Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 34; pp. E8017 - E8026
• Main Authors: Liebmann, Marie, Hucke, Stephanie, Koch, Kathrin, Eschborn, Melanie, Ghelman, Julia, Chasan, Achmet I., Glander, Shirin, Schädlich, Martin, Kuhlencord, Meike, Daber, Niklas M., Eveslage, Maria, Beyer, Marc, Dietrich, Michael, Albrecht, Philipp, Stoll, Monika, Busch, Karin B., Wiendl, Heinz, Roth, Johannes, Kuhlmann, Tanja, Klotz, Luisa
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.08.2018
• Series: PNAS Plus
• Subjects: Allergies; Alternative splicing; Animals; Autoimmunity; Biological Sciences; Cell activation; Central Nervous System - immunology; Central Nervous System - metabolism; Chromatin; Control rods; Differentiation; ERRalpha Estrogen-Related Receptor; Euchromatin; Fibroblasts; Gene expression; Gene Expression Profiling; Genetics; Genomes; Heterochromatin; Immunity (Disease); Immunology; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - immunology; Mitochondria - metabolism; Molecular modelling; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - immunology; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Nur77 protein; Oxygen Consumption - immunology; Photoreception; Photoreceptors; PNAS Plus; Polycomb group proteins; Receptors, Estrogen - genetics; Receptors, Estrogen - immunology; Receptors, Estrogen - metabolism; Retina; Rods; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Zinc; Zinc finger proteins; Nur77; autoimmunity; T cells; immunometabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1721049115

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.