title: DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells.
abstract: T-cell development depends upon interactions between thymocytes and thymic epithelial cells (TECs). The engagement of delta-like 4 (DL4) on TECs by Notch1 expressed by blood-borne BM-derived precursors is essential for T-cell commitment in the adult thymus. In contrast to the adult, the earliest T-cell progenitors in the embryo originate in the fetal liver and migrate to the nonvascularized fetal thymus via chemokine signals. Within the fetal thymus, some T-cell precursors undergo programmed TCRγ and TCRδ rearrangement and selection, giving rise to unique γδ T cells. Despite these fundamental differences between fetal and adult T-cell lymphopoiesis, we show here that DL4-mediated Notch signaling is essential for the development of both αβ and γδ T-cell lineages in the embryo. Deletion of the DL4 gene in fetal TECs results in an early block in αβ T-cell development and a dramatic reduction of all γδ T-cell subsets in the fetal thymus. In contrast to the adult, no dramatic deviation of T-cell precursors to alternative fates was observed in the fetal thymus in the absence of Notch signaling. Taken together, our data reveal a common requirement for DL4-mediated Notch signaling in fetal and adult thymopoiesis.
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferrero
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.forename: Stephanie
authors.initials: S
authors.lastname: Claudinot
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Favre
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.forename: H R
authors.initials: HR
authors.lastname: MacDonald
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002135:Calcium-Binding Proteins; D019070:Cell Lineage; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D038041:Lymphopoiesis; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D051881:Receptor, Notch1 / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000196:embryology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: Delta-like 4; Fetal T-cell development; FoxN1Cre; Thymic epithelial cells