| First Author | Van de Walle I | Year | 2013 |
| Journal | J Exp Med | Volume | 210 |
| Issue | 4 | Pages | 683-97 |
| PubMed ID | 23530123 | Mgi Jnum | J:198219 |
| Mgi Id | MGI:5495870 | Doi | 10.1084/jem.20121798 |
| Citation | Van de Walle I, et al. (2013) Specific Notch receptor-ligand interactions control human TCR-alphabeta/gammadelta development by inducing differential Notch signal strength. J Exp Med 210(4):683-97 |
| abstractText | In humans, high Notch activation promotes gammadelta T cell development, whereas lower levels promote alphabeta-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-alphabeta and -gammadelta development, Jagged1 induces mainly alphabeta-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in gammadelta T cell development and represses alphabeta-lineage differentiation by inhibiting TCR-beta formation. Consistently, TCR-alphabeta T cell development is rescued through transduction of a TCR-beta 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 gammadelta T cell development, whereas Notch1 is a weaker activator supporting both TCR-alphabeta and -gammadelta 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-gammadelta differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-alphabeta and -gammadelta T cell differentiation and provide a mechanistic insight into the high Notch dependency of human gammadelta T cell development. |
