activity. In particular, effector CD4 T cells (Teff; Th1, Th2, and Th17) drive SLE pathology, while regulatory CD4 T cells (Treg) are protective. A key therapeutic objective is to identify selective differences between these subsets to inhibit Teff and promote Treg function. Based on our findings that Teff and Treg utilize and require distinct metabolic programs, we propose that T cell metabolism provides a new opportunity to modulate CD4 subsets to treat SLE. Specifically, we have shown Teff have high expression of the glucose transporter, Glut1, and pyruvate dehydrogenase kinase (PDHK) and utilize a glycolytic metabolism similar to that of many cancer cells. Treg, in contrast, have low expression of Glut1 and PDHK and primarily oxidize lipids. We have used T cell specific Glut1 conditional knockouts to show that Teff require Glut1, but Treg are Glut1-independent. While mitochondria from SLE patient T cells can be hyperpolarized, the mechanisms and how to target this metabolic dysfunction to selectively impair Teff in SLE are unknown. To address this gap and potential therapeutic target opportunity, we propose to test the hypothesis that glucose metabolism is selectively regulated to promote Teff function in SLE. Further, targeting the metabolic program of Teff will promote Treg function and protect from SLE. To test this hypothesis we will define the metabolic characteristics and dependencies of T cells in SLE models and test two potential metabolic targets to treat SLE. (1) We will determine the glucose dependencies of Teff and Treg in SLE by direct metabolic measurements on T cells from NZB/NZW and Baff-transgenic mouse SLE models and the Glut1-dependence of T cell subsets in SLE using Glut1 conditional knockout mice. (2) We will test the role of ERRalpha (NR3b1) to promote aerobic glycolysis of T cells and oppose the related transcription factor, ERRgamma (NR3b3) in SLE. NR3b1 has been shown to drive aerobic glycolysis in cancer and we reported a similar role in T cell activation to regulate pyruvate metabolism. Further, loss of NR3b3 can increase glycolysis and predispose to SLE and we will test if loss of NR3b1 promotes NR3b3 function to protect from SLE. (3) We will establish the impact of PDHK inhibition to promote oxidation on pyruvate on T cell subsets and SLE. Targeting PDHK is promising in cancer therapy and we show the PDHK inhibitor dichloroacetate (DCA) selectively targets Teff and promotes Treg. This pathway is also regulated by NR3b1 and we will determine how DCA impacts T cell subsets and SLE. Together, these studies will apply our unique animal models and expertise to examine T cell metabolism in SLE and directly test mechanisms of metabolic regulation and checkpoints in CD4 T cell specification to provide new directions for SLE therapy.