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
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
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Research Article

Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism

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, Esrrg-deficient 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.

Authors

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

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Figure 5

Esrrg maintains mitochondrial metabolism in Tregs.

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Esrrg maintains mitochondrial metabolism in Tregs. (A and B) ATP and NA...
(A and B) ATP and NAD+ production by Tregs from 2- to 4-month-old B6N.Foxp3YFP-Cre (WT) or B6N.Esrrgfl/fl Foxp3YFP-Cre (cKO) mice (n = 4). Basal OCR (C) and ECAR (D) in Tregs. Data were combined from 3 independent experiments with n = 2 each and expressed as fold change of the mean WT value for each experiment. (E) Glucose uptake in Tregs measured with 2-NBDG (n = 5–6). Mitochondrial mass (F), mitochondrial membrane potential (MMP, G), and mitochondrial ROS (mROS, H) in Tregs. Data were combined from 3 independent experiments with n = 3–4 each and expressed as fold change of the mean WT value for each experiment. Representative images of mROS staining in CD4+FOXP3+ cells (I) and quantification as MFI (J). Scale bar: 10 μm. Each symbol represents an individual Treg from WT (n = 62) and cKO (n = 25) mice. Data are shown as mean ± SEM. Unpaired 2-tailed t tests, *P < 0.05, **P < 0.01, ***P < 0.001.