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Reduced Number and Function of CD4+ CD25 high FoxP3 + Regulatory T Cells in Patients with Systemic Lupus Erythematosus

  • Elena Yu. Lyssuk
  • Anna V. Torgashina
  • Sergey K. Soloviev
  • Evgeny L. Nassonov
  • Svetlana N. Bykovskaia
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)

Abstract

CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining tolerance to self-antigens controlling occurrence of autoimmune diseases. Recently, it has been shown that the transcription factor forkhead box P3 (FoxP3) is specifically expressed on CD4+CD25+ T cells. FoxP3 has been described as the master control gene for the development and function of Tregs. We characterized CD4+CD25+CTLA-4+FoxP3+ T cells in 43 patients with systemic lupus erythematosus (SLE). Twenty of them comprised a group of newly admitted patients with the first manifestations of the disease, and the second group included patients that were treated with cytostatics and steroids. The results revealed a significant decrease in CD4+CD25+ and CD4+CD25high T cells numbers in patients from group I compared with control and group II patients. Coexpression of FoxP3 on CD4+CD25+ T cells was significantly reduced in both groups regardless the therapy. The ability of Tregs to suppress proliferation of autologous CD8+ and CD4+ T cells was significantly reduced in both groups of patients compared to healthy donors. Our data revealed impaired production of Tregs in SLE patients that can be partly restored by conventional treatments.

Keywords

Systemic Lupus Erythematosus Systemic Lupus Erythematosus Patient Healthy Donor FOXP3 Expression Autoimmune Polyglandular Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Allan, S.E., Passerini, L., Bacchetta, R., Crellin, N., Dai, M., Orban, P.C., Ziegler, S.F., Roncarolo, M.G. and Levings, M.K. (2005) The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276–3284.CrossRefPubMedGoogle Scholar
  2. Alvarado-Sanchez, B., Hernandez-Castro, B., Portales-Perez, D., Baranda, L., Layseca-Espinosa, E., Abud-Mendoza, C., Cubillas-Tejeda, A.C. and Gonzalez-Amaro, R. (2006) Regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun. 27, 110–118.CrossRefPubMedGoogle Scholar
  3. Beacher-Allan, C., Brown, J.A., Freeman, G.J. and Hafler, D.A. (2001) CD4+CD25high regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253.Google Scholar
  4. Bennett, C.L., Christie, J., Ramsdell, F., Brunkow, M.E., Ferguson, P.J., Whitesell, L., Kelly, T.E., Saulsbury, F.T., Chance, P.F. and Ochs, H.D. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21.CrossRefPubMedGoogle Scholar
  5. Chen, Z., Herman, A.E., Matos, M., Mathis, D. and Benoist, C. (2005) Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J. Exp. Med. 202, 1387–1397.CrossRefPubMedGoogle Scholar
  6. Crispin, J.C., Martinez, A. and Alcocer-Varela, J. (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun. 21, 273–276.CrossRefPubMedGoogle Scholar
  7. Fontenot, J.D., Gavin, M.A. and Rudensky, A.Y. (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336.CrossRefPubMedGoogle Scholar
  8. Gavin, M.A., Taogerson, T.R., Houston, E., DeRoos, P., Ho, W.Y., Stray-Pedersen, A., Ocheltree, E.L., Greenberg, P.D., Ochs, H.D. and Rudensky, A.Y. (2006) Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl. Acad. Sci. U.S.A. 103, 6659–6664.CrossRefPubMedGoogle Scholar
  9. Hori, S., Takahashi, T. and Sakaguchi, S. (2003) Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv. Immunol. 81, 331–371.CrossRefPubMedGoogle Scholar
  10. Kriegel, M.A., Lohmann, T., Gabler, C., Blank, N., Kalden, J.R. and Lorenz, H.M. (2004) Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J. Exp. Med. 199, 1285–1291.CrossRefPubMedGoogle Scholar
  11. Lee, J.H., Wang, L.C., Lin, Y.T., Yang, Y.H., Lin, D.T. and Bhiang, B.L. (2006) Inverse correlation between CD4+ regulatory T cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 117, 280–286.CrossRefPubMedGoogle Scholar
  12. Lindley, S., Dayan, C.M., Bishop, A., Roep, B.O., Peakman, M. and Treem T.I. (2005) Defective suppressor function in CD4(+)CD25(+) T cells from patients with type 1 diabetes. Diabetes 54, 92–99.CrossRefPubMedGoogle Scholar
  13. Liu, M.F., Wang, C.R., Fung, L.L. and Wu, C.R. (2004) Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand. J. Immunol. 59, 198–202.CrossRefPubMedGoogle Scholar
  14. Lyons, A.B. (2000) Analyzing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. J. Immunol. Methods 243, 147–154.CrossRefPubMedGoogle Scholar
  15. Miyara, M., Amoura, Z., Parizot, C., Badoual, C., Dorgham, K., Trad, S., Nochy, D., Debre, P., Piette, J.C. and Gorochov, G. (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J. Immunol. 175, 8392–8400.PubMedGoogle Scholar
  16. Read, S., Greenwald, R., Izcue, A., Robinson, N., Mandelbrot, D., Francisco, L., Sharpe, A.H. and Powrie, F. (2006) Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177, 4376–4383.PubMedGoogle Scholar
  17. Schubert, L.A., Jeffery, E., Zang, Y., Ramsdell, F. and Ziegler, S.F. (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276, 37672–37679.CrossRefPubMedGoogle Scholar
  18. Shevach, E.M. (2001) Certified professionals: CD4(+)CD25(+) suppressor T cells. J. Exp. Med. 193, F41–F46.CrossRefPubMedGoogle Scholar
  19. Suarez, A., Lopez, P., Gomez, J. and Gutierrez, C. (2006) Enrichment of CD4+ CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann. Rheum. Dis. 65, 1512–1517.CrossRefPubMedGoogle Scholar
  20. Sugiyama, H., Gyulai, R., Toichi, E., Garaczi, E., Shimada, S., Stevens, S.R., McCormick, T.S. and Cooper, K.D. (2005) Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol. 174, 164–173.PubMedGoogle Scholar
  21. van Amelsfort, J.M., Jaclbs, K.M., Bijlsma, J.W., Lafeber, F.P. and Taams, L.S. (2004) CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 50, 2775–2785.CrossRefPubMedGoogle Scholar
  22. Viglietta, V., Baecher-Allan, C., Wiener, H.L. and Hafler, D.A. (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med 199, 971–979.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Elena Yu. Lyssuk
    • 1
  • Anna V. Torgashina
    • 1
  • Sergey K. Soloviev
    • 1
  • Evgeny L. Nassonov
    • 1
  • Svetlana N. Bykovskaia
    • 1
  1. 1.Laboratory of Cell Monitoring, Institution of RheumatologyRussian Academy of Medical SciencesMoscowRussia

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