Zinc enhances the number of regulatory T cells in allergen-stimulated cells from atopic subjects
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The trace element zinc is essential for immune function and its regulation. Since zinc deficiency and allergic hyperresponsive reactions are often accompanied, the influence of zinc on allergen-induced cell growth, CD4+ regulatory T (Treg) cell numbers and cytokine expression during allergic immune reactions was investigated.
Peripheral blood mononuclear cells (PBMCs) from non-atopic and atopic subjects were treated with timothy grass allergen pre-incubated with or without zinc. Proliferation was determined by analyzing the incorporation of 3H-thymidine. Intracellular zinc and Foxp3 levels and cell surface antigens were measured by FACS, cytokine expression by ELISA and real-time PCR.
Incubation with 50 μM zinc sulfate (Zn50) enhances cytosolic zinc concentrations in CD3+ T cells. The data also reveal that the combination of Zn50 plus allergen significantly reduces PBMC proliferation of atopic subjects. Additionally, Zn50 plus allergen enhances Th1 cytokine responses shown by increased interferon (IFN)-γ/interleukin (IL)-10 ratios as well as enhanced tumor necrosis factor-α release. In response to allergen, zinc increases Treg cells and upregulates the mRNA expression of cytotoxic T-lymphocyte antigen-4 in atopic subjects. Interestingly, Zn50 alone leads to an increase of CD4+CD25high(hi)+ cells in atopic and non-atopic subjects.
Zinc may regulate unwanted hyperresponsive immune reactions by suppressing proliferation through a significant shift from IL-10 to the Th1 cytokine IFN-γ, and enhanced regulatory T cell numbers. Therefore, zinc supplementation may be a promising tool for the therapy of allergies, without negatively affecting the immune system.
KeywordsZinc Nutritional immunology Allergy Regulatory T cells Treg Foxp3
We acknowledge grant support SFB/TR22 A03 and Z01 from the Deutsche Forschungsgemeinschaft for A.P. L.R. is a member of the European COST action Zinc-Net (TDI304).
Compliance with ethical standards
The study was approved by the local ethical committee (No. AZ 016/09) and had therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Ibs KH, Rink L (2003) Zinc-altered immune function. J Nutr 133:1452S–1456SGoogle Scholar
- 6.Rink L (2011) Zinc in human health. IOS Press, AmsterdamGoogle Scholar
- 13.Bhatnagar S, Wadhwa N, Aneja S, Lodha R, Kabra SK, Natchu UCM, Sommerfelt H, Dutta AK, Chandra J, Rath B, Sharma M, Sharma VK, Kumari M, Strand TA (2012) Zinc as adjunct treatment in infants aged between 7 and 120 days with probable serious bacterial infection: a randomised, double-blind, placebo-controlled trial. Lancet 379:2072–2078CrossRefGoogle Scholar
- 24.Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, Kegel C, Disch R, Schmidt-Weber CB, Blaser K, Akdis CA (2004) Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 199:1567–1575CrossRefGoogle Scholar
- 31.Ahangarani RR, Janssens W, VanderElst L, Carlier V, VandenDriessche T, Chuah M, Weynand B, Vanoirbeek JAJ, Jacquemin M, Saint-Remy JM (2009) In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. J Immunol 183:8232–8243CrossRefGoogle Scholar
- 40.Cohn L, Homer R, Niu N, Bottomly K (1999) Th1 cells inhibit TH2-induced airway eosinophilia and mucus production. Am J Respir Crit Care Med 159:A336Google Scholar
- 43.Boscolo P, Di Gioacchino M, Sabbioni E, Benvenuti F, Conti P, Reale M, Bavazzano P, Giuliano G (1999) Expression of lymphocyte subpopulations, cytokine serum levels, and blood and urinary trace elements in asymptomatic atopic men exposed to an urban environment. Int Arch Occup Environ Health 72:26–32CrossRefGoogle Scholar
- 45.Tudor R, Zalewski PD, Ratnaike RN (2005) Zinc in health and chronic disease. J Nutr Health Aging 9:45–51Google Scholar
- 50.Urushidate S, Matsuzaka M, Okubo N, Iwasaki H, Hasebe T, Tsuya R, Iwane K, Inoue R, Yamai K, Danjo K, Takahashi I, Umeda T, Ando S, Itai K, Nakaji S (2010) Association between concentration of trace elements in serum and bronchial asthma among Japanese general population. J Trace Elem Med Biol 24:236–242CrossRefGoogle Scholar
- 57.Cosmi L, Liotta F, Angeli R, Mazzinghi B, Santarlasci V, Manetti R, Lasagni L, Vanini V, Romagnani P, Maggi E, Annunziato F, Romagnani S (2004) Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25(+) regulatory thymocytes because of their responsiveness to different cytokines. Blood 103:3117–3121CrossRefGoogle Scholar
- 66.Sumitomo S, Fujio K, Okamura T, Morita K, Ishigaki K, Suzukawa K, Kanaya K, Kondo K, Yamasoba T, Furukawa A, Kitahara N, Shoda H, Shibuya M, Okamoto A, Yamamoto K (2013) Transcription factor early growth response 3 is associated with the TGF-β1 expression and the regulatory activity of CD4-positive T cells in vivo. J Immunol 191:2351–2359CrossRefGoogle Scholar