Zinc supplementation augments TGF- beta 1-dependent regulatory T cell induction

• Published in: Molecular nutrition & food research Vol. 61; no. 3; p. np
• Main Authors: Maywald, Martina, Meurer, Steffen K, Weiskirchen, Ralf, Rink, Lothar
• Format: Journal Article
• Language: English
• Published: 01.03.2017
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201600493

Scope Regulatory T cells (Treg) play a pivotal role in immune regulation. For proper immune function, also trace elements such as zinc, and anti-inflammatory cytokines, including transforming growth factor beta 1 (TGF- beta 1) and interleukin (IL)-10 are indispensable. Hence, in this study the influence of TGF- beta 1, IL-10, and zinc supplementation on Treg cells differentiation was investigated. Methods and results A synergistic effect of a combined zinc and TGF- beta 1 treatment on Foxp3 expression in peripheral blood mononuclear cells and mixed lymphocyte cultures (MLC) was found by performing Western blot analysis. Additionally, combined treatment causes elevated Smad 2/3 phosphorylation, which plays an important role in Foxp3 expression. This is due to a TGF- beta 1-mediated increase of intracellular-free zinc measured by zinc probes Fluozin3-AM and ZinPyr-1. Moreover, zinc as well as TGF- beta 1 treatment caused significantly reduced interferon (IFN)- gamma secretion in MLC. Conclusion Combined zinc and TGF- beta 1 treatment provoked an increased Treg cell induction due to a triggered intracellular zinc signal, which in association with an increased Smad 2/3 activation leads to a boosted Foxp3 expression and resulting in an ameliorated allogeneic reaction in MLC. Thus, zinc can be used as a favorable additive to elevate the induction of Treg cells in adverse immune reactions. TGF- beta 1 stimulation triggers the Smad signaling pathway in T cells by increasing Smad 2/3 and Smad 1/5/8 phosphorylation. Zinc supplementation as well as TGF- beta 1 stimulation lead to an increased free zinc level in the cytosol by zinc uptake via several transporter located in the cell membrane (green arrow) or zinc release from intracellular stores (black arrows). The elevated zinc concentration amplifies the Smad 2/3 phosphorylation and Foxp3 expression, and dampens the IFN- gamma production (red arrows).