Zinc supplementation induces regulatory T cells by inhibition of Sirt-1 deacetylase in mixed lymphocyte cultures
Eva Rosenkranz
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorClaudia H.D. Metz
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorMartina Maywald
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorRalf-Dieter Hilgers
Institute of Medical Statistics, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorInga Weßels
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorTina Senff
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorHajo Haase
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany
Search for more papers by this authorMaximilian Jäger
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorMelanie Ott
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA, USA
Search for more papers by this authorRichard Aspinall
Translational Medicine Group, Cranfield University, Cranfield, Bedfordshire, UK
Search for more papers by this authorBirgit Plümäkers
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorCorresponding Author
Lothar Rink
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Correspondence: Lothar Rink E-mail: [email protected]Search for more papers by this authorEva Rosenkranz
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorClaudia H.D. Metz
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorMartina Maywald
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorRalf-Dieter Hilgers
Institute of Medical Statistics, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorInga Weßels
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorTina Senff
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorHajo Haase
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany
Search for more papers by this authorMaximilian Jäger
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorMelanie Ott
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA, USA
Search for more papers by this authorRichard Aspinall
Translational Medicine Group, Cranfield University, Cranfield, Bedfordshire, UK
Search for more papers by this authorBirgit Plümäkers
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Search for more papers by this authorCorresponding Author
Lothar Rink
Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
Correspondence: Lothar Rink E-mail: [email protected]Search for more papers by this authorAbstract
Scope
Zinc is an essential trace element, regulating immune function. Its deficiency results in immune dysfunction and transplant rejection. In here, a benefit of zinc supplementation for the induction of tolerance was investigated, focusing on the TH1-dominated allogeneic immune reaction.
Methods and results
Allogeneic immune reaction was modeled by mixed lymphocyte culture (MLC). The effect of zinc supplementation was monitored via expression of cytokines and surface lineage markers using ELISA and flow cytometry. Epigenetic analyses were performed to investigate mechanisms underlying zinc-induced changes in regulatory T cell (Treg) activation. Results reveal that Tregs are induced when MLCs are treated with 50 μM zinc causing a decrease in IFNγ production. IL-2 and IL-10 expression were not affected. The teleology of this effect includes the inhibition of histone deacetylase Sirt-1-mediated Foxp3 deacetylation, resulting in its decreased degradation.
Conclusion
In conclusion, zinc should be considered to prevent graft-versus-host disease (GVHD) as it is capable of stabilizing iTregs, resulting in increased numbers of this cell type while not suppressing the immune system.
Supporting Information
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| mnfr2537-sup-0001-figureS1.docx35.8 KB | Supplemental Figure 1 Zinc increases MLC induced expression of Foxp3 positive regulatory T cells |
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5 References
- 1Passerini, A., Andreini, C., Menchetti, S., Rosato, A., Frasconi, P., Predicting zinc binding at the proteome level. BMC Bioinformatics 2007, 8, 39.
- 2Ibs, K. H., Rink, L., Zinc-altered immune function. J. Nutr. 2003, 133, 1452S–1456S.
- 3Fischer, W.-C., Black, R.-E., Zinc and the risk for infectious disease. Annu. Rev. Nutr. 2004, 24, 255–275.
- 4Sprietsma, J.-E., Zinc-controlled Th1/Th2 switch significantly determines development of diseases. Med. Hypotheses 1997, 49, 1–14.
- 5Niedermeier, W., Griggs, J.-H., Trace metal composition of synovial fluid and blood serum of patients with rheumatoid arthritis. J. Chronic. Dis. 1971, 23, 527–536.
- 6Kim, P.-W., Sun, Z.-Y., Blacklow, S.-C., Wagner, G., Eck, M.-J., A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science 2003, 301, 1725–1728.
- 7Haase, H., Rink, L., Functional significance of zinc-related signaling pathways in immune cells. Annu. Rev. Nutr. 2009, 29, 133–152.
- 8Chandra, R.-K., Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992, 340, 1124–1127.
- 9Bhatnagar, S., Wadhwa, N., Aneja, S., Lodha, R. et al., 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 2012, 379, 2072–2078.
