Published online September 29, 2008
doi:10.1084/jem.20080829
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Koch et al.
Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment
Ute Koch1,
Emma Fiorini2,
Rui Benedito3,
Valerie Besseyrias4,
Karin Schuster-Gossler5,
Michel Pierres6,
Nancy R. Manley7,
Antonio Duarte3,
H. Robson MacDonald2, and
Freddy Radtke1
1 Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland
2 Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland
3 Faculdade de Medicina Veterinária, 1300-477 Lisboa, Portugal
4 Department of Biomedicine, Institute of Physiology, University of Basel, 4056 Basel, Switzerland
5 Institute for Molecular Biology OE5250, Medizinische Hochschule Hannover, 30625 Hannover, Germany
6 Centre d'Immunologie de Marseille-Luminy, Parc Scientifique de Luminy, Case 906, 13288 Marseille, Cedex 9, France
7 Department of Genetics, University of Georgia, Athens, GA 30603
CORRESPONDENCE Freddy Radtke: Freddy.Radtke{at}epfl.ch
Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor–mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1- and DL4-lacZ reporter knock-in mice and novel monoclonal antibodies to DL1 and DL4, we show that DL4 is expressed on thymic epithelial cells (TECs), whereas DL1 is not detected. The function of DL4 was further explored in vivo by generating mice in which DL4 could be specifically inactivated in TECs or in hematopoietic progenitors. Although loss of DL4 in hematopoietic progenitors did not perturb thymus development, inactivation of DL4 in TECs led to a complete block in T cell development coupled with the ectopic appearance of immature B cells in the thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional N1 mutant mice. Collectively, our results demonstrate that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment. Moreover, they strongly suggest that N1-expressing thymic progenitors interact with DL4-expressing TECs to suppress B lineage potential and to induce the first steps of intrathymic T cell development.
© 2008 Koch et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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