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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1571-1579. Prepublished online as a Blood First Edition Paper on April 27, 2006; DOI 10.1182/blood-2006-02-004747. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-02-004747v1 108/5/1571    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zorn, E. Articles by Ritz, J. Search for Related Content PubMed PubMed Citation Articles by Zorn, E. Articles by Ritz, J. Related Collections Immunobiology Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo Emmanuel Zorn, Erik A. Nelson, Mehrdad Mohseni, Fabrice Porcheray, Haesook Kim, Despina Litsa, Roberto Bellucci, Elke Raderschall, Christine Canning, Robert J. Soiffer, David A. Frank, and Jerome Ritz From the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. IL-2 plays a critical role in the maintenance of CD4+CD25+ FOXP3+ regulatory T cells (Tregs) in vivo. We examined the effects of IL-2 signaling in human Tregs. In vitro, IL-2 selectively up-regulated the expression of FOXP3 in purified CD4+CD25+ T cells but not in CD4+CD25- cells. This regulation involved the binding of STAT3 and STAT5 proteins to a highly conserved STAT-binding site located in the first intron of the FOXP3 gene. We also examined the effects of low-dose IL-2 treatment in 12 patients with metastatic cancer and 9 patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation. Overall, IL-2 treatment resulted in a 1.9 median fold increase in the frequency of CD4+CD25+ cells in peripheral blood as well as a 9.7 median fold increase in FOXP3 expression in CD3+ T cells. CD56+CD3- natural killer (NK) cells also expanded during IL-2 therapy but did not express FOXP3. In vitro treatment of NK cells with 5-aza-2'-deoxycytidine restored the IL-2 signaling pathway leading to FOXP3 expression, suggesting that this gene was constitutively repressed by DNA methylation in these cells. Our findings support the clinical evaluation of low-dose IL-2 to selectively modulate CD4+CD25+ Tregs and increase expression of FOXP3 in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Nagar, H. Vernitsky, Y. Cohen, D. Dominissini, Y. Berkun, G. Rechavi, N. Amariglio, and I. Goldstein Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells Int. Immunol., July 9, 2008; (2008) dxn062v2. [Abstract] [Full Text] [PDF] A. L. Bayer, J. Y. Lee, A. de la Barrera, C. D. Surh, and T. R. Malek A Function for IL-7R for CD4+CD25+Foxp3+ T Regulatory Cells J. Immunol., July 1, 2008; 181(1): 225 - 234. [Abstract] [Full Text] [PDF] M. Bonelli, A. Savitskaya, K. von Dalwigk, C. W. Steiner, D. Aletaha, J. S. Smolen, and C. 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