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Hypothesis: Human Umbilical Cord Blood-Derived Stromal Cells Regulate the Foxp3 Expression of Regulatory T Cells Through the TGF-β1/Smad3 Pathway

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Abstract

Despite the improvements in transplant immunology and clinical and supportive care, graft-versus-host disease (GVHD) is still among the most common causes of overall mortality and morbidity after allogeneic hematopoietic cell transplantation. The development and severity of GVHD are strongly related with post-transplant outcomes. New strategies should be explored to overcome GVHD. Regulatory T cells (Treg cells), as dedicated suppressors of diverse immune responses and inflammation and important gatekeepers of immune homeostasis, contribute to the prevention of graft rejection and induce transplantation tolerance. Foxp3, a transcription factor, is predominantly expressed in Treg cells and is a master regulator of the development and function of Treg cells. Foxp3 mutations and Foxp3 deficiency lead to lethal autoimmune lymphoproliferative disease, which results from a defect in Treg cells. TGF-β1 is required to maintain Foxp3 expression in Treg cells. We isolated a novel population from among CD34+ cells in our laboratory, referred to as human umbilical cord blood-derived stromal cells (hUCBDSCs), which exert an immunosuppressive effect and can notably increase Foxp3 expression in Treg cells. Our previous study also revealed that hUCBDSCs constantly secrete TGF-β1. Based on the literature searchings and our experimental findings, we hypothesize that hUCBDSCs, which secrete a high level of TGF-β1, modulate the Foxp3 expression of Treg cells through the TGF-β1/Smad3 pathway to regulate GVHD.

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Abbreviations

allo-HSCT:

Allogeneic hematopoietic cell transplantation

GVHD:

Graft-versus-host disease

hUCBDSCs:

Human umbilical cord blood-derived stromal cells

Treg cells:

Regulatory T cells

IPEX syndrome:

Immune dysfunction/polyendocrinopathy/enteropathy/x-linked syndrome

References

  1. Trenado, A., Charlotte, F., Fisson, S., Yagello, M., Klatzmann, D., Salomon, B. L., et al. (2003). Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. Journal of Clinical Investigation, 112, 1688–1696.

    PubMed  CAS  Google Scholar 

  2. Hara, M., Kingsley, C. I., Niimi, M., Read, S., Turvey, S. E., Bushell, A. R., et al. (2001). IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. Journal of Immunology, 166, 3789–3796.

    CAS  Google Scholar 

  3. Taylor, P. A., Noelle, R. J., & Blazar, B. R. (2011). CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. Journal of Experimental Medicine, 193, 1311–1318.

    Article  Google Scholar 

  4. Gregori, S., Casorati, M., Amuchastegui, S., Smiroldo, S., Davalli, A. M., & Adorini, L. (2001). Regulatory T cells induced by 1 alpha, 25-dihydroxy vitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. Journal of Immunology, 167, 1945–1953.

    CAS  Google Scholar 

  5. Sanchez-Fueyo, A., Weber, M., Domenig, C., Strom, T. B., & Zheng, X. X. (2002). Tracking the immunoregulatory mechanisms active during allograft tolerance. Journal Immunology, 168, 2274–2281.

    CAS  Google Scholar 

  6. Graca, L., Cobbold, S. P., & Waldmann, H. (2002). Identification of regulatory T cells in tolerated allografts. Journal of Experimental Medicine, 195, 1641–1646.

    Article  PubMed  CAS  Google Scholar 

  7. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M. (1995). Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alphachains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal Immunology, 155, 1151–1164.

    CAS  Google Scholar 

  8. Sakaguchi, S., Sakaguchi, N., Shimizu, J., Yamazaki, S., Sakihama, T., Itoh, M., et al. (2001). Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunological Reviews, 182, 18–32.

    Article  PubMed  CAS  Google Scholar 

  9. Hori, S., Nomura, T., & Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299, 1057–1061.

    Article  PubMed  CAS  Google Scholar 

  10. Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nature Immunology, 4, 330–336.

