Immune modulation by zinc induced regulatory T cells
Year: 2014
Type: dissertation
Abstract: The trace element zinc is essential for immune cell function as documented by impaired immune activity in zinc-deficient patients. But also supplementation of physiological zinc doses modulates immune responses. It was demonstrated before that zinc-treated MLCs are inhibited relative to control MLCs as indicated by decreased IFN-ƒ× production. In addition, zinc was used successfully to ameliorate autoimmune diseases in mice. Therefore, an immunomodulatory effect of zinc was anticipated in this study, offering the opportunity to elaborate zinc application as a useful tool in controlling diseases, which involve excessive T cell activation. This thesis confirms the ability of zinc to modulate Th1, Th2, and Th17 driven immune responses. More precisely, zinc was capable of inducing immune tolerance in in vitro MLCs, of inhibiting in vitro allergic immune responses towards timothy grass allergen, and of attenuating the in vivo EAE disease, an animal model of multiple sclerosis. Furthermore, this work expands on known zinc effects and reveals that the induction of Tregs by zinc is responsible for the presented immunomodulation. In fact, zinc prolonged levels of specific CD4+CD25hiCTLA-4+ iTrges derived from activated T cells thereby accumulating antigen-specific Tregs with immunosuppressive capacity. This zinc-mediated effect was observed in alloantigen-, allergen-, and autoantigen-activated T cells. The molecular mechanism underlying zinc-mediated induction of Tregs involves increased K31-Foxp3 acetylation, which prevents Foxp3 degradation and stabilizes Foxp3 activity. In accordance, deacetylation of Foxp3 by the histone deacetylase Sirt-1 promotes ubiquitination of the vacant lysine residues leading to Foxp3 removal by the proteasome. One important finding of this work is that zinc inhibits Sirt-1 and thereby stabilizes Foxp3. The Sirt-1 inhibitor EX-527 mirrored the impact of zinc in the MLC, supporting the idea of zinc-mediated Sirt-1 inhibition. Experimental preincubation with zinc in the above mentioned scenarios reinforced the potential use of zinc as a preventive molecule. Further evidence for this powerful capacity is provided by the finding that orally administered zinc for 10 days enhanced Foxp3 expression in ex vivo generated MLCs. Altogether, this work illustrates that zinc may modulate adverse T cell-driven immune responses by upregulating Tregs and Treg-mediated immune cell alleviation. Advancing our understanding of how zinc modulates immune responses can help to establish zinc as a new therapeutic tool for the fields of transplantation, allergy, and autoimmunity. The advantage of a zinc-based therapy as compared to immunosuppressive strategies becomes obvious in its lack of toxicity and its ability to induce immune tolerance without completely abrogating antigenic immune defence. This is an important aspect of the immune system's ability to fight infectious diseases, and hence a topic of broad interest which warrants further studies.
Source: RWTH Publications (RWTH Aachen)
Authors: Eva Rosenkranz, Lothar Rink
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2588790448