Murine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor γ

Daniel J. Perry, Yiming Yin, Tiffany Telarico, Henry V. Baker, Igor Dozmorov, Andras Perl, Laurence Morel

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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-γ - 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.

Original languageEnglish (US)
Pages (from-to)793-803
Number of pages11
JournalJournal of Immunology
Volume189
Issue number2
DOIs
StatePublished - Jul 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Murine lupus susceptibility locus Sle1c2 mediates CD4<sup>+</sup> T cell activation and maps to estrogen-related receptor γ'. Together they form a unique fingerprint.

  • Cite this