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Sodium Selenite Diminished the Regulatory T Cell Differentiation In Vitro

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Abstract

Sodium selenite modulates the activity of lymphocytes. It negatively regulates the suppressive activity of cells and increases the immune response. In this study, we evaluated whether the regulatory T cell differentiation was modulated by sodium selenite. The percentages of CD4+CD25+Foxp3+, CD4+CD25+, and CD4+CTLA-4+ cells in CD4+ T cells cultures stimulated with IL-2 and TGF-β in the presence or absence of selenium, in the form of sodium selenite (2.0×10−6M), were evaluated by flow cytometry. The mRNA expression of TET2/3 enzymes and IL-10 was analyzed by RT-qPCR and the levels of IL-10 were measured by an ELISA. We observed a decrease in CD4+CD25+Foxp3+ and CD4+CTLA-4+ cells in presence of selenium. However, normal percentages were reached again after selenium removal. An increase in CD4+CTL4-4+ cells was detected in selenium-primed cell cultures in absence of IL-2 and TGF-β. In addition, we observed a decrease in TET3 in presence of selenium. Finally, we observed an augment in IL-10 transcription and protein levels and relative expression of TET2 in cultures exposed to selenium. We suggest that selenium reversibly affects the regulatory T cell differentiation in vitro. Likewise, selenium may modulate Treg percentages promoting optimal immune responses and, at the same time, the expression of specific suppressor molecules.

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References

  1. Neve J (2002) Selenium as a 'nutraceutical': how to conciliate physiological and supra-nutritional effects for an essential trace element. Curr Opin Clin Nutr Metab Care 5:659–663. https://doi.org/10.1097/00075197-200211000-00008

    Article  CAS  PubMed  Google Scholar 

  2. Rayman MP (2005) Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc Nutr Soc 64:527–542. https://doi.org/10.1079/pns2005467

    Article  CAS  PubMed  Google Scholar 

  3. Watson RR, Moriguchi S, McRae B, Tobin L, Mayberry JC, Lucas D (1986) Effects of selenium in vitro on human T-lymphocyte functions and K-562 tumor cell growth. J Leukoc Biol 39:447–456. https://doi.org/10.1002/jlb.39.4.447

    Article  CAS  PubMed  Google Scholar 

  4. Petrie HT, Klassen LW, Kay HD (1989) Selenium and the immune response: 1. Modulation of alloreactive human lymphocyte functions in vitro. J Leukoc Biol 45:207–214. https://doi.org/10.1002/jlb.45.3.207

    Article  CAS  PubMed  Google Scholar 

  5. Spallholz JE, Martin JL, Gerlach ML, Heinzerling RH (1973) Enhanced immunoglobulin M and immunoglobulin G antibody titers in mice fed selenium. Infect Immun 8:841–842. https://doi.org/10.1128/iai.8.5.841-842.1973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Petrie HT, Klassen LW, Klassen PS, O'Dell JR, Kay HD (1989) Selenium and the immune response: 2. Enhancement of murine cytotoxic T-lymphocyte and natural killer cell cytotoxicity in vivo. J Leukoc Biol 45:215–220. https://doi.org/10.1002/jlb.45.3.215

    Article  CAS  PubMed  Google Scholar 

  7. Yamaguchi T, Wing JB, Sakaguchi S (2011) Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol 23:424–430. https://doi.org/10.1016/j.smim.2011.10.002

    Article  CAS  PubMed  Google Scholar 

  8. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164

    Article  CAS  PubMed  Google Scholar 

  9. Kim CH (2009) FOXP3 and its role in the immune system. Adv Exp Med Biol 665:17–29. https://doi.org/10.1007/978-1-4419-1599-3_2

    Article  CAS  PubMed  Google Scholar 

  10. Annunziato F, Cosmi L, Liotta F, Lazzeri E, Manetti R, Vanini V, Romagnani MPE, Romagnani S (2002) Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 196:379–387. https://doi.org/10.1084/jem.20020110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Manzotti CN, Tipping H, Perry LC, Mead KI, Blair PJ, Zheng Y, Sansom DM (2002) Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells. Eur J Immunol 32:2888–2896. https://doi.org/10.1002/1521-4141(2002010)32:10<2888::AID-IMMU2888>3.0.CO;2-F

    Article  CAS  PubMed  Google Scholar 

  12. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101. https://doi.org/10.1038/ni846

    Article  CAS  PubMed  Google Scholar 

  13. Toker A, Engelbert D, Garg G, Polansky JK, Floess S, Miyao T, Baron U, Duber S, Geffers R, Giehr P, Schallenberg S, Kretschmer K, Olek S, Walter J, Weiss S, Hori S, Hamann A, Huehn J (2013) Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J Immunol 190:3180–3188. https://doi.org/10.4049/jimmunol.1203473

    Article  CAS  PubMed  Google Scholar 

  14. Huehn J, Polansky JK, Hamann A (2009) Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nature reviews. Immunology 9:83–89. https://doi.org/10.1038/nri2474

    Article  CAS  PubMed  Google Scholar 

  15. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352. https://doi.org/10.1038/ni1178

    Article  CAS  PubMed  Google Scholar 

  16. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811. https://doi.org/10.1182/blood-2006-02-002774

    Article  CAS  PubMed  Google Scholar 

  17. Nair VS, Oh KI (2014) Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells. Biochem Biophys Res Commun 450:918–924. https://doi.org/10.1016/j.bbrc.2014.06.110

    Article  CAS  PubMed  Google Scholar 

  18. Sasidharan Nair V, Song MH, Oh KI (2016) Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J Immunol 196:2119–2131. https://doi.org/10.4049/jimmunol.1502352

