Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

被引:342
作者
Koch, Ute [1 ]
Fiorini, Emma [2 ]
Benedito, Rui [3 ]
Besseyrias, Valerie [4 ]
Schuster-Gossler, Karin [5 ]
Pierres, Michel [6 ]
Manley, Nancy R. [7 ]
Duarte, Antonio [3 ]
MacDonald, H. Robson [2 ]
Radtke, Freddy [1 ]
机构
[1] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland
[2] Univ Lausanne, Ludwig Inst Canc Res, Lausanne Branch, CH-1066 Epalinges, Switzerland
[3] Fac Med Vet, P-1300477 Lisbon, Portugal
[4] Univ Basel, Dept Biomed, Inst Physiol, CH-4056 Basel, Switzerland
[5] Hannover Med Sch, Inst Mol Biol OE5250, D-30625 Hannover, Germany
[6] Ctr Immunol Marseille Luminy, F-13288 Marseille 9, France
[7] Univ Georgia, Dept Genet, Athens, GA 30603 USA
基金
瑞士国家科学基金会;
关键词
D O I
10.1084/jem.20080829
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:2515 / 2523
页数:9
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