Abstract
The intracellular free zinc level and zinc distribution are important for cellular function. Both are highly variable and are altered due to intrinsic zinc pool fluctuation via buffering and muffling reactions. Multiple autoimmune diseases are associated with pathologically changed zinc levels, which provoke altered signal transduction leading to changed immune responses, cell differentiation, and function. For instance, immunological tolerance can be impaired, causing autoimmune diseases because of a malfunction of regulatory T cells (Tregs). We investigated the intracellular free zinc concentration of resting and activated T helper (Th) cells and Tregs in an allogeneic graft versus host disease model using fluorescence-activated cell sorting (FACS) analysis and enlightened cell function under nontoxic zinc concentrations and zinc deficiency by detecting cytokine secretion via enzyme-linked immunosorbent assay (ELISA). We exhibited for the first time that Tregs could be explicitly discriminated from other Th cell subsets using significantly increased intracellular free zinc levels. Moreover, the intracellular free zinc level was essential in maintaining the Treg phenotype and function, since zinc deficiency favored the pro-inflammatory immune response. Therefore, we hypothesize that the intracellular free zinc level in Th cells is essential in guaranteeing proper cellular function and can be used to discriminate Tregs from other Th cell subsets.
Highlights
IntroductionProper zinc homeostasis is indispensable to an adequate immune response, since zinc deficiency is known to increase the incidence of bacterial or viral infections, the development of cancer, graft rejection, and autoimmune diseases [1,2,3]
Since the early 1960s, zinc has been discovered to be essential in humans
We hypothesize that the intracellular free zinc level in T helper (Th) cells is essential in guaranteeing proper cellular function and can be used to discriminate Tregs from other Th cell subsets
Summary
Proper zinc homeostasis is indispensable to an adequate immune response, since zinc deficiency is known to increase the incidence of bacterial or viral infections, the development of cancer, graft rejection, and autoimmune diseases [1,2,3]. It is well known that especially T cells are affected by altered zinc levels, as shown in T cell development, maturation, activation, and differentiation [8,9,10]. Zinc deficiency can lead to reduced proliferation, reduced response to mitogens, thymic atrophy, a selective decrease in Th cells (CD4-expressing T cells), and overall altered T cell differentiation [11,12,13,14]
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