T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4-CD8- double-negative (DN) stage 2 (DN2). Zeb1 expression was further increased in the CD4+CD8+ double-positive (DP) stage before decreasing in more mature T cell subsets. We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb1 hypomorphic mutations. The Zeb1 mutation profoundly affected all thymic subsets, especially DN2 and DP cells. Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner. In the periphery of Cellophane mice, the number of conventional T cells was near normal, but invariant NKT cells, NK1.1+ γδ T cells and Ly49+ CD8 T cells were virtually absent. This suggested that Zeb1 regulates the development of unconventional T cell types from DP progenitors. A transcriptomic analysis of WT and Cellophane DP cells revealed that Zeb1 regulated the expression of multiple genes involved in the cell cycle and TCR signaling, which possibly occurred in cooperation with Tcf1 and Heb. Indeed, Cellophane DP cells displayed stronger signaling than WT DP cells upon TCR engagement in terms of the calcium response, phosphorylation events, and expression of early genes. Thus, Zeb1 is a key regulator of the cell cycle and TCR signaling during thymic T cell development. We propose that thymocyte selection is perturbed in Zeb1-mutated mice in a way that does not allow the survival of unconventional T cell subsets.

中文翻译：

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Zeb1 抑制 TCR 信号传导，促进 T 细胞祖细胞增殖，对于 NK1.1+ T 细胞发育至关重要。


T 细胞的发育在转录因子 (TF) 网络的影响下进行。该网络的成员 Zeb1 的确切作用仍不清楚。在此，我们报道了 Zeb1 表达在 CD4-CD8-双阴性 (DN) 2 期 (DN2) 的 T 细胞发育早期被诱导。 Zeb1 表达在 CD4+CD8+ 双阳性 (DP) 阶段进一步增加，然后在更成熟的 T 细胞亚群中减少。我们对携带 Zeb1 亚态突变的 Cellophane 小鼠中的 T 细胞进行了详尽的表征。 Zeb1 突变深刻影响所有胸腺亚群，尤其是 DN2 和 DP 细胞。 Zeb1 以细胞固有的方式促进两种细胞群的存活和增殖。在 Cellophane 小鼠的外周，常规 T 细胞的数量接近正常，但不变的 NKT 细胞、NK1.1+ γδ T 细胞和 Ly49+ CD8 T 细胞几乎不存在。这表明 Zeb1 调节 DP 祖细胞的非常规 T 细胞类型的发育。对 WT 和 Cellophane DP 细胞的转录组分析表明，Zeb1 调节参与细胞周期和 TCR 信号传导的多个基因的表达，这可能与 Tcf1 和 Heb 协同发生。事实上，在 TCR 参与后，Cellophane DP 细胞在钙反应、磷酸化事件和早期基因表达方面表现出比 WT DP 细胞更强的信号传导。因此，Zeb1 是胸腺 T 细胞发育过程中细胞周期和 TCR 信号传导的关键调节因子。我们提出，Zeb1 突变小鼠的胸腺细胞选择受到干扰，导致非常规 T 细胞亚群无法存活。