Regulation of T cell metabolism and autoimmunity by the orphan nuclear receptor ERRγ (123.47)

Abstract

Abstract Autoreactive T cells and abnormal cytokine production are key features of human and mouse systemic lupus erythematosus (SLE). The SLE susceptibility locus Sle1c2 is associated with CD4+ T cell hyperactivation, hyperproliferation and hyperproduction of IFNγ in the NZM2410 mouse model. Sle1c2 contains two genes, only one of which, Esrrg, is expressed in mouse CD4+ T cells. qRT-PCR and Western blot analysis showed that Esrrg is expressed in CD4+ T cells, albeit at a low level. Esrrg expression is significantly decreased in B6.Sle1c2 CD4+ T cells as compared to B6, and negatively correlates with T cell activation. In vitro, Esrrg expression is dramatically decreased after CD4+ T cells are stimulated with anti-CD3/CD28. These data suggest that Esrrg is required to maintain T cells in a quiescent state. Esrrg is a key regulator of cell metabolism. Consistently, Sle1c2 is associated with increased expression of genes involved in the glycolytic pathway, such as MCT4 and Hif1a, which have been previously associated with enhanced T cell effector functions. Sle1c2 is also associated with a decreased mitochondrial mass and functions, which is consistent with Esrrg playing a key role in these processes. Furthermore, treatment of CD4+ T cells with ERRγ agonist and reverse agonist affects T cell survival, proliferation, Foxp3 expression, and IL-2 and IFNγ production. Our study suggests that decreased Esrrg expression contributes to T cell autoimmunity through regulating cell metabolism.