Journal of Clinical Immunology

, Volume 29, Issue 4, pp 461–469 | Cite as

Effect of Arsenic on Regulatory T Cells

  • B. Hernández-Castro
  • L. M. Doníz-Padilla
  • M. Salgado-Bustamante
  • D. Rocha
  • M. D. Ortiz-Pérez
  • M. E. Jiménez-Capdeville
  • D. P. Portales-Pérez
  • A. Quintanar-Stephano
  • R. González-Amaro



Arsenic (As) affects the function and survival of lymphocytes, and some arsenic compounds exert a relevant antineoplastic effect. We have explored the effect of As on T regulatory cells.

Results and Discussion

In vitro experiments with peripheral blood mononuclear cells from healthy subjects showed that low concentrations of As tended to increase the number of natural T regulatory (nTreg) lymphocytes, whereas concentrations >5.0 μM had an opposite effect. Furthermore, rats exposed to As showed redistribution of nTreg cells, and As administration to rats with experimental allergic encephalomyelitis increased the levels of nTreg cells in spleen and diminished the severity of this condition. On the other hand, in 47 apparently healthy subjects chronically exposed to As, we found significant inverse correlation between urinary As levels and the number and function of nTreg lymphocytes. Although most of these individuals showed enhanced levels of apoptotic lymphocytes in peripheral blood, with a diminution of mitochondrial membrane potential, no significant correlation between these parameters and urinary As was detected.


Our data indicate that As seems to have a relevant and complex effect on nTreg cells.


