CD4 T cell metabolism in SLE: characterization and target identification
CD4+ T cells play a crucial role in lupus pathogenesis by providing help to B cells to secrete class-switched pathogenic autoantibodies. Recently, metabolic substrate utilization has been identified as a major determinant of T cell effector functions, with aerobic glycolysis being required for activation into Th1 and Th17 subsets, while Tregs rely of fatty acid oxidation. In the lupus-prone NZM2410 mouse, we have determined that a genetic locus, Sle1c2, leads to the production of autoreactive CD4+ T cells and an increased aerobic glycolysis to the expense of oxidative phosphorylation. We have determined that Sle1c2 corresponds to the reduced expression of Esrrg, a nuclear receptor known to regulate mitochondrial biogenesis and fatty acid oxidation in other tissues. Based on our results and the recent literature, we hypothesize that a reduced Esrrg expression limits oxidative lipid metabolism that fuels naïve T cells, and favors glycolysis that is required by activated effector T cells that induce the production of pathogenic autoantibodies. We hypothesize that dysregulation of T cell metabolism plays an important role in lupus pathogenesis. Our genetic model of reduced Esrrg expression and our access to lupus patients constitute a unique approach to test this hypothesis with the three following specific aims:
1. To determine how Esrrg regulates CD4+ T cell metabolism and contribute to lupus in a mouse model
2. To determine whether inhibitors of glucose metabolism can prevent and reverse lupus in the mouse
3. To determine whether CD4+ T cell metabolism is altered in lupus patients and whether it correlates with Esrrg expression
We have on hand all the reagents necessary to achieve these aims, and, in addition to our published results, we have obtained strong preliminary results supporting our hypothesis.
The results obtained from this project will characterize a novel pathway that regulate autoreactive T cells in lupus and identify novel therapeutic targets.