| First Author | Höflinger S | Year | 2004 |
| Journal | J Immunol | Volume | 173 |
| Issue | 6 | Pages | 3935-44 |
| PubMed ID | 15356142 | Mgi Jnum | J:92741 |
| Mgi Id | MGI:3054460 | Doi | 10.4049/jimmunol.173.6.3935 |
| Citation | Hoflinger S, et al. (2004) Analysis of notch1 function by in vitro T cell differentiation of pax5 mutant lymphoid progenitors. J Immunol 173(6):3935-44 |
| abstractText | Signaling through the Notch1 receptor is essential for T cell development in the thymus. Stromal OP9 cells ectopically expressing the Notch ligand Delta-like1 mimic the thymic environment by inducing hemopoietic stem cells to undergo in vitro T cell development. Notch1 is also expressed on Pax5-/- pro-B cells, which are clonable lymphoid progenitors with a latent myeloid potential. In this study, we demonstrate that Pax5-/- progenitors efficiently differentiate in vitro into CD4+CD8+ alphabeta and gammadelta T cells upon coculture with OP9-Delta-like1 cells. In vitro T cell development of Pax5-/- progenitors strictly depends on Notch1 function and progresses through normal developmental stages by expressing T cell markers and rearranging TCRbeta, gamma, and delta loci in the correct temporal sequence. Notch-stimulated Pax5-/- progenitors efficiently down-regulate the expression of B cell-specific genes, consistent with a role of Notch1 in preventing B lymphopoiesis in the thymus. At the same time, Notch signaling rapidly induces cell surface expression of the c-Kit receptor and transcription of the target genes Deltex1 and pre-Talpha concomitant with the activation of TCR Vbeta germline transcription and the regulatory genes GATA3 and Tcf1. These data suggest that Notch1 acts upstream of GATA3 and Tcf1 in early T cell development and regulates Vbeta-DJbeta rearrangements by controlling the chromatin accessibility of Vbeta genes at the TCRbeta locus. |
