Visan Ioana, Yuan Julie S, Tan Joanne B, Cretegny Kira, Guidos Cynthia J
Program in Developmental Biology, Hospital for Sick Children Research Institute, and Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Immunol Rev. 2006 Feb;209:76-94. doi: 10.1111/j.0105-2896.2006.00360.x.
Intrathymic Notch1 signaling critically regulates T-lineage specification and commitment as well as T-cell progenitor survival and differentiation. Notch1 activation is continuously required during progression of early CD4/CD8-double-negative thymocytes to the CD4/CD8-double-positive stage. This developmental transition occurs as thymocytes migrate from the corticomedullary junction (CMJ) to the outer subcapsular zone (SCZ) of the thymus. Members of two families of structurally distinct Notch ligands, Delta-like 1 and Jagged-1, are expressed by cortical thymic epithelial cells, but it is not known which ligands are functionally required within the CMJ and SCZ microenvironmental niches. Our laboratory has investigated this question by genetically manipulating thymocyte expression of Lunatic Fringe (L-Fng), a glycosyltransferase that enhances sensitivity of Notch receptors to Delta-like ligands. This approach has revealed that low-threshold intrathymic Notch1 signals instruct multipotent thymus-seeding progenitors to suppress their B-cell potential and choose the T-cell fate. This strategy has also revealed that Delta-like Notch ligands are functionally limiting in both the CMJ and SCZ microenvironmental niches. Finally, we discuss our recent demonstration that L-Fng-mediated competition for Delta-like ligands is an important mechanism for regulating thymus size.
胸腺内Notch1信号通路对T细胞谱系的特化与定向以及T细胞祖细胞的存活和分化起着关键的调控作用。在早期CD4/CD8双阴性胸腺细胞向CD4/CD8双阳性阶段发育的过程中，持续需要Notch1激活。这种发育转变发生在胸腺细胞从胸腺的皮质髓质交界处（CMJ）迁移至被膜下外侧区（SCZ）时。两类结构不同的Notch配体家族成员，即Delta样1和Jagged-1，由皮质胸腺上皮细胞表达，但尚不清楚在CMJ和SCZ微环境龛中哪些配体具有功能需求。我们实验室通过基因操纵胸腺细胞中Lunatic Fringe（L-Fng）的表达来研究这个问题，L-Fng是一种糖基转移酶，可增强Notch受体对Delta样配体的敏感性。该方法揭示了低阈值的胸腺内Notch1信号指导多能胸腺播种祖细胞抑制其B细胞潜能并选择T细胞命运。该策略还揭示了Delta样Notch配体在CMJ和SCZ微环境龛中在功能上具有局限性。最后，我们讨论了我们最近的证明，即L-Fng介导的对Delta样配体的竞争是调节胸腺大小的重要机制。