    Article  CAS  PubMed  Google Scholar 

  19. Petrie HT, Klassen LW, Tempero MA, Kay HD (1986) In vitro regulation of human lymphocyte proliferation by selenium. Biol Trace Elem Res 11:129–146. https://doi.org/10.1007/BF02795530

    Article  CAS  PubMed  Google Scholar 

  20. Hoffmann FW, Hashimoto AC, Shafer LA, Dow S, Berry MJ, Hoffmann PR (2010) Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols. J Nutr 140:1155–1161. https://doi.org/10.3945/jn.109.120725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Safir N, Wendel A, Saile R, Chabraoui L (2003) The effect of selenium on immune functions of J774.1 cells. Clin Chem Lab Med 41:1005–1011. https://doi.org/10.1515/CCLM.2003.154

    Article  CAS  PubMed  Google Scholar 

  22. Xiang N, Zhao R, Song G, Zhong W (2008) Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Carcinogenesis 29:2175–2181. https://doi.org/10.1093/carcin/bgn179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Robb RJ (1986) Conversion of low-affinity interleukin 2 receptors to a high-affinity state following fusion of cell membranes. Proc Natl Acad Sci U S A 83:3992–3996. https://doi.org/10.1073/pnas.83.11.3992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hoffmann PR, Jourdan-Le Saux C, Hoffmann FW, Chang PS, Bollt O, He Q, Tam EK, Berry MJ (2007) A role for dietary selenium and selenoproteins in allergic airway inflammation. J Immunol 179:3258–3267. https://doi.org/10.4049/jimmunol.179.5.3258

    Article  CAS  PubMed  Google Scholar 

  25. Roy M, Kiremidjian-Schumacher L, Wishe HI, Cohen MW, Stotzky G (1992) Effect of selenium on the expression of high affinity interleukin 2 receptors. Proc Soc Exp Biol Med 200:36–43. https://doi.org/10.3181/00379727-200-43391

    Article  CAS  PubMed  Google Scholar 

  26. Mitchell RE, Hassan M, Burton BR, Britton G, Hill EV, Verhagen J, Wraith DC (2017) IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. Sci Rep 7:11315. https://doi.org/10.1038/s41598-017-11803-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barron L, Dooms H, Hoyer KK, Kuswanto W, Hofmann J, O'Gorman WE, Abbas AK (2010) Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol 185:6426–6430. https://doi.org/10.4049/jimmunol.0903940

    Article  CAS  PubMed  Google Scholar 

  28. Altin JA, Goodnow CC, Cook MC (2012) IL-10+ CTLA-4+ Th2 inhibitory cells form in a Foxp3-independent, IL-2-dependent manner from Th2 effectors during chronic inflammation. J Immunol 188:5478–5488. https://doi.org/10.4049/jimmunol.1102994

    Article  CAS  PubMed  Google Scholar 

  29. Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J, Martin MG, Chatila TA (2005) Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 116:1106–1115. https://doi.org/10.1016/j.jaci.2005.08.046

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Perez Ruiz-Esparza Julian for his technical assistance

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Authors and Affiliations

  1. Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Sciences, Autonomous University of San Luis Potosí, UASLP, San Luis Potosí, Mexico

    E. E. Uresti-Rivera

  2. Unidad de Investigación Biomédica, Delegación Zacatecas, Instituto Mexicano del Seguro Social, IMSS, Interior de la Alameda No.45, 98000, Zacatecas, Zac, México

    G. Méndez-Frausto & M. H. García-Hernández

  3. Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico

    M. N. Medina-Rosales & J. Ventura-Juárez

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  1. E. E. Uresti-Rivera
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  3. M. N. Medina-Rosales
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  4. J. Ventura-Juárez
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  5. M. H. García-Hernández
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Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Mendez-Frausto G and Uresti-Rivera EE. The first draft of the manuscript was written by Garcia-Hernandez MH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript

Corresponding author

Correspondence to M. H. García-Hernández.

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Conflict of Interest

Author Mendez-Frausto G received a research grant from Company CONACYT (scholarship number: 461538). She declares that she has no conflict of interest. In addition, all authors depicted in this study declare that they have no conflict of interest.

Ethical Approval

All procedures performed in the study were in accordance with the ethical standards of the bioethical committee of the National Commission for Scientific Research of IMSS (project R-2018-785-072) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Supplementary Fig. 1

Flow cytometry analyses. a) The percentage of viable, early apoptotic, late apoptotic, and necrotic cells are shown. The cells were incubated in presence of sodium selenite concentrations without stimulation for 24 hours, according to depicted in the material and methods section. Dead cell apoptosis was measured through Annexin-V and PI staining by flow cytometry. Data are presented as mean ± SEM. A two-way ANOVA test was used for statistical analysis. *P<0.05 was considered significant. Horizontal lines show statistically significant differences between the indicated groups. b) Representative dot plot of the purity of CD4+ T cells after isolation, as shown in the Material and Methods section. c) Representative dot plot showed the gating strategy for CD4+CD25+Foxp3+ cells evaluation after Treg differentiation. Fluorescence minus one (FMO) control is shown. First, CD4 + cells were observed in the absence of the CD25 marker, then a gate location was defined to determine CD4 + CD25 + cells. Finally, to determine CD4+CD25+Foxp3+ cells, CD4 + CD25 + cells were in the absence of a Foxp3 marker to delimit a gate location. (PNG 310 kb)

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Uresti-Rivera, E.E., Méndez-Frausto, G., Medina-Rosales, M.N. et al. Sodium Selenite Diminished the Regulatory T Cell Differentiation In Vitro. Biol Trace Elem Res 201, 1559–1566 (2023). https://doi.org/10.1007/s12011-022-03263-x

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  • DOI: https://doi.org/10.1007/s12011-022-03263-x

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