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 β 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.
Hierarchy of Notch–Delta interactions promoting T cell lineage commitment and maturation
Abbreviations used: DL1, Delta1; DN, double negative; DP, double positive; EGFP, enhanced GFP; ES, embryonic stem; HPRT, hypoxanthine guanine phosphoribosyl transferase; HSC, hematopoietic stem cell; ISP, immature SP; KLS, CD117+lin−Sca1+; Lfng, Lunatic fringe; MZB cell, marginal zone B cell; N1, Notch1; SP, single positive.
V. Besseyrias, E. Fiorini, L.J. Strobl, and U. Zimber-Strobl contributed equally to this work.
Valerie Besseyrias, Emma Fiorini, Lothar J. Strobl, Ursula Zimber-Strobl, Alexis Dumortier, Ute Koch, Marie-Laure Arcangeli, Sophie Ezine, H. Robson MacDonald, Freddy Radtke; Hierarchy of Notch–Delta interactions promoting T cell lineage commitment and maturation . J Exp Med 19 February 2007; 204 (2): 331–343. doi: https://doi.org/10.1084/jem.20061442
Download citation file:
Sign in
Client Account
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Email alerts
Advertisement