Specific notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential notch signal strength

Inge Van de Walle, Els Waegemans, Jelle De Medts, Greet De Smet, Magda De Smedt, Sylvia Snauwaert, Bart Vandekerckhove, Tessa Kerre, Georges Leclercq, Jean Plum, Thomas Gridley, Tao Wang, Ute Koch, Freddy Radtke, Tom Taghon

    Research output: Contribution to journalArticlepeer-review

    Abstract

    In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-lineage differentiation. How these different Notch signals are generated has remained unclear. We show that differential Notch receptor-ligand interactions mediate this process. Whereas Delta-like 4 supports both TCR-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β transgene. Jagged2 induces the strongest Notch signal through interactions with both Notch1 and Notch3, whereas Delta-like 4 primarily binds Notch1. In agreement, Notch3 is a stronger Notch activator and only supports γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and-γδ development.Fetal thymus organ cultures in JAG2-deficient thymic lobes or with Notch3-blocking antibodies confirm the importance of Jagged2/Notch3 signaling in human TCR-γδ differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-αβ and-γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development. © 2013 Van de Walle et al.
    Original languageEnglish
    Pages (from-to)683-697
    Number of pages14
    JournalJournal of Experimental Medicine
    Volume210
    Issue number4
    DOIs
    Publication statusPublished - 2013

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