Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREMa expression in T cells

Background & aims: The micronutrient zinc is essential for proper immune function. Consequently, zinc deficiency leads to impaired immune function, as seen in decreased secretion of interleukin (IL)-2 by T cells. Although this association has been known since the late 1980s, the underlying molecular mechanisms are still unknown. Zinc deficiency and reduced IL-2 levels are especially found in the elderly, which in turn are prone to chronic diseases. Here, we describe a new molecular link between zinc deficiency and reduced IL-2 expression in T cells. Methods: The effects of zinc deficiency were first investigated in vitro in the human T cell lines Jurkat and Hut-78 and complemented by in vivo data from zinc-supplemented pigs. A short-and long-term model for zinc deficiency was established. Zinc levels were detected by flow cytometry and expression profiles were investigated on the mRNA and protein level. Results: The expression of the transcription factor cAMP-responsive-element modulator a (CREMa) is increased during zinc deficiency in vitro, due to increased protein phosphatase 2A (PP2A) activity, resulting in decreased IL-2 production. Additionally, zinc supplementation in vivo reduced CREMa levels causing increased IL-2 expression. On epigenetic levels increased CREMa binding to the IL-2 promoter is mediated by histone deacetylase 1 (HDAC1). The HDAC1 activity is inhibited by zinc. Moreover, deacetylation of the activating histone mark H3K9 was increased under zinc deficiency, resulting in reduced IL 2 expression. Conclusions: With the transcription factor CREMa a molecular link was uncovered, connecting zinc deficiency with reduced IL-2 production due to enhanced PP2A and HDAC1 activity. (C) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Automated summary

The study revealed that zinc deficiency leads to reduced IL-2 expression in T cells due to enhanced PP2A and HDAC1 activity, and a molecular link through the transcription factor CREMa was uncovered in connecting zinc deficiency with this decreased IL-2 production.