Taghon Tom, Yui Mary A, Rothenberg Ellen V
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent University, 9000 Ghent, Belgium.
Nat Immunol. 2007 Aug;8(8):845-55. doi: 10.1038/ni1486. Epub 2007 Jul 1.
GATA-3 is essential for T cell development from the earliest stages. However, abundant GATA-3 can drive T lineage precursors to a non-T cell fate, depending on Notch signaling and developmental stage. Here, overexpression of GATA-3 blocked the survival of pro-T cells when Notch-Delta signals were present but enhanced viability in their absence. In fetal thymocytes at the double-negative 1 (DN1) stage and DN2 stage but not those at the DN3 stage, overexpression of GATA-3 rapidly induced respecification to the mast cell lineage with high frequency by direct transcriptional 'reprogramming'. Normal DN2 thymocytes also showed mast cell potential when interleukin 3 and stem cell factor were added in the absence of Notch signaling. Our results suggest a close relationship between the pro-T cell and mast cell programs and a previously unknown function for Notch in T lineage fidelity.
GATA-3对于T细胞从最早阶段开始的发育至关重要。然而,大量的GATA-3可促使T系前体细胞走向非T细胞命运,这取决于Notch信号和发育阶段。在此,当存在Notch-Delta信号时,GATA-3的过表达会阻断前T细胞的存活,但在其缺失时则会增强细胞活力。在双阴性1(DN1)阶段和DN2阶段的胎儿胸腺细胞中,而非DN3阶段的胎儿胸腺细胞中,GATA-3的过表达通过直接转录“重编程”高频快速诱导其重新分化为肥大细胞系。在无Notch信号的情况下添加白细胞介素3和干细胞因子时,正常的DN2胸腺细胞也显示出肥大细胞潜能。我们的结果表明前T细胞程序与肥大细胞程序之间存在密切关系,以及Notch在T系保真度方面具有先前未知的功能。