1. Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity
- Author
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Johannes Roth, Karin B. Busch, Luisa Klotz, Shirin Glander, Philipp Albrecht, Meike Kuhlencord, Julia Ghelman, Marc Beyer, Monika Stoll, Achmet Imam Chasan, Niklas Daber, Heinz Wiendl, Marie Liebmann, Maria Eveslage, Melanie Eschborn, Martin Schädlich, Stephanie Hucke, Kathrin Koch, Tanja Kuhlmann, and Michael Dietrich
- Subjects
0301 basic medicine ,Central Nervous System ,genetics [Nuclear Receptor Subfamily 4, Group A, Member 1] ,T-Lymphocytes ,Regulator ,Autoimmunity ,medicine.disease_cause ,Lymphocyte Activation ,metabolism [Receptors, Estrogen] ,immunology [T-Lymphocytes] ,Mice ,0302 clinical medicine ,immunology [Inflammation] ,Transcriptional regulation ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Receptor ,Mice, Knockout ,metabolism [Inflammation] ,Multidisciplinary ,Chemistry ,immunology [Oxygen Consumption] ,ERRalpha estrogen-related receptor ,Nr4a1 protein, mouse ,Cell biology ,Mitochondria ,medicine.anatomical_structure ,PNAS Plus ,Receptors, Estrogen ,metabolism [Central Nervous System] ,ddc:500 ,Reprogramming ,immunology [Receptors, Estrogen] ,Nerve growth factor IB ,T cell ,immunology [Nuclear Receptor Subfamily 4, Group A, Member 1] ,03 medical and health sciences ,genetics [Inflammation] ,Oxygen Consumption ,medicine ,Animals ,Transcription factor ,metabolism [T-Lymphocytes] ,Inflammation ,metabolism [Nuclear Receptor Subfamily 4, Group A, Member 1] ,immunology [Central Nervous System] ,Gene Expression Profiling ,immunology [Mitochondria] ,metabolism [Mitochondria] ,030104 developmental biology ,genetics [Mitochondria] ,genetics [Receptors, Estrogen] ,030215 immunology - Abstract
T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.
- Published
- 2018
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