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¹ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland
² Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, 81377 Munich, Germany
³ Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland
⁴ Institut National de la Santé et de la Recherche Médicale, U591, Université Paris V, 75730 Paris Cedex 15, France

CORRESPONDENCE Freddy Radtke: Freddy.Radtke{at}isrec.unil.ch

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 ß 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.

V. Besseyrias, E. Fiorini, L.J. Strobl, and U. Zimber-Strobl contributed equally to this work.

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