Zinc supplementation augments TGF-β1-dependent regulatory T cell induction

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.