title: Hierarchy of Notch-Delta interactions promoting T cell lineage commitment and maturation.
abstract: Notch1 (N1) receptor signaling is essential and sufficient for T cell development, and recently developed in vitro culture systems point to members of the Delta family as being the physiological N1 ligands. We explored the ability of Delta1 (DL1) and DL4 to induce T cell lineage commitment and/or maturation in vitro and in vivo from bone marrow (BM) precursors conditionally gene targeted for N1 and/or N2. In vitro DL1 can trigger T cell lineage commitment via either N1 or N2. N1- or N2-mediated T cell lineage commitment can also occur in the spleen after short-term BM transplantation. However, N2-DL1-mediated signaling does not allow further T cell maturation beyond the CD25(+) stage due to a lack of T cell receptor beta expression. In contrast to DL1, DL4 induces and supports T cell commitment and maturation in vitro and in vivo exclusively via specific interaction with N1. Moreover, comparative binding studies show preferential interaction of DL4 with N1, whereas binding of DL1 to N1 is weak. Interestingly, preferential N1-DL4 binding reflects reduced dependence of this interaction on Lunatic fringe, a glycosyl transferase that generally enhances the avidity of Notch receptors for Delta ligands. Collectively, our results establish a hierarchy of Notch-Delta interactions in which N1-DL4 exhibits the greatest capacity to induce and support T cell development.
authors.affiliation: Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Besseyrias
authors.forename: Emma
authors.initials: E
authors.lastname: Fiorini
authors.forename: Lothar J
authors.initials: LJ
authors.lastname: Strobl
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.forename: Alexis
authors.initials: A
authors.lastname: Dumortier
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Arcangeli
authors.forename: Sophie
authors.initials: S
authors.lastname: Ezine
authors.forename: H Robson
authors.initials: HR
authors.lastname: Macdonald
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology*; D017931:DNA Primers; D005434:Flow Cytometry; D016695:Glycosyltransferases / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells; D013601:T-Lymphocytes / Q000166:cytology*; D014162:Transfection
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C064045:delta protein; D016695:Glycosyltransferases; C498392:Lfng protein, mouse