Ionic mitigation of CD4+ T cell metabolic fitness, Th1 central nervous system autoimmunity and Th2 asthmatic airway inflammation by therapeutic zinc

• Published in: Scientific reports Vol. 12; no. 1; p. 1943
• Main Authors: Krone, Anna, Fu, Yan, Schreiber, Simon, Kotrba, Johanna, Borde, Loisa, Nötzold, Aileen, Thurm, Christoph, Negele, Jonas, Franz, Tobias, Stegemann-Koniszewski, Sabine, Schreiber, Jens, Garbers, Christoph, Shukla, Aniruddh, Geffers, Robert, Schraven, Burkhart, Reinhold, Dirk, Dudeck, Anne, Reinhold, Annegret, Müller, Andreas J., Kahlfuss, Sascha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1619; 631/250/1932; 631/250/1933; 631/250/2152; 631/250/24; 631/250/38; 631/250/516; 692/53; Allergies; Animals; Aspartic Acid - analogs & derivatives; Aspartic Acid - pharmacology; Asthma; Asthma - drug therapy; Asthma - genetics; Asthma - immunology; Asthma - metabolism; Autoimmunity; Bioavailability; CD28 antigen; CD3 antigen; CD4 antigen; Cell activation; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell differentiation; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Central nervous system; Central Nervous System - drug effects; Central Nervous System - immunology; Central Nervous System - metabolism; DNA biosynthesis; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Energy metabolism; Energy Metabolism - drug effects; Energy Metabolism - genetics; Fitness; Gene Expression Regulation; Glycolysis; Helper cells; House dust; Humanities and Social Sciences; Immunomodulating Agents - pharmacology; Immunomodulation; Inflammation; Lung - drug effects; Lung - immunology; Lung - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - genetics; Lymphocytes; Lymphocytes T; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Multiple sclerosis; Nervous system; Oxidative phosphorylation; Pneumonia - drug therapy; Pneumonia - genetics; Pneumonia - immunology; Pneumonia - metabolism; Pyroglyphidae - immunology; Respiratory tract; Respiratory tract diseases; Science; Science (multidisciplinary); Signal Transduction; Th1 Cells - drug effects; Th1 Cells - immunology; Th1 Cells - metabolism; Th2 Cells - drug effects; Th2 Cells - immunology; Th2 Cells - metabolism; Trace elements; Transcription, Genetic; Tricarboxylic acid cycle; Zinc; Zinc Compounds - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-04827-6

T helper (Th) cells provide immunity to pathogens but also contribute to detrimental immune responses during allergy and autoimmunity. Th2 cells mediate asthmatic airway inflammation and Th1 cells are involved in the pathogenesis of multiple sclerosis. T cell activation involves complex transcriptional networks and metabolic reprogramming, which enable proliferation and differentiation into Th1 and Th2 cells. The essential trace element zinc has reported immunomodulatory capacity and high zinc concentrations interfere with T cell function. However, how high doses of zinc affect T cell gene networks and metabolism remained so far elusive. Herein, we demonstrate by means of transcriptomic analysis that zinc aspartate (UNIZINK), a registered pharmaceutical infusion solution with high bioavailability, negatively regulates gene networks controlling DNA replication and the energy metabolism of murine CD3/CD28-activated CD4 + T cells. Specifically, in the presence of zinc, CD4 + T cells show impaired expression of cell cycle, glycolytic and tricarboxylic acid cycle genes, which functionally cumulates in reduced glycolysis, oxidative phosphorylation, metabolic fitness and viability. Moreover, high zinc concentrations impaired nuclear expression of the metabolic transcription factor MYC, prevented Th1 and Th2 differentiation in vitro and reduced Th1 autoimmune central nervous system (CNS) inflammation and Th2 asthmatic airway inflammation induced by house dust mites in vivo. Together, we find that higher zinc doses impair the metabolic fitness of CD4 + T cells and prevent Th1 CNS autoimmunity and Th2 allergy.