γδ T cells acquire their functional properties in the thymus, enabling them to exert rapid innate‐like responses. To understand how distinct γδ T cell subsets are generated, we have developed a Two‐Stage model for γδ T cell development. This model is predicated on the finding that γδTCR signal strength impacts E protein activity through graded upregulation of Id3. Our model proposes that cells enter Stage 1 in response to a γδTCR signaling event in the cortex that activates a γδ T cell–specific gene network. Part of this program includes the upregulation of chemokine receptors that guide them to the medulla. In the medulla, Stage 1 cells receive distinct combinations of γδTCR, cytokine, and/co‐stimulatory signals that induce their transit into Stage 2, either toward the γδT1 or the γδT17 lineage. The intersection between γδTCR and cytokine signals can tune Id3 expression, leading to different outcomes even in the presence of strong γδTCR signals. The thymic signaling niches required for γδT17 development are segregated in time and space, providing transient windows of opportunity during ontogeny. Understanding the regulatory context in which E proteins operate at different stages will be key in defining how their activity levels impose functional outcomes.

中文翻译：

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γδTCR 信号与 E 蛋白-Id 轴在 γδ T 细胞发育中的相互作用

γδ T 细胞在胸腺中获得其功能特性，使它们能够发挥快速的先天样反应。为了了解不同的 γδ T 细胞亚群是如何产生的，我们开发了一个用于 γδ T 细胞发育的两阶段模型。该模型基于以下发现：γδTCR 信号强度通过 Id3 的分级上调影响 E 蛋白活性。我们的模型建议细胞进入第 1 阶段，以响应皮层中激活 γδ T 细胞特异性基因网络的 γδTCR 信号事件。该程序的一部分包括引导它们进入髓质的趋化因子受体的上调。在髓质中，第 1 阶段细胞接收 γδTCR、细胞因子和/共刺激信号的不同组合，诱导它们进入第 2 阶段，无论是向 γδT1 还是 γδT17 谱系。γδTCR 和细胞因子信号之间的交叉可以调节 Id3 的表达，即使在存在强γδTCR 信号的情况下也会导致不同的结果。γδT17 发育所需的胸腺信号壁龛在时间和空间上是分开的，在个体发育过程中提供了短暂的机会窗口。了解 E 蛋白在不同阶段运作的监管背景将是定义其活动水平如何施加功能结果的关键。