T lymphocytes apoptosis immunoregulation cytokines immunosuppression 


  1. 1.
    Stockinger B, Kassiotis G, Bourgeois C. Homeostasis and T cell regulation. Curr Opin Immunol. 2004;16:775–9. doi:10.1016/j.coi.2004.09.003.PubMedCrossRefGoogle Scholar
  2. 2.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87. doi:10.1016/j.cell.2008.05.009.PubMedCrossRefGoogle Scholar
  3. 3.
    Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007;13:108–16. doi:10.1016/j.molmed.2007.01.003.PubMedCrossRefGoogle Scholar
  4. 4.
    Sakaguchi S, Ono M, Setoguchi R, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27. doi:10.1111/j.0105-2896.2006.00427.x.PubMedCrossRefGoogle Scholar
  5. 5.
    Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7:875–88. doi:10.1038/nri2189.PubMedCrossRefGoogle Scholar
  6. 6.
    Shevach EM. Regulatory/suppressor T cells in health and disease. Arthritis Rheum. 2004;50:2721–4. doi:10.1002/art.20500.PubMedCrossRefGoogle Scholar
  7. 7.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001;182:68–79. doi:10.1034/j.1600-065X.2001.1820105.x.PubMedCrossRefGoogle Scholar
  8. 8.
    Cortesini R, LeMaoult J, Ciubotariu R, Foca-Cortesini NS. CD8+CD28 T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol Rev. 2001;182:201–6. doi:10.1034/j.1600-065X.2001.1820116.x.PubMedCrossRefGoogle Scholar
  9. 9.
    ATSDR. Toxicological profile for arsenic: agency for toxic substances and disease register. US, Atlanta GA: Department of Health & Human Services; 1999.Google Scholar
  10. 10.
    Vega L, Ostrosky-Wegman P, Fortoul TI, Diaz C, Madrid V, Saavedra R. Sodium arsenite reduces proliferation of human activated T-cells by inhibition of the secretion of interleukin-2. Immunopharmacol Immunotoxicol. 1999;21:203–20. doi:10.3109/08923979909052758.PubMedCrossRefGoogle Scholar
  11. 11.
    Soto-Peña GA, Luna AL, Acosta-Saavedra L, et al. Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. FASEB J. 2006;20:779–81.PubMedGoogle Scholar
  12. 12.
    Conde P, Acosta-Saavedra LC, Gotilla-Acevedo RC, Calderón-Aranda ES. Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells. Arch Toxicol. 2007;81:251–9. doi:10.1007/s00204-006-0152-7.PubMedCrossRefGoogle Scholar
  13. 13.
    Pineda-Zavaleta AP, García-Vargas G, Borja-Aburto VH, et al. Nitric oxide and superoxide anion production in monocytes from children exposed to arsenic and lead in region Lagunera, Mexico. Toxicol Appl Pharmacol. 2004;198:283–90. doi:10.1016/j.taap.2003.10.034.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith AH, Hopenhayn-Rich C, Bates MN, et al. Cancer risks from Arsenic in drinking water. Environ Health Perspect. 1992;97:259–67. doi:10.2307/3431362.PubMedCrossRefGoogle Scholar
  15. 15.
    Rossman TG. Mechanisms of arsenic carcinogenesis: an integrated approach. Mutat Res. 2003;533:37–65. doi:10.1016/j.mrfmmm.2003.07.009.PubMedGoogle Scholar
  16. 16.
    Diaz Z, Mann KK, Marcoux S, et al. A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. Leukemia. 2008;22:1853–63. doi:10.1038/leu.2008.194.PubMedCrossRefGoogle Scholar
  17. 17.
    Litzow MR. Arsenic trioxide. Expert Opin Pharmacother. 2008;9:1773–85. doi:10.1517/14656566.9.10.1773.PubMedCrossRefGoogle Scholar
  18. 18.
    de la Fuente H, Portales-Pérez D, Baranda L, et al. Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human mononuclear cells. Clin Exp Immunol. 2002;129:69–77. doi:10.1046/j.1365-2249.2002.01885.x.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang SL, Chang FH, Liou SH, Wang HJ, Li WF, Hsieh DP. Inorganic arsenic exposure and its relation to metabolic syndrome in an industrial area of Taiwan. Environ Int. 2007;33:805–11. doi:10.1016/j.envint.2007.03.004.PubMedCrossRefGoogle Scholar
  20. 20.
    Naithani R, Mahapatra M, Kumar R, Kumar A, Agrawal N. Arsenic trioxide induced acute flare-up of rheumatoid arthritis in a patient with APL. Ann Hematol. 2007;86:151–2. doi:10.1007/s00277-006-0208-z.PubMedCrossRefGoogle Scholar
  21. 21.
    Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, Guallar E. Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA. 2008;300:814–22. doi:10.1001/jama.300.7.814.PubMedCrossRefGoogle Scholar
  22. 22.
    Vigna-Pérez M, Abud-Mendoza C, Portillo-Salazar H, et al. Immune effects of therapy with Adalimumab in patients with rheumatoid arthritis. Clin Exp Immunol. 2005;141:372–80. doi:10.1111/j.1365-2249.2005.02859.x.PubMedCrossRefGoogle Scholar
  23. 23.
    O’Connor RA, Anderton SM. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J Neuroimmunol. 2008;193:1–11. doi:10.1016/j.jneuroim.2007.11.016.PubMedCrossRefGoogle Scholar
  24. 24.
    Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307. doi:10.1038/nri1806.PubMedCrossRefGoogle Scholar
  25. 25.
    Tone M, Tone Y, Adams E, et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A. 2003;100:15059–64. doi:10.1073/pnas.2334901100.PubMedCrossRefGoogle Scholar
  26. 26.
    Prieto GA, Rosenstein Y. Oestradiol potentiates the suppressive function of human CD4+CD25+ regulatory T cells by promoting their proliferation. Immunology. 2006;118:58–65. doi:10.1111/j.1365-2567.2006.02339.x.PubMedCrossRefGoogle Scholar
  27. 27.
    Urzainqui A, Martínez del Hoyo G, Lamana A, et al. Functional role of P-selectin glycoprotein ligand 1/P-selectin interaction in the generation of tolerogenic dendritic cells. J Immunol. 2007;179:7457–65.PubMedGoogle Scholar
  28. 28.
    Vigna-Perez M, Hernández-Castro B, Paredes-Saharopulos O, et al. Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther. 2006;8:R83. doi:10.1186/ar1954.PubMedCrossRefGoogle Scholar
  29. 29.
    Quintana FJ, Basso AS, Iglesias AH, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453:65–71. doi:10.1038/nature06880.PubMedCrossRefGoogle Scholar
  30. 30.
    Bobé P, Bonardelle D, Benihoud K, Opolon P, Chelbi-Alix MK. Arsenic trioxide: a promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice. Blood. 2006;108:3967–75. doi:10.1182/blood-2006-04-020610.PubMedCrossRefGoogle Scholar
  31. 31.
    Nadkarni S, Mauri C, Ehrenstein M. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med. 2007;204:33–9. doi:10.1084/jem.20061531.PubMedCrossRefGoogle Scholar
  32. 32.
    Chen YZ, Wu Y, Huang MJ, Lu LH. Effect of endogenous TGF-beta1 and TNF-alpha on the As(2)O(3) inducing apoptosis of HL-60 cells. Zhonghua Xue Ye Xue Za Zhi. 2003;24:231–4.PubMedGoogle Scholar
  33. 33.
    Yoshida T, Shimamura T, Shigeta S. Enhancement of the immune response in vitro by arsenic. Int J Immunopharmacol. 1987;9:411–5. doi:10.1016/0192-0561(87)90068-3.PubMedCrossRefGoogle Scholar
  34. 34.
    Ehrenstein MR, Evans JG, Singh A, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF-alpha therapy. J Exp Med. 2004;200:277–85. doi:10.1084/jem.20040165.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • B. Hernández-Castro
    • 1
  • L. M. Doníz-Padilla
    • 1
  • M. Salgado-Bustamante
    • 1
  • D. Rocha
    • 2
  • M. D. Ortiz-Pérez
    • 3
  • M. E. Jiménez-Capdeville
    • 3
  • D. P. Portales-Pérez
    • 4
  • A. Quintanar-Stephano
    • 5
  • R. González-Amaro
    • 1
  1. 1.Department of Immunology, Facultad de MedicinaUASLPSan Luis PotosíMéxico
  2. 2.Department of Environmental Toxicology, Facultad de MedicinaUASLPSan Luis PotosíMéxico
  3. 3.Department of Biochemistry, Facultad de MedicinaUASLPSan Luis PotosíMéxico
  4. 4.Laboratory of Cellular and Molecular Immunology, Facultad de Ciencias QuímicasUASLPSan Luis PotosíMéxico
  5. 5.Laboratory of NeuroimmunoendocrinologyCentro de Ciencias Básicas, UAAAguascalientesMéxico

Personalised recommendations