Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.
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.
Koch
Ute
U
Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland.
Fiorini
Emma
E
Benedito
Rui
R
Besseyrias
Valerie
V
Schuster-Gossler
Karin
K
Pierres
Michel
M
Manley
Nancy R
NR
Duarte
Antonio
A
Macdonald
H Robson
HR
Radtke
Freddy
F
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D001616:beta-Galactosidase
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D001616:beta-Galactosidase