    Article  PubMed  CAS  Google Scholar 

  11. Khattri, R., Cox, T., Yasayko, S. A., & Ramsdell, F. (2003). An essential role for Scurfin in CD4(+)CD25(+) T regulatory cells. Nature Immunology, 4, 337–342.

    Article  PubMed  CAS  Google Scholar 

  12. Williams, L. M., & Rudensky, A. Y. (2007). Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nature Immunology, 8, 277–284.

    Article  PubMed  CAS  Google Scholar 

  13. Bennett, C. L., Brunkow, M. E., Ramsdell, F., O’Briant, K. C., Zhu, Q., Fuleihan, R. L., et al. (2001). A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA → AAUGAA) leads to the IPEX syndrome. Immunogenetics, 53, 435–439.

    Article  PubMed  CAS  Google Scholar 

  14. Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., et al. (2001). The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics, 27, 20–21.

    Article  PubMed  CAS  Google Scholar 

  15. Kim, J. Y., Kim, H. J., Hurt, E. M., Chen, X., Howard, O. M. Z., & Farrar, W. L. (2007). Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T (Treg)-like cells. Biochemical and Biophysical Research Communications, 362, 44–50.

    Article  PubMed  CAS  Google Scholar 

  16. Gavin, M. A., Rasmussen, J. P., Fontenot, J. D., Vasta, V., Manganiello, V. C., Beavo, J. A., et al. (2007). Foxp3-dependent programme of regulatory T-cell differentiation. Nature, 445, 771–775.

    Article  PubMed  CAS  Google Scholar 

  17. He, H., Zhang, Y., & Lv, Y. (2011). Transcriptional regulation of Foxp3 in regulatory T cells. Immunology, 216, 678–685.

    CAS  Google Scholar 

  18. Derynck, R., & Zhang, Y. E. (2003). Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 425, 577–584.

    Article  PubMed  CAS  Google Scholar 

  19. Buenafe, A. C., Tsaknaridis, L., Spencer, L., Hicks, K. S., McMahan, R. H., Watson, L., et al. (2004). Specificity of regulatory CD4+CD25+ T cells for self-T cell receptor determinants. Journal of Neuroscience Research, 76, 129–140.

    Article  PubMed  CAS  Google Scholar 

  20. Chen, W., & Wahl, S. M. (2003). TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine & Growth Factor Reviews, 14, 59–85.

    Article  Google Scholar 

  21. Nakamura, K., Kitani, A., & Strober, W. (2001). Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface bound transforming growth factor beta. Journal of Experimental Medicine, 194, 629–644.

    Article  PubMed  CAS  Google Scholar 

  22. Davidson, T. S., DiPaolo, R. J., Andersson, J., & Shevach, E. M. (2007). Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp(3+) T regulatory cells. Journal of Immunology, 178, 4022–4026.

    CAS  Google Scholar 

  23. Liu, Y. Z., Zhang, P., Li, J., Kulkarni, A. B., Perruche, S., & Chen, W. J. (2008). A critical function for TGF-beta signaling in the development of natural CD4(+)CD25(+)Foxp3(+) regulatory T cells. Nature Immunology, 9, 632–640.

    Article  PubMed  CAS  Google Scholar 

  24. Amarnath, S., Dong, L., Li, J., Wu, Y., & Chen, W. (2007). Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25− T cells. Retrovirology, 4, 57.

    Article  PubMed  Google Scholar 

  25. Fantini, M. C., Becker, C., Monteleone, G., Pallone, F., Galle, P. R., & Neurath, M. F. (2004). Cutting edge: TGF-beta induces a regulatory phenotype in CD4(+)CD25(−) T cells through Foxp3 induction and down-regulation of Smad7. Journal of Immunology, 172, 5149–5153.

    CAS  Google Scholar 

  26. Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M. L., Greene, M. I., & Tone, M. (2008). Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nature Immunology, 9, 194–202.

