Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism

Wei Li, Minghao Gong, Yuk Pheel Park, Ahmed S. Elshikha, Seung Chul Choi, Josephine Brown, Nathalie Kanda, Wen I. Yeh, Leeana Peters, Anton A. Titov, Xiangyu Teng, Todd M. Brusko, Laurence Morel

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Estrogen-related receptor γ (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls Tregs through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Tregs, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Tregs presented an impaired differentiation into follicular Tregs that enhanced follicular helper T cells' responses. Mechanistically, Esrrgdeficient Tregs presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD+ production. In addition, Esrrg-deficient Tregs exhibited decreased phosphatidylinositol and TGF-β signaling pathways and increased mTOR complex 1 activation. We found that the expression of human ESRRG, which is high in Tregs, was lower in CD4+ T cells from patients with lupus than in healthy controls. Finally, knocking down ESRRG in Jurkat T cells decreased their metabolism. Together, our results reveal a critical role of Esrrg in the maintenance and metabolism of Tregs, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells.

Original languageEnglish (US)
Article numbere143540
JournalJCI Insight
Volume6
Issue number14
DOIs
StatePublished - Jul 22 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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