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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3068-3073. Prepublished online as a Blood First Edition Paper on July 14, 2005; DOI 10.1182/blood-2005-04-1531. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-04-1531v1 106/9/3068    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 Li, L. Articles by Boussiotis, V. A. Search for Related Content PubMed PubMed Citation Articles by Li, L. Articles by Boussiotis, V. A. Related Collections Immunobiology Signal Transduction Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY CD4+CD25+ regulatory T-cell lines from human cord blood have functional and molecular properties of T-cell anergy Lequn Li, Wayne R. Godfrey, Stephen B. Porter, Ying Ge, Carle H. June, Bruce R. Blazar, and Vassiliki A. Boussiotis From the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; the Department of Pediatrics, University of Minnesota Cancer Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN; and the Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA. CD4+CD25+ regulatory T cells (Tregs) are essential negative regulators of immune responses. Here, we examined the signaling properties of human Tregs, using CD4+CD25+ Treg and CD4+CD25– control (Tcont) cell lines generated from cord blood. Treg cell lines were markedly hyporesponsive to stimulation with dendritic cells and with anti-CD3/CD28–coated beads. Hyporesponsiveness was reversed by exogenous interleukin-2 (IL-2). T-cell receptor (TCR)–CD3/CD28–mediated activation of Rap1 and Akt was retained in Tregs, but activation of Ras, mitogenactivated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated kinase 1/2 (Erk1/2) was impaired. Tregs were blocked from cell cycle progression due to decrease of cyclin E and cyclin A and increase of p27kip1 (p27kip cyclin dependent kinase inhibitor). IL-2 induced sustained increase of cyclin E and cyclin A and prevented up-regulation of p27kip1. Tregs had high susceptibility to apoptosis that was reversed by IL-2, which correlated with activation of Erk1/2, up-regulation of Bcl-xL (B-cell CLL/lymphoma 2-like nuclear gene encoding mitochondrial protein, transcript variant 2), and phosphorylation of Bad (Bcl2 antagonist of cell death) at Ser112. Thus, Tregs share biochemical characteristics of anergy, including abortive activation of Ras-MEK-Erk, increased activation of Rap1, and increased expression of p27kip1. In addition, our results indicate that TCR–CD3/CD28–mediated and IL-2 receptor–mediated signals converge at the level of MEK-Erk kinases to regulate Treg survival and expansion and suggest that manipulation of the MEK-Erk axis may represent a novel strategy for Treg expansion for immunotherapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Pierau, S. Engelmann, D. Reinhold, T. Lapp, B. Schraven, and U. H. 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