Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism
| Autor: | Xiangyu Teng, Wei Li, Anton A. Titov, Josephine Brown, Leeana D. Peters, Wen-I Yeh, Nathalie Kanda, Minghao Gong, Todd M. Brusko, Yuk Pheel Park, Seung-Chul Choi, Laurence Morel, Ahmed S. Elshikha |
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| Rok vydání: | 2021 |
| Předmět: |
T cell
T cells Lupus chemical and pharmacologic phenomena Autoimmunity mTORC1 Mitochondrion Biology medicine.disease_cause T-Lymphocytes Regulatory Jurkat cells Jurkat Cells Mice medicine Animals Humans Lupus Erythematosus Systemic Systemic lupus erythematosus hemic and immune systems General Medicine medicine.disease Mitochondria Cell biology Disease Models Animal medicine.anatomical_structure Receptors Estrogen Gene Knockdown Techniques Female Signal transduction Homeostasis Research Article |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | Estrogen-related receptor gamma (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls regulatory T cells (Treg) through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Treg cells, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Treg cells presented an impaired differentiation into follicular Treg (Tfr) cells that enhanced follicular helper T cells (Tfh) responses. Mechanistically, Esrrg-deficient Treg cells presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD+ production. In addition, Esrrg-deficient Treg cells exhibited decreased phosphatidylinositol and TGF-β signaling pathways and increased mTORC1 activation. We found that the expression of human ESRRG, which is high in Treg cells, was lower in CD4+ T cells from lupus patients 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 Treg cells, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells. |
| Databáze: | OpenAIRE |
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