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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4260-4267. Prepublished online as a Blood First Edition Paper on August 17, 2006; DOI 10.1182/blood-2006-06-027409. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-06-027409v1 108/13/4260    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 Hoffmann, P. Articles by Edinger, M. Search for Related Content PubMed PubMed Citation Articles by Hoffmann, P. Articles by Edinger, M. Related Collections Immunobiology Transplantation Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion Petra Hoffmann, Ruediger Eder, Tina J. Boeld, Kristina Doser, Biserka Piseshka, Reinhard Andreesen, and Matthias Edinger From the Institute of Immunology and Department of Hematology & Oncology, University Hospital Regensburg, Germany. Thymus-derived CD4+CD25+ regulatory T cells suppress autoreactive CD4+ and CD8+ T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4+CD25+ regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications. We now demonstrate that only CCR7- and L-selectin (CD62L)–coexpressing cells within expanded CD4+CD25high T cells maintain phenotypic and functional characteristics of regulatory T cells. Further analysis revealed that these cells originate from CD45RA+ naive cells within the CD4+CD25high T-cell compartment, as only this subpopulation homogeneously expressed CD62L, CCR7, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), and forkhead box P3 (FOXP3), produced no inflammatory cytokines and maintained robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA– memory-type CD4+CD25high T cells lost expression of lymph node homing receptors CCR7 and CD62L, contained interleukin-2 (IL-2) and interferon- (IFN-) as well as IL-10–secreting cells, showed only moderate suppression and, most importantly, did not maintain FOXP3 expression. Based on these unexpected findings, we suggest that isolation and expansion of CD45RA+ naive CD4+ CD25high T cells is the best strategy for adoptive regulatory T (Treg)–cell therapies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Treg-cell expansion: better to be "naive" Benny J. Chen Blood 2006 108: 3963-3964. [Full Text] [PDF] This article has been cited by other articles: C. Schmidl, M. Klug, T. J. Boeld, R. Andreesen, P. Hoffmann, M. Edinger, and M. Rehli Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity Genome Res., July 1, 2009; 19(7): 1165 - 1174. [Abstract] [Full Text] [PDF] D. Q. Tran, J. Andersson, D. Hardwick, L. Bebris, G. G. Illei, and E. M. Shevach Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures Blood, May 21, 2009; 113(21): 5125 - 5133. [Abstract] [Full Text] [PDF] J. F. Hutton, T. Gargett, T. J. Sadlon, S. Bresatz, C. Y. Brown, H. Zola, M. F. Shannon, R. J. D'Andrea, and S. C. Barry Development of CD4+CD25+FoxP3+ regulatory T cells from cord blood hematopoietic progenitor cells J. Leukoc. Biol., March 1, 2009; 85(3): 445 - 451. [Abstract] [Full Text] [PDF] E K Geissler and H J Schlitt Immunosuppression for liver transplantation Gut, March 1, 2009; 58(3): 452 - 463. [Abstract] [Full Text] [PDF] M. Kleinewietfeld, M. Starke, D. Di Mitri, G. Borsellino, L. Battistini, O. Rotzschke, and K. Falk CD49d provides access to "untouched" human Foxp3+ Treg free of contaminating effector cells Blood, January 22, 2009; 113(4): 827 - 836. [Abstract] [Full Text] [PDF] D. S. Game, X. Cao, and S. Jiang Regulatory T Cells: The Cunning Fox and Its Clinical Application Sci. Signal., December 23, 2008; 1(51): mr3 - mr3. [Abstract] [Full Text] [PDF] T. J Boeld, E. Obermann, R. Andreesen, P. Hoffmann, and M. Edinger Delayed Onset of T Cell-Mediated Xenogeneic Disease in Rag2-/- {gamma}c -/- mice after Co- Transplantation of in Vitro Expanded Human CD4+CD25highCD45RA+ Regulatory T Cells Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 4609 - 4609. [Abstract] A. K. Antons, R. Wang, K. Oswald-Richter, M. Tseng, C. W. Arendt, S. A. Kalams, and D. Unutmaz Naive Precursors of Human Regulatory T Cells Require FoxP3 for Suppression and Are Susceptible to HIV Infection J. Immunol., January 15, 2008; 180(2): 764 - 773. [Abstract] [Full Text] [PDF] S. Li, E. J. Gowans, C. Chougnet, M. Plebanski, and U. Dittmer Natural Regulatory T Cells and Persistent Viral Infection J. Virol., January 1, 2008; 82(1): 21 - 30. [Full Text] [PDF] P. Monti, M. Scirpoli, A. 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Sotiriadou, E. G. Iliopoulou, M. L. Salagianni, G. Orphanos, C. N. Baxevanis, G. Rigatos, et al. CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients Clin. Cancer Res., May 1, 2007; 13(9): 2714 - 2721. [Abstract] [Full Text] [PDF] D. Baatar, P. Olkhanud, K. Sumitomo, D. Taub, R. Gress, and A. Biragyn Human Peripheral Blood T Regulatory Cells (Tregs), Functionally Primed CCR4+ Tregs and Unprimed CCR4- Tregs, Regulate Effector T Cells Using FasL J. Immunol., April 15, 2007; 178(8): 4891 - 4900. [Abstract] [Full Text] [PDF] I L Huibregtse, A U van Lent, and S J H van Deventer Immunopathogenesis of IBD: insufficient suppressor function in the gut? Gut, April 1, 2007; 56(4): 584 - 592. [Full Text] [PDF]

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