Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell–Th17 Balance

Abstract

Zinc (Zn) is an essential metal for development and maintenance of both the innate and adaptive compartments of the immune system. Zn homeostasis impacts maturation of dendritic cells (DCs) that are important in shaping T cell responses. The mechanisms by which Zn regulates the tolerogenic phenotype of DCs remain largely unknown. In this study, we investigated the effect of Zn on DC phenotype and the generation of Foxp3+ regulatory T cells (Tregs) using a model of Histoplasma capsulatum fungal infection. Exposure of bone marrow–derived DCs to Zn in vitro induced a tolerogenic phenotype by diminishing surface MHC class II (MHCII) and promoting the tolerogenic markers, programmed death–ligand (PD-L)1, PD-L2, and the tryptophan degrading enzyme, IDO. Zn triggered tryptophan degradation by IDO and kynurenine production by DCs and strongly suppressed the proinflammatory response to stimulation by TLR ligands. In vivo, Zn supplementation and subsequent H. capsulatum infection supressed MHCII on DCs, enhanced PD-L1 and PD-L2 expression on MHCIIlo DCs, and skewed the Treg–Th17 balance in favor of Foxp3+ Tregs while decreasing Th17 cells. Thus, Zn shapes the tolerogenic potential of DCs in vitro and in vivo and promotes Tregs during fungal infection.

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

“…Zinc is known to act as a modulator of immune responses through its availability, and zinc deficiency affects the immune system leading to increased inflammation and inflammatory diseases such as RA ( 38 ). In DCs, zinc supplementation has been shown to interfere with maturation, by inhibiting the upregulation of MHCII and co-stimulatory molecules ( 42 ), as well as to induce the expression of the tolerogenic markers PD-L1, IDO1, and CD103 ( 43 ). Thus, a tight regulation of zinc concentration is required and zinc may contribute to the immunoregulatory functions of DM-DCs, since several regulators of intracellular zinc concentration are overexpressed in these cells.…”

Zinc Nutrition and Inflammation in the Aging Retina

“…Depletion of Tregs at the peak of uveitis delayed resolution and, following resolution, (when mice displayed a low grade chronic inflammation), Treg depletion precipitated disease relapse . One mechanism by which zinc has been shown to influence levels of T‐cell mediated inflammation is by inducing a tolerogenic dendritic cell phenotype (characterized by diminishing surface MHC class II (MHCII) and promoting programmed death–ligand (PD‐L)1, PD‐L2, and the tryptophan degrading enzyme, IDO), which in turn skews the Treg cell–Th17 balance against inflammation . Zinc supplementation has also been found to augment T‐reg induction through upregulation of FoxP3 and TGF‐β dependent mechanisms .…”

Cu, Zn doped borate bioactive glasses: antibacterial efficacy and dose-dependent in vitro modulation of murine dendritic cells

“…For instance, Zn was shown to influence the tolerogenic potential of DCs in vitro and in vivo . 26 As discussed in a recently published review paper, 27 the present study is relevant for BG applications because the immune system is involved in any regeneration process in humans and therefore the influence of BGs on the immune system needs to be considered. In addition, the BG compositions were investigated for their antibacterial effects since the immune system plays an important role in bacterial infections.…”