    Article  PubMed  CAS  Google Scholar 

  27. Samon, J. B., Champhekar, A., Minter, L. M., Telfer, J. C., Miele, L., Fauq, A., et al. (2008). Notch1 and TGF beta 1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood, 112, 1813–1821.

    Article  PubMed  CAS  Google Scholar 

  28. Ruan, Q. G., Kameswaran, V., Tone, Y., Li, L., Liou, H. C., Greene, M. I., et al. (2009). Development of Foxp3(+) regulatory T cells is driven by the c-Rel enhanceosome. Immunity, 31, 932–940.

    Article  PubMed  CAS  Google Scholar 

  29. Jana, S., Jailwala, P., Haribhai, D., Waukau, J., Glisic, S., Grossman, W., et al. (2009). The role of NF-kappa B and Smad3 in TGF-beta-mediated Foxp3 expression. European Journal of Immunology, 39, 2571–2583.

    Article  PubMed  CAS  Google Scholar 

  30. Takimoto, T., Wakabayashi, Y., Sekiya, T., Inoue, N., Morita, R., Ichiyama, K., et al. (2010). Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. Journal of Immunology, 185, 842–855.

    Article  CAS  Google Scholar 

  31. Zhang, C., Chen, X. H., Zhang, X., Gao, L., Kong, P. Y., Peng, X. G., et al. (2011). Human umbilical cord blood-derived stromal cells, a new resource in the suppression of acute graft-versus-host disease in haploidentical stem cell transplantation in sublethally irradiated mice. Journal of Biological Chemistry, 286, 13723–13732.

    Article  PubMed  CAS  Google Scholar 

  32. Zhang, C., Chen, X. H., Zhang, X., Gao, L., Gao, L., Kong, P. Y., et al. (2011). Regulation of acute graft-versus-host disease by human umbilical cord blood derived stromal cells in haploidentical stem cell transplantation in mice through very late activation antigen-4. Clinical Immunology, 139, 94–101.

    Article  PubMed  CAS  Google Scholar 

  33. Hao, L., Gao, L., Chen, X. H., Zou, Z. M., Zhang, X., Kong, P. Y., et al. (2011). Human umbilical cord blood-derived stromal cells prevent graft-versus-host disease in mice following haplo-identical stem cell transplantation. Cytotherapy, 13, 83–91.

    Article  PubMed  CAS  Google Scholar 

  34. Miura, y., Thoburm, C. J., Bright, E. C., Phelps, M. L., Shin, T., Matsui, E. C., et al. (2004). Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood, 104, 2187–2193.

    Article  PubMed  CAS  Google Scholar 

  35. Hao, L., Zhang, C., Chen, X. H., Zou, Z. M., Zhang, X., Kong, P. Y., et al. (2009). Human umbilical cord blood derived stromal cells suppress xenogeneic immune cell response in vitro. Croatian Medical Journal, 50, 351–360.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was funded by Grants from the National Natural Science Foundation (No. 81170529), the Natural Science Foundation Project of CQ “CSTC” (CSTC, 2010BA5178), the Key Discipline of Medical Science of Chongqing, and the special foundation for the “1520 project” of Xinqiao Hospital of Third Military Medical University.

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None declared.

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Authors and Affiliations

  1. Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing, 400037, People’s Republic of China

    Cheng Zhang, Xi Zhang & Xing-Hua Chen

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  1. Cheng Zhang
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  2. Xi Zhang
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Correspondence to Xing-Hua Chen.

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Zhang, C., Zhang, X. & Chen, XH. Hypothesis: Human Umbilical Cord Blood-Derived Stromal Cells Regulate the Foxp3 Expression of Regulatory T Cells Through the TGF-β1/Smad3 Pathway. Cell Biochem Biophys 62, 463–466 (2012). https://doi.org/10.1007/s12013-011-9328-8

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  • DOI: https://doi.org/10.1007/s12013-011-9328-8

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