The Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
J Exp Med. 2013 Apr 8;210(4):683-97. doi: 10.1084/jem.20121798. Epub 2013 Mar 25.
In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-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-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β 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 γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and -γδ 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-γδ differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-αβ and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.
在人类中，高 Notch 激活促进 γδ T 细胞发育，而较低水平的 Notch 激活则促进 αβ 谱系分化。这些不同的 Notch 信号是如何产生的仍然不清楚。我们表明，不同的 Notch 受体-配体相互作用介导了这一过程。Delta-like 4 既能支持 TCR-αβ 又能支持 TCR-γδ 的发育，而 Jagged1 主要诱导 αβ 谱系分化。相比之下，Jagged2 介导的 Notch 激活主要导致 γδ T 细胞发育，并通过抑制 TCR-β 的形成来抑制 αβ 谱系分化。相反，通过转导 TCR-β 转基因可挽救 TCR-αβ T 细胞的发育。Jagged2 通过与 Notch1 和 Notch3 的相互作用诱导最强的 Notch 信号，而 Delta-like 4 主要与 Notch1 结合。一致地，Notch3 是更强的 Notch 激活剂，仅支持 γδ T 细胞发育，而 Notch1 是较弱的激活剂，支持 TCR-αβ 和 -γδ 发育。在 JAG2 缺陷的胸腺小叶或用 Notch3 阻断抗体的胎儿胸腺器官培养物中证实了 Jagged2/Notch3 信号在人类 TCR-γδ 分化中的重要性。我们的发现表明，不同的 Notch 受体-配体相互作用介导了人类 TCR-αβ 和 -γδ T 细胞的分化，并为人类 γδ T 细胞发育对 Notch 的高度依赖性提供了机制上的见解。
