Specific Notch receptor-ligand interactions control human TCR-αß/γδ development by inducing differential Notch signal strength.

ABSTRACT

In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αß-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-αß and -γδ development, Jagged1 induces mainly αß-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αß-lineage differentiation by inhibiting TCR-ß formation. Consistently, TCR-αß T cell development is rescued through transduction of a TCR-ß 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-αß 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-αß and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.