- 10Campo, C.-A., Wellinghausen, N., Faber, C., Fischer, A., Rink, L., Zinc inhibits the mixed lymphocyte culture. Biol. Trace Elem. Res. 2001, 79, 15–22.
- 11Faber, C., Gabriel, P., Ibs, K. H., Rink, L., Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response. Bone Marrow Transplant. 2004, 33, 1241–1246.
- 12Stoye, D., Schubert, C., Goihl, A., Guttek, K. et al., Zinc aspartate suppresses T cell activation in vitro and relapsing experimental autoimmune encephalomyelitis in SJL/J mice. Biometals 2012, 25, 529–539.
- 13Kown, M.-H., van der Steenhoven, T.-J., Jahncke, C.-L., Mari, C. et al., Zinc chloride-mediated reduction of apoptosis as an adjunct immunosuppressive modality in cardiac transplantation. J. Heart Lung Transplant. 2002, 21, 360–365.
- 14Kitabayashi, C., Fukada, T., Kanamoto, M., Ohashi, W. et al., Zinc suppresses Th17 development via inhibition of STAT3 activation. Int. Immunol. 2010, 22, 375–386.
- 15Jacobsohn, D.-A., Vogelsang, G.-B., Acute graft versus host disease. Orphanet. J. Rare. Dis. 2007, 2, 35.
- 16Li, X.-C., Turka, L.-A., An update on regulatory T cells in transplant tolerance and rejection. Nat. Rev. Nephrol. 2010, 6, 577–583.
- 17Overbeck, S., Uciechowski, P., Ackland, M.-L., Ford, D., Rink, L., Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9. J. Leukoc. Biol. 2008, 83(2), 368–380.
- 18Kwon, H.-S., Lim, H.-W., Wu, J., Schnolzer, M. et al., Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J. Immunol. 2012, 188, 2712–2721.
- 19Holemon, H., Korshunova, Y., Ordway, J.-M., Bedell, J.-A. et al., MethylScreen: DNA methylation density monitoring using quantitative PCR. Biotechniques 2007, 43, 683–693.
- 20Haase, H., Hebel, S., Engelhardt, G., Rink, L., Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells. Anal. Biochem. 2006, 352, 222–230.
- 21Danzer, S.-G., Rink, L., Reverse transcription polymerase chain reaction for cytokines in the mixed lymphocyte culture. Is there a role in renal transplantation? Nephrol. Dial. Transplant. 1996, 11, 1246–1247.
- 22Lal, G., Zhang, N., van der Touw, W., Ding, Y. et al., Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 2009, 182, 259–273.
- 23Wessels, I., Haase, H., Engelhardt, G., Rink, L., Uciechowski, P., Zinc deficiency induces production of the proinflammatory cytokines IL-1beta and TNFalpha in promyeloid cells via epigenetic and redox-dependent mechanisms. J. Nutr. Biochem. 2013, 24, 289–297.
- 24Haase, H., Ober-Blobaum, J.-L., Engelhardt, G., Hebel, S. et al., Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes. J. Immunol. 2008, 181, 6491–6502.
- 25Jansen, J., Rosenkranz, E., Overbeck, S., Warmuth, S. et al., Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc. J. Nutr. Biochem. 2012, 23, 1458–1466.
- 26van der Meer, A., Wissink, W.-M., Schattenberg, A.-V., Joosten, I., Interferon-gamma-based mixed lymphocyte culture as a selection tool for allogeneic bone marrow donors other than identical siblings. Br. J. Haematol. 1999, 105, 340–348.
- 27Okamoto, T., Kuroki, T., Adachi, T., Ono, S. et al., Effect of zinc on early graft failure following intraportal islet transplantation in rat recipients. Ann. Transplant. 2011, 16, 114–120.
- 28Kown, M.-H., Van der Steenhoven, T., Blankenberg, F.-G., Hoyt, G. et al., Zinc-mediated reduction of apoptosis in cardiac allografts. Circulation 2000, 102, III228–III232.
- 29Spivey, T.-L., Uccellini, L., Ascierto, M.-L., Zoppoli, G. et al., Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis. J. Transl. Med. 2011, 9, 174.
