Zinc supplementation induces CD4^sup +^CD25^sup +^Foxp3^sup +^ antigen-specific regulatory T cells and suppresses IFN-[gamma] production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1

• Published in: European journal of nutrition Vol. 56; no. 5; p. 1859
• Main Authors: Maywald, Martina, Rink, Lothar
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01-08-2017
• Subjects: Antigens; Autoimmunity; CD25 antigen; CD4 antigen; Cell growth; Cell proliferation; CTLA-4 protein; Cytokines; Enzyme-linked immunosorbent assay; Flow cytometry; Foxp3 protein; Graft rejection; Immune response; Immunological tolerance; Immunoregulation; Inflammation; Interferon regulatory factor 1; Lymphocytes; Lymphocytes T; Molecular modelling; mRNA; Supplements; Thymidine; Trace elements; Up-regulation; Western blotting; Zinc
• ISSN: 1436-6207; 1436-6215
• DOI: 10.1007/s00394-016-1228-7

Purpose The essential trace element zinc plays a fundamental role in immune function and regulation since its deficiency is associated with autoimmunity, allergies, and transplant rejection. Thus, we investigated the influence of zinc supplementation on the Th1-driven alloreaction in mixed lymphocyte cultures (MLC), on generation of antigen-specific T cells, and analyzed underlying molecular mechanisms. Methods Cell proliferation and pro-inflammatory cytokine production were monitored by [3H]-thymidine proliferation assay and ELISA, respectively. Analysis of surface and intracellular T cell marker was performed by flow cytometry. Western blotting and mRNA analysis were used for Foxp3, KLF-10, and IRF-1 expression. Results Zinc supplementation on antigen-specific T cells in physiological doses (50 µM) provokes a significant amelioration of cell proliferation and pro-inflammatory cytokine production after reactivation compared to untreated controls. Zinc administration on MLC results in an increased induction and stabilization of CD4+CD25+Foxp3+ and CD4+CD25+CTLA-4+ T cells (p < 0.05). The effect is based on zinc-induced upregulation of Foxp3 and KLF-10 and downregulation of IRF-1. However, in resting lymphocytes zinc increases IRF-1. Conclusion In summary, zinc is capable of ameliorating the allogeneic immune reaction by enhancement of antigen-specific iTreg cells due to modulation of essential molecular targets: Foxp3, KLF-10, and IRF-1. Thus, zinc can be seen as an auspicious tool for inducing tolerance in adverse immune reactions.