Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20060-5. doi: 10.1073/pnas.1110230108. Epub 2011 Nov 22.
Although transcriptional programs associated with T-cell specification and commitment have been described, the functional hierarchy and the roles of key regulators in structuring/orchestrating these programs remain unclear. Activation of Notch signaling in uncommitted precursors by the thymic stroma initiates the T-cell differentiation program. One regulator first induced in these precursors is the DNA-binding protein T-cell factor 1 (Tcf-1), a T-cell-specific mediator of Wnt signaling. However, the specific contribution of Tcf-1 to early T-cell development and the signals inducing it in these cells remain unclear. Here we assign functional significance to Tcf-1 as a gatekeeper of T-cell fate and show that Tcf-1 is directly activated by Notch signals. Tcf-1 is required at the earliest phase of T-cell determination for progression beyond the early thymic progenitor stage. The global expression profile of Tcf-1-deficient progenitors indicates that basic processes of DNA metabolism are down-regulated in its absence, and the blocked T-cell progenitors become abortive and die by apoptosis. Our data thus add an important functional relationship to the roadmap of T-cell development.
虽然已经描述了与 T 细胞特异性和承诺相关的转录程序，但这些程序的功能层次结构和关键调节因子在构建/协调这些程序中的作用仍不清楚。胸腺基质中未分化前体中的 Notch 信号的激活启动了 T 细胞分化程序。在这些前体中首先诱导的一种调节剂是 DNA 结合蛋白 T 细胞因子 1（Tcf-1），它是 Wnt 信号的 T 细胞特异性介质。然而，Tcf-1 对早期 T 细胞发育的具体贡献及其在这些细胞中诱导的信号仍不清楚。在这里，我们将 Tcf-1 赋予作为 T 细胞命运的守门员的功能意义，并表明 Tcf-1 直接被 Notch 信号激活。Tcf-1 在 T 细胞决定的最早阶段是必需的，以超越早期胸腺祖细胞阶段的进展。Tcf-1 缺陷祖细胞的全基因组表达谱表明，在其缺失的情况下，DNA 代谢的基本过程被下调，并且被阻断的 T 细胞祖细胞变得夭折并通过细胞凋亡死亡。因此，我们的数据为 T 细胞发育的路线图添加了一个重要的功能关系。
