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

Abstract

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.

Protective role of zinc in the pathogenesis of respiratory diseases

“…The lung is the gateway for gas exchange between the body and outside world. Following exposure to harmful substances (cadmium, cigarette smoke), zinc levels in the lungs are increased to protect the lung tissue by affecting the functions of certain cells (macrophages, T lymphocytes and neutrophils) [ 38 – 40 ]. ZIP8 is a zinc transporter that is highly expressed in alveolar epithelial cells and is the main entry point for Cd, a toxic heavy metal and carcinogen that exists in large quantities in cigarette smoke [ 41 ].…”

“…Studies have shown that T cell development, differentiation, and activation are zinc-dependent processes [ 46 ]. In clinical trials, mild zinc deficiency in humans (3–5 mg/day) caused dysfunctions in Th1 and Th2, leading to a decline in cell-mediated immunity [ 47 ] However, in vitro and in vivo experiments demonstrated that therapeutic zinc supplements can mediate Th1 and Th2 immune functions and reduce Th2-mediated chronic airway inflammation by activating regulatory T cells [ 40 , 48 ]. Zinc in the lung tissue is regulated by zinc transporters and mainly binds to MT.…”

“…Th2 cells primarily secrete cytokines IL-4, IL-5, and IL-13 to promote the increase of airway eosinophils and airway remodeling and to stimulate the occurrence of the type 2 immune response [ 44 , 45 ]. After intraperitoneal injection of zinc aspartate (30 µg) in mice with allergic asthma, the ability of CD4 + T cells to proliferate and differentiate in the lungs was significantly reduced [ 40 ]. In cell experiments, zinc aspartate dose-dependently (200 > 150 > 100 μM) inhibited the activation, proliferation, and Th1 and Th2 differentiation of murine CD4+ T cells [ 40 ].…”

“…After intraperitoneal injection of zinc aspartate (30 µg) in mice with allergic asthma, the ability of CD4 + T cells to proliferate and differentiate in the lungs was significantly reduced [ 40 ]. In cell experiments, zinc aspartate dose-dependently (200 > 150 > 100 μM) inhibited the activation, proliferation, and Th1 and Th2 differentiation of murine CD4+ T cells [ 40 ]. In a mouse model of allergic airway inflammation, Morgan et al found that zinc supplementation (10 mg/kg, intraperitoneal injection) enhanced the activity of the zinc finger protein A20, which inhibits the NF-κB pathway by degrading receptor-interacting protein 1, inhibits the inflammatory cascade caused by downstream NF-κB activation, reduces inflammatory cell infiltration and TNF-α cytokine release in the airway of mice, and considerably reduces airway hyperresponsiveness and serum IgE levels [ 79 ] (Fig.…”

Investigation of the Immunogenic Properties of Ovalbumin Modified by Urban Airborne Particulate Matter

“…We have shown that for both native OVA and OVA 323–339 peptide, the OT-II TCR-transgenic epitope stimulated OT-II T cells more effectively in the presence of PM. OT-II transgenic mice have been commonly used as a model for studies on antigen-specific T cell responses in various contexts (Clemen et al 2021 ; Krone et al 2022 ). Our results exclude the effect of PM on antigen (Ag) processing, since OVA 323–339 peptide (epitope) presentation does not require any intracellular processing.…”