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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3498-3506. Prepublished online as a Blood First Edition Paper on July 19, 2005; DOI 10.1182/blood-2005-02-0496. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 2005-02-0496v1 106/10/3498    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 De Smedt, M. Articles by Plum, J. Search for Related Content PubMed PubMed Citation Articles by De Smedt, M. Articles by Plum, J. Related Collections Immunobiology Phagocytes Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment Magda De Smedt, Inge Hoebeke, Katia Reynvoet, Georges Leclercq, and Jean Plum From the Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, Belgium. Notch receptors are involved in lineage decisions in multiple developmental scenarios, including hematopoiesis. Here, we treated hybrid human-mouse fetal thymus organ culture with the -secretase inhibitor 7 (N-[N-(3,5-difluorophenyl)-L-alanyl]-S-phenyl-glycine t-butyl ester) (DAPT) to establish the role of Notch signaling in human hematopoietic lineage decisions. The effect of inhibition of Notch signaling was studied starting from cord blood CD34+ or thymic CD34+CD1-, CD34+CD1+, or CD4ISP progenitors. Treatment of cord blood CD34+ cells with low DAPT concentrations results in aberrant CD4ISP and CD4/CD8 double-positive (DP) thymocytes, which are negative for intracellular T-cell receptor (TCR). On culture with intermediate and high DAPT concentrations, thymic CD34+CD1- cells still generate aberrant intracellular TCR- DP cells that have undergone DJ but not VDJ recombination. Inhibition of Notch signaling shifts differentiation into non-T cells in a thymic microenvironment, depending on the starting progenitor cells: thymic CD34+CD1+ cells do not generate non-T cells, thymic CD34+CD1- cells generate NK cells and monocytic/dendritic cells, and cord blood CD34+Lin- cells generate B, NK, and monocytic/dendritic cells in the presence of DAPT. Our data indicate that Notch signaling is crucial to direct human progenitor cells into the T-cell lineage, whereas it has a negative impact on B, NK, and monocytic/dendritic cell generation in a dose-dependent fashion. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Haraguchi, T. Suzuki, N. Koyama, K. Kumano, F. Nakahara, A. Matsumoto, Y. Yokoyama, M. Sakata-Yanagimoto, S. Masuda, T. Takahashi, et al. Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15 J. Immunol., May 15, 2009; 182(10): 6168 - 6178. [Abstract] [Full Text] [PDF] S. Gonzalez-Garcia, M. Garcia-Peydro, E. Martin-Gayo, E. Ballestar, M. Esteller, R. Bornstein, J. L. de la Pompa, A. A. Ferrando, and M. L. Toribio CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia J. Exp. Med., April 13, 2009; 206(4): 779 - 791. [Abstract] [Full Text] [PDF] T. Taghon, I. Van de Walle, G. De Smet, M. De Smedt, G. Leclercq, B. Vandekerckhove, and J. Plum Notch signaling is required for proliferation but not for differentiation at a well-defined {beta}-selection checkpoint during human T-cell development Blood, April 2, 2009; 113(14): 3254 - 3263. [Abstract] [Full Text] [PDF] I. Van de Walle, G. De Smet, M. De Smedt, B. Vandekerckhove, G. Leclercq, J. Plum, and T. Taghon An early decrease in Notch activation is required for human TCR-{alpha}{beta} lineage differentiation at the expense of TCR-{gamma}{delta} T cells Blood, March 26, 2009; 113(13): 2988 - 2998. [Abstract] [Full Text] [PDF] L. J. Anderson and R. Longnecker Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo Blood, January 1, 2009; 113(1): 108 - 116. [Abstract] [Full Text] [PDF] M. De Smedt, T. Taghon, I. Van de Walle, G. De Smet, G. Leclercq, and J. Plum Notch signaling induces cytoplasmic CD3{epsilon} expression in human differentiating NK cells Blood, October 1, 2007; 110(7): 2696 - 2703. [Abstract] [Full Text] [PDF] Y. Zhao, M. R. Parkhurst, Z. Zheng, C. J. Cohen, J. P. Riley, L. Gattinoni, N. P. Restifo, S. A. Rosenberg, and R. A. Morgan Extrathymic Generation of Tumor-Specific T Cells from Genetically Engineered Human Hematopoietic Stem Cells via Notch Signaling Cancer Res., March 15, 2007; 67(6): 2425 - 2429. [Abstract] [Full Text] [PDF] M. Garcia-Peydro, V. G. de Yebenes, and M. L. Toribio Notch1 and IL-7 Receptor Interplay Maintains Proliferation of Human Thymic Progenitors while Suppressing Non-T Cell Fates J. Immunol., September 15, 2006; 177(6): 3711 - 3720. [Abstract] [Full Text] [PDF] R. Ceredig, M. Rauch, G. Balciunaite, and A. G. Rolink Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment Blood, August 15, 2006; 108(4): 1216 - 1222. [Abstract] [Full Text] [PDF] K. 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