Murine Lupus Susceptibility Locus Sle1c2 Mediates CD4 T Cell Activation and Maps to Estrogen-Related Receptor g

Sle1c is a sublocus of the NZM2410-derived Sle1 major lupus susceptibility locus. We have shown previously that Sle1c contributes to lupus pathogenesis by conferring increased CD4 + T cell activation and increased susceptibility to chronic graft-versus-host disease (cGVHD), which mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675-kb interval, termed Sle1c2. Mice from recombinant congenic strains expressing Sle1c2 exhibited increased CD4 + T cell intrinsic activation and cGVHD susceptibility, similar to mice with the parental Sle1c. In addition, B6.Sle1c2 mice displayed a robust expansion of IFN-g–expressing T cells. NZB complementation studies showed that Sle1c2 expression exacerbated B cell activation, autoantibody production, and renal pathology, verifying that Sle1c2 contributes to lupus pathogenesis. The Sle1c2 interval contains two genes, only one of which, Esrrg, is expressed in T cells. B6.Sle1c2 CD4 + T cells expressed less Esrrg than B6 CD4 + T cells, and Esrrg expression was correlated negatively with CD4 + T cell activation. Esrrg encodes an orphan nuclear receptor that regulates oxidative metabolism and mitochondrial functions. In accordance with reduced Esrrg expression, B6. Sle1c2 CD4 + T cells present reduced mitochondrial mass and altered mitochondrial functions as well as altered metabolic pathway utilization when compared with B6 CD4 + T cells. Taken together, we propose Esrrg as a novel lupus susceptibility gene regulating CD4 + T cell function through their mitochondrial metabolism. T he murine NZM2410 strain spontaneously develops an autoimmune disease that mimics systemic lupus eryth-ematosus (SLE), including the presence of anti-nuclear autoantibody, immune activation, and immune-complex–induced glomerulonephritis (GN). Derived from the classic (NZB 3 NZW) F 1 (NZB/W F 1) lupus model, it has an advantage over its parental strains in that it is homozygous, making it an ideal model to identify novel genetic determinants of lupus (1). Linkage analysis of NZM2410 to GN identified the major lupus susceptibility locus Sle1 as an NZW-derived interval on telomeric chromosome 1 (2). This region overlaps with syntenic human SLE quantitative trait loci, 1q22–23 and 1q41–42, suggesting that similar genetic factors may mediate pathogenesis in both species (3). Subsequent studies using congenic mice demonstrated distinct functional requirements that Sle1 imparted in the induction of murine lupus. Specifically, B6.Sle1 mice display B and T cell intrinsic loss of tolerance to chromatin (4–6). Furthermore, complementation analyses with the other NZM2410-derived SLE susceptibility loci (7) and with the NZW genome (8) demonstrated that …