Hierarchy of Notch-Delta interactions promoting T cell lineage commitment and maturation.
Hierarchy of Notch-Delta interactions promoting T cell lineage commitment and maturation.
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DOI：
10.1084/jem.20061442
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发表时间：
2007-02-19
期刊：
影响因子：
--
通讯作者：
Radtke F
中科院分区：
文献类型：
--
作者：
Besseyrias V;Fiorini E;Strobl LJ;Zimber-Strobl U;Dumortier A;Koch U;Arcangeli ML;Ezine S;Macdonald HR;Radtke F
Notch 1（N1）受体信号传导对于T细胞发育是必需的和足够的，并且最近开发的体外培养系统指出Delta家族的成员是生理N1配体。我们探索了Delta 1（DL 1）和DL 4在体外和体内诱导T细胞谱系定型和/或成熟的能力，这些T细胞谱系定型和/或成熟来自骨髓（BM）前体，这些前体有条件地靶向N1和/或N2。在体外，DL 1可以通过N1或N2触发T细胞谱系定型。N1或N2介导的T细胞谱系定型也可以在短期骨髓移植后在脾脏中发生。然而，由于缺乏T细胞受体β表达，N2-DL 1介导的信号传导不允许T细胞进一步成熟超过CD 25+阶段。与DL 1相反，DL 4仅通过与N1的特异性相互作用在体外和体内诱导和支持T细胞定型和成熟。此外，比较结合研究显示，DL 4与N1的优先相互作用，而DL 1与N1的结合较弱。有趣的是，优先N1-DL 4结合反映了这种相互作用对Lunatic fringe的依赖性降低，Lunatic fringe是一种糖基转移酶，通常增强Notch受体对Delta配体的亲和力。总的来说，我们的结果建立了Notch-Delta相互作用的层次结构，其中N1-DL 4表现出诱导和支持T细胞发育的最大能力。
Notch1 (N1) receptor signaling is essential and sufficient for T cell development, and recently developed in vitro culture systems point to members of the Delta family as being the physiological N1 ligands. We explored the ability of Delta1 (DL1) and DL4 to induce T cell lineage commitment and/or maturation in vitro and in vivo from bone marrow (BM) precursors conditionally gene targeted for N1 and/or N2. In vitro DL1 can trigger T cell lineage commitment via either N1 or N2. N1- or N2-mediated T cell lineage commitment can also occur in the spleen after short-term BM transplantation. However, N2–DL1–mediated signaling does not allow further T cell maturation beyond the CD25+ stage due to a lack of T cell receptor β expression. In contrast to DL1, DL4 induces and supports T cell commitment and maturation in vitro and in vivo exclusively via specific interaction with N1. Moreover, comparative binding studies show preferential interaction of DL4 with N1, whereas binding of DL1 to N1 is weak. Interestingly, preferential N1–DL4 binding reflects reduced dependence of this interaction on Lunatic fringe, a glycosyl transferase that generally enhances the avidity of Notch receptors for Delta ligands. Collectively, our results establish a hierarchy of Notch–Delta interactions in which N1–DL4 exhibits the greatest capacity to induce and support T cell development.
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