- 30Ju, X., Wang, J., Xu, B., Cao, Y., Lu, S., Roles of interleukin-10 in acute graft-versus-host disease and graft rejection. Chin Med. J. 2003, 116, 534–537.
- 31Zheng, H.-X., Burckart, G.-J., McCurry, K., Webber, S. et al., Interleukin-10 production genotype protects against acute persistent rejection after lung transplantation. J. Heart Lung Transplant. 2004, 23, 541–546.
- 32Akimova, T., Beier, U.-H., Wang, L., Levine, M.-H., Hancock, W.-W., Helios expression is a marker of T cell activation and proliferation. PLoS One 2011, 6, e24226.
- 33Wijdicks, E.-F., Neurotoxicity of immunosuppressive drugs. Liver Transpl. 2001, 7, 937–942.
- 34Sobieszczanska, M., Tubek, S., Szygula, R., Bunio, A., Is the zinc neuroprotective effect caused by prevention of intracellular zinc accumulation? Adv. Clin. Exp. Med. 2012, 21, 245–248.
- 35Singla, N., Dhawan, D.-K., Zinc, a neuroprotective agent against aluminum-induced oxidative DNA injury. Mol. Neurobiol. 2013, 48, 1–12.
- 36Walker, M.-R., Kasprowicz, D.-J., Gersuk, V.-H., Benard, A. et al., Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+. J. Clin. Invest 2003, 112, 1437–1443.
- 37Walsh, P.-T., Taylor, D.-K., Turka, L.-A., Tregs and transplantation tolerance. J. Clin. Invest 2004, 114, 1398–1403.
- 38Venick, R.-S., Farmer, D.-G., Saikali, D., Gordon, S. et al., Nutritional outcomes following pediatric intestinal transplantation. Transplant. Proc. 2006, 38, 1718–1719.
- 39Uckan, D., Cetin, M., Dincer, N., Kalkan, G. et al., Serum zinc and alkaline phosphatase values in pediatric bone marrow transplantation patients. Pediatr. Hematol. Oncol. 2003, 20, 265–271.
- 40Chen, L., Feng, Y., Zhou, Y., Zhu, W. et al., Dual role of Zn2+ in maintaining structural integrity and suppressing deacetylase activity of SIRT1. J. Inorg. Biochem. 2010, 104, 180–185.
- 41van, L.-J., Brunen, D., Fleskens, V., Pals, C.-E. et al., Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLoS One 2011, 6, e19047.
- 42Bobat, R., Coovadia, H., Stephen, C., Naidoo, K.-L. et al., Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial. Lancet 2005, 366, 1862–1867.
- 43Beier, U.-H., Wang, L., Bhatti, T.-R., Liu, Y. et al., Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol. Cell Biol. 2011, 31, 1022–1029.
- 44Yu, M., Lee, W.-W., Tomar, D., Pryshchep, S. et al., Regulation of T cell receptor signaling by activation-induced zinc influx. J. Exp. Med. 2011, 208, 775–785.
- 45Kaltenberg, J., Plum, L.-M., Ober-Blobaum, J.-L., Honscheid, A. et al., Zinc signals promote IL-2-dependent proliferation of T cells. Eur. J. Immunol. 2010, 40, 1496–1503.
- 46Plum, L.-M., Brieger, A., Engelhardt, G., Hebel, S. et al., PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation. Metallomics 2014, 6, 1277–1287.
- 47Waldmann, H., Chen, T.-C., Graca, L., Adams, E. et al., Regulatory T cells in transplantation. Semin. Immunol. 2006, 18, 111–119.
- 48Venken, K., Hellings, N., Broekmans, T., Hensen, K. et al., Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J. Immunol. 2008, 180, 6411–6420.
- 49Provoost, S., Maes, T., van Durme, Y.-M., Gevaert, P. et al., Decreased FOXP3 protein expression in patients with asthma. Allergy 2009, 64, 1539–1546.
- 50Huter, E.-N., Stummvoll, G.-H., DiPaolo, R.-J., Glass, D.-D., Shevach, E.-M., Cutting edge: antigen-specific TGF beta-induced regulatory T cells suppress Th17-mediated autoimmune disease. J. Immunol. 2008, 181, 8209–8213.
