Biological Trace Element Research

, Volume 170, Issue 1, pp 194–200 | Cite as

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

  • Songna Yin
  • Haibo Wu
  • Chao Song
  • Xin Chen
  • Yong ZhangEmail author


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.


Sodium fluoride Mice Thymus T cells TECs 



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) (


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

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12011_2015_458_MOESM1_ESM.docx (18 kb)
Table S1 Sequences of primers for Real-Time PCR. (DOCX 18 kb)


  1. 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 308:138–145Google Scholar
  2. 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):461–465Google Scholar
  3. 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):218–224Google Scholar
  4. 4.
    Agalakova NI, Gusev GP (2012) Molecular mechanisms of cytotoxicity and apoptosis induced by inorganic fluoride. ISRN Cell Biol 2012:1–16CrossRefGoogle Scholar
  5. 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):685–692Google Scholar
  6. 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):413–420Google Scholar
  7. 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):219–227Google Scholar
  8. 8.
    Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4(+)T cells: differentiation and functions. Clin Dev Immunol 2012:925135PubMedCentralCrossRefPubMedGoogle Scholar
  9. 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):177–190CrossRefPubMedGoogle Scholar
  10. 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):e114584Google Scholar
  11. 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–S77Google Scholar
  12. 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):353–361Google Scholar
  13. 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):1–5CrossRefPubMedGoogle Scholar
  14. 14.
    Gray DHD, Chidgey AP, Boyd RL (2002) Analysis of thymic stromal cell populations using flow cytometry. J Immunol Methods 260(1–2):15–28CrossRefPubMedGoogle Scholar
  15. 15.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9), e45PubMedCentralCrossRefPubMedGoogle Scholar
  16. 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):46–51Google Scholar
  17. 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):103–111CrossRefPubMedGoogle Scholar
  18. 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 18:185–216CrossRefPubMedGoogle Scholar
  19. 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):106–110PubMedCentralCrossRefPubMedGoogle Scholar
  20. 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 148:35–44Google Scholar
  21. 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):953–961Google Scholar
  22. 22.
    Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33(6):256–263CrossRefPubMedGoogle Scholar
  23. 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):347–357Google Scholar
  24. 24.
    Coffer PJ, Burgering BMT (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4(11):889–899CrossRefPubMedGoogle Scholar
  25. 25.
    Cunningham-Rundles C, Ponda PP (2005) Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol 5(11):880–892CrossRefPubMedGoogle Scholar
  26. 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):780–788Google Scholar
  27. 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):2507–2513Google Scholar
  28. 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):468–474Google Scholar
  29. 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):263–263Google Scholar
  30. 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):6084–6089Google Scholar
  31. 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):149–159CrossRefPubMedGoogle Scholar
  32. 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):2808–2814Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Songna Yin
    • 1
    • 2
  • Haibo Wu
    • 1
    • 2
  • Chao Song
    • 1
    • 2
  • Xin Chen
    • 1
    • 2
  • Yong Zhang
    • 1
    • 2
    Email author
  1. 1.College of Veterinary MedicineNorthwest A&F UniversityYanglingChina
  2. 2.Key Laboratory of Animal Biotechnology, Ministry of AgricultureNorthwest A&F UniversityYanglingChina

Personalised recommendations