Miyazaki Kazuko, Horie Kenta, