SEARCH:   Advanced

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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 15, 2005 Accepted May 12, 2005 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* The Abramson Family Cancer research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA, USA Department of Pediatrics, Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA; The Abramson Family Cancer research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA, USA Department of Pediatrics, Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA * Corresponding author; email: vassiliki_boussiotis{at}dfci.harvard.edu. CD4+CD25+ regulatory T cells (Treg) are essential negative regulators of immune responses. Here, we examined the signaling properties of human Treg, 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 IL-2. TCR/CD3-plus-CD28 mediated activation of Rap1 and Akt was retained in Treg but activation of Ras, MEK1/2 and Erk1/2 was impaired. Treg were blocked from cell cycle progression due to decrease of cyclin E and cyclin A and increase of p27kip1. IL-2 induced sustained increase of cyclin E and cyclin A and prevented upregulation of p27kip1. Treg had high susceptibility to apoptosis that was reversed by IL-2, which correlated with activation of Erk1/2, upregulation of Bcl-xL and phosphorylation of Bad at Ser112. Thus, Treg 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-plus-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: A. Yessoufou, A. Ple, K. Moutairou, A. Hichami, and N. A. Khan Docosahexaenoic acid reduces suppressive and migratory functions of CD4CD25 regulatory T-cells J. Lipid Res., December 1, 2009; 50(12): 2377 - 2388. [Abstract] [Full Text] [PDF] M. Pierau, S. Engelmann, D. Reinhold, T. Lapp, B. Schraven, and U. H. Bommhardt Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation J. Immunol., November 15, 2009; 183(10): 6124 - 6134. [Abstract] [Full Text] [PDF] C. W. Ashley and C. Baecher-Allan Cutting Edge: Responder T Cells Regulate Human DR+ Effector Regulatory T Cell Activity via Granzyme B J. Immunol., October 15, 2009; 183(8): 4843 - 4847. [Abstract] [Full Text] [PDF] D. Pozo, P. Anderson, and E. Gonzalez-Rey Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide J. Immunol., October 1, 2009; 183(7): 4346 - 4359. [Abstract] [Full Text] [PDF] A. D. Wells New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting J. Immunol., June 15, 2009; 182(12): 7331 - 7341. [Abstract] [Full Text] [PDF] F. Flores-Borja, E. C. Jury, C. Mauri, and M. R. Ehrenstein Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis PNAS, December 9, 2008; 105(49): 19396 - 19401. [Abstract] [Full Text] [PDF] K. L. Hippen, P. Harker-Murray, S. B. Porter, S. C. Merkel, A. Londer, D. K. Taylor, M. Bina, A. Panoskaltsis-Mortari, P. Rubinstein, N. Van Rooijen, et al. Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells Blood, October 1, 2008; 112(7): 2847 - 2857. [Abstract] [Full Text] [PDF] T. N. Golovina, T. Mikheeva, M. M. Suhoski, N. A. Aqui, V. C. Tai, X. Shan, R. Liu, R. R. Balcarcel, N. Fisher, B. L. Levine, et al. CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function J. Immunol., August 15, 2008; 181(4): 2855 - 2868. [Abstract] [Full Text] [PDF] B. Kavanagh, S. O'Brien, D. Lee, Y. Hou, V. Weinberg, B. Rini, J. P. Allison, E. J. Small, and L. Fong CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion Blood, August 15, 2008; 112(4): 1175 - 1183. [Abstract] [Full Text] [PDF] M. Muzio, B. Apollonio, C. Scielzo, M. Frenquelli, I. Vandoni, V. Boussiotis, F. Caligaris-Cappio, and P. Ghia Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy Blood, July 1, 2008; 112(1): 188 - 195. [Abstract] [Full Text] [PDF] A. M. Morton, B. McManus, P. Garside, A. McI. Mowat, and M. M. Harnett Inverse Rap1 and Phospho-ERK Expression Discriminate the Maintenance Phase of Tolerance and Priming of Antigen-Specific CD4+ T Cells In Vitro and In Vivo J. Immunol., December 15, 2007; 179(12): 8026 - 8034. [Abstract] [Full Text] [PDF] J. Yates, F. Rovis, P. Mitchell, B. Afzali, J.-S Tsang, M. Garin, R. Lechler, G. Lombardi, and O. Garden The maintenance of human CD4+CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro Int. Immunol., June 1, 2007; 19(6): 785 - 799. [Abstract] [Full Text] [PDF] J. Gonzalez, E. Tamayo, I. Santiuste, R. Marquina, L. Buelta, M. A. Gonzalez-Gay, S. Izui, M. Lopez-Hoyos, J. Merino, and R. Merino CD4+CD25+ T Cell-Dependent Inhibition of Autoimmunity in Transgenic Mice Overexpressing Human Bcl-2 in T Lymphocytes J. Immunol., March 1, 2007; 178(5): 2778 - 2786. [Abstract] [Full Text] [PDF] N. K. Crellin, R. V. Garcia, and M. K. Levings Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells Blood, March 1, 2007; 109(5): 2014 - 2022. [Abstract] [Full Text] [PDF] J. Nilsson, A. Boasso, P. A. Velilla, R. Zhang, M. Vaccari, G. Franchini, G. M. Shearer, J. Andersson, and C. Chougnet HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS Blood, December 1, 2006; 108(12): 3808 - 3817. [Abstract] [Full Text] [PDF] E. C. Jury, D. A. Isenberg, C. Mauri, and M. R. Ehrenstein Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus J. Immunol., November 15, 2006; 177(10): 7416 - 7422. [Abstract] [Full Text] [PDF] S. P. Hickman, J. Yang, R. M. Thomas, A. D. Wells, and L. A. Turka Defective Activation of Protein Kinase C and Ras-ERK Pathways Limits IL-2 Production and Proliferation by CD4+CD25+ Regulatory T Cells J. Immunol., August 15, 2006; 177(4): 2186 - 2194. [Abstract] [Full Text] [PDF] J. Y.-S. Tsang, N. O. S. Camara, E. Eren, H. Schneider, C. Rudd, G. Lombardi, and R. Lechler Altered proximal T cell receptor (TCR) signaling in human CD4+CD25+ regulatory T cells J. Leukoc. Biol., July 1, 2006; 80(1): 145 - 151. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020