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Modulation and the Underlying Mechanism of T Cells in Thymus of Mice by Oral Administration of Sodium Fluoride

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Abstract

The underlying mechanism of thymic T cell regulation has been a hot topic of research in recent years. Fluoride is toxic at high concentrations and fluoride toxicity to thymic T cells was assessed in our study. To explore T cell responses to excess fluoride, different concentrations of fluoride were uptake by mice for 6 weeks. The expression of genes, including Foxn1, Cbx4, DLL4, and IL-7 gene, associated with the development and differentiation of T cells in thymic epithelial cells(TECs) was lower in the experimental groups than that in the control group. The percentages of CD4+ and CD8+ T cells that decreased with the fluoride administration were confirmed by flow cytometry. The mRNA levels of immunoregulatory cytokines IL-2 and IL-10, which participate in T cell proliferation, also declined in the experimental groups as compared with the control group. Expression of the T cell function-related genes CD2, PTPRC, CD69, and CD101, which are involved in thymic function in mice, decreased with the fluoride administration. Our findings suggest that the administration of high concentrations of fluoride to mice induces a decrease in CD4+ and CD8+ thymus T cells by harming TECs leading to the dysfunction of the thymus by altering the expression of T cell function-related genes and immunoregulatory cytokine production.

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References

  1. Li P, Xue YP, Zhang WB, Teng F, Sun Y, Qu TJ (2013) Sodium fluoride induces apoptosis in odontoblasts via a JNK-dependent mechanism. Toxicology 308:138–145

  2. Karube H, Nishitai G, Inageda K, Kurosu H, Matsuoka M (2009) NaF activates MAPKs and induces apoptosis in odontoblast-like cells. J Dent Res 88(5):461–465

  3. Wang HW, Zhou BH, Cao JL, Gu XL, Cao CF, Wang JD et al (2009) Effects of dietary protein and calcium on thymus apoptosis induced by fluoride in female rats (Wistar Rats). Environ Toxicol 24(3):218–224

  4. Agalakova NI, Gusev GP (2012) Molecular mechanisms of cytotoxicity and apoptosis induced by inorganic fluoride. ISRN Cell Biol 2012:1–16

    Article  Google Scholar 

  5. Chen T, Cui HM, Cui Y, Bai CM, Gong T, Peng X (2011) Cell-cycle blockage associated with increased apoptotic cells in the thymus of chickens fed on diets high in fluorine. Hum Exp Toxicol 30(7):685–692

  6. Liu H, Gao YH, Sun LY, Li M,  Li BY, Sun, DJ (2014) Assessment of relationship on excess fluoride intake from drinking water and carotid atherosclerosis development in adults in fluoride endemic areas, China. Int J Hyg Envir Heal 217(2–3):413–420

  7. Cao AC, Guo MX, Yan DD, Mao LG, Wang QX, Li Y et al (2014) Evaluation of sulfuryl fluoride as a soil fumigant in China. Pest Manag Sci 70(2):219–227

  8. Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4(+)T cells: differentiation and functions. Clin Dev Immunol 2012:925135

    Article  PubMed Central  PubMed  Google Scholar 

  9. Alexandropoulos K, Danzl NM (2012) Thymic epithelial cells: antigen presenting cells that regulate T cell repertoire and tolerance development. Immunol Res 54(1–3):177–190

    Article  CAS  PubMed  Google Scholar 

  10. Cuervo-Escobar S, Losada-Barragan M, Umana-Perez A, Porrozzi R, Saboia-Vahia L, Miranda LH et al (2014) T-cell populations and cytokine expression are impaired in thymus and spleen of protein malnourished BALB/c mice infected with leishmania infantum. PLoS ONE 9(12):e114584

  11. Stawiarska-Pieta B, Grzegorzak N, Kuczera K, Hells A, Zalejska-Fiolka J, Bielec B et al (2013) The effect of antioxidants on the morphological picture of thymus and heart of rats intoxicated with sodium fluoride. Toxicol Lett 221:S77–S77

  12. Sun Z, Niu R, Su K, Wang B, Wang JM, Zhang JH  et al (2010) Effects of sodium fluoride on hyperactivation and Ca2+ signaling pathway in sperm from mice: an in vivo study. Arch Toxicol 84(5):353–361

  13. Zhang M, Wang A, Xia T, He P (2008) Effects of fluoride on DNA damage, S-phase cell-cycle arrest and the expression of NF-kappaB in primary cultured rat hippocampal neurons. Toxicol Lett 179(1):1–5

