Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling

Abstract

Scope T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, the study aims to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism. Methods and results Mixed lymphocyte culture and anti‐CD3/CD28 stimulation is used as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. Promoted glucose uptake, insulin receptor expression, and signaling in both zinc conditions are observed, whereas key metabolic enzymes are stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune‐activating effect of zinc deprivation and a balancing effect of zinc supplementation. Conclusion The results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc.

Zinc Modulates Glutamine Metabolism in T Cells

“…demonstrated a relation between Zn levels and expression of activation marker CD69 in in vitro activated T cells in MLC. [ 30 ] We could not prove that ZS increases CD69 expression in CD3/CD28‐stimulated T cells, but we could show that ZD decreased activation marker expression. Moreover, we could confirm that T cell activation is sensitive to glutaminase inhibition.…”

“…In a previous study we have shown that zinc deficiency did not modulate activation marker expression in MLC, whereas ZS caused their upregulation. [ 30 ]…”

“…[22][23][24][25][26][27][28][29] Interestingly, recently it has been shown that Zn impacts glycolysis in T cells. [30] Several studies indicate that Zn deficiency (ZD) drives T h 17 polarization and promotes loss of T reg cell function. [25] In line with that, Zn supplementation (ZS) increases the number of T reg cells.…”

Zinc Modulates the Priming of T Helper 1, T Helper 17, and T Regulatory Cells in Allogeneic and Autologous in vitro Models

“…While immune function is boosted by a moderate concentration of zinc, it is also suppressed by high doses of zinc. 7 , 8 According to these studies, zinc administration has a potential therapeutic role in graft-versus-host diseases (GVHD) and T cell-mediated autoimmunity. 5 , 9 …”

“…While immune function is boosted by a moderate concentration of zinc, it is also suppressed by high doses of zinc. 7,8 According to these studies, zinc administration has a potential therapeutic role in graft-versus-host diseases (GVHD) and T cell-mediated autoimmunity. 5,9 The T helper 17 (Th17) cells are a subtype of CD4 T lymphocytes and are responsible for extracellular pathogen clearance; however, they also cause several autoimmune diseases.…”