    Article  CAS  PubMed  Google Scholar 

  14. Gray DHD, Chidgey AP, Boyd RL (2002) Analysis of thymic stromal cell populations using flow cytometry. J Immunol Methods 260(1–2):15–28

    Article  CAS  PubMed  Google Scholar 

  15. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9), e45

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Freedman AR, Zhu HH, Levine JD, Kalams S, Scadden DT (1996) Generation of human T lymphocytes from bone marrow CD34(+) cells in vitro. Nat Med 2(1):46–51

  17. Hayball JD, Robinson BWS, Lake RA (2004) CD4(+) T cells cross-compete for MHC class II-restricted peptide antigen complexes on the surface of antigen presenting cells. Immunol Cell Biol 82(2):103–111

    Article  CAS  PubMed  Google Scholar 

  18. Jiang H, Chess L (2000) The specific regulation of immune responses by CD8+ T cells restricted by the MHC class IB molecule, QA-1. Annu Rev Immunol 18:185–216

    Article  CAS  PubMed  Google Scholar 

  19. Ozdemir C, Akdis M, Akdis CA (2008) Nature of regulatory T cells in the context of allergic disease. Allergy Asthma Clin Immunol 4(3):106–110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Horak I, Lohler J, Ma A, Smith KA (1995) Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev 148:35–44

  21. Ogilvie RL, Abelson M, Hau HH, Vlasova I, Blackshear PJ, Bohjanen PR (2005) Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. J Immunol 174(2):953–961

  22. Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33(6):256–263

    Article  CAS  PubMed  Google Scholar 

  23. Sun LG, Guo JF, Brown R, Amagai T, Zhao Y, Su DM (2010) Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell 9(3):347–357

  24. Coffer PJ, Burgering BMT (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4(11):889–899

    Article  CAS  PubMed  Google Scholar 

  25. Cunningham-Rundles C, Ponda PP (2005) Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol 5(11):880–892

    Article  CAS  PubMed  Google Scholar 

  26. Liu B, Liu YF, Du YR, Mardaryev AN, Yang W, Chen H et al (2013) Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development 140(4):780–788

  27. Hozumi K, Mailhos C, Negishi N, Hirano KI, Yahata T, Ando T et al (2008) Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med 205(11):2507–2513

  28. Alves NL, Huntington ND, Rodewald HR, Di Santo JP (2009) Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”. Trends Immunol 30(10):468–474

  29. Teh HS, Killeen N, Teh SJ (1996) CD2 regulates the positive selection and function of antigen-specific CD4(−)CD8(+) T cells. FASEB J 10(6):263–263

    Google Scholar 

  30. Fortin M, Steff AM, Felberg J, Ding I, Schraven B, Johnson P et al (2002) Apoptosis mediated through CD45 is independent of its phosphatase activity and association with leukocyte phosphatase-associated phosphoprotein. J Immunol 168(12):6084–6089

  31. Alfonso C, McHeyzer-Williams MG, Rosen H (2006) CD69 down-modulation and inhibition of thymic egress by short- and long-term selective chemical agonism of sphingosine 1-phosphate receptors. Eur J Immunol 36(1):149–159

    Article  CAS  PubMed  Google Scholar 

  32. Fernandez I, Zeiser R, Karsunky H, Kambham N, Beilhack A, Soderstrom K et al (2007) CD101 surface expression discriminates potency among murine FoxP3+ regulatory T cells. J Immunol 179(5):2808–2814

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Acknowledgements

We thank Dr. Jianhui Wei and Dr. Zhikun Xu for insightful discussions and carefully correcting the paper. This work was supported by the National High Technology Research and Development Program of China (863 Program) (No. 2011AA100303) (http://www.most.gov.cn).

Funding

This study was funded by the National High Technology Research and Development Program of China (863 Program) (No. 2011AA100303) (http://www.most.gov.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare that they have no conflict of interest.

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Correspondence to Yong Zhang.

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Table S1

Sequences of primers for Real-Time PCR. (DOCX 18 kb)

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Yin, S., Wu, H., Song, C. et al. Modulation and the Underlying Mechanism of T Cells in Thymus of Mice by Oral Administration of Sodium Fluoride. Biol Trace Elem Res 170, 194–200 (2016). https://doi.org/10.1007/s12011-015-0458-5

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  • DOI: https://doi.org/10.1007/s12011-015-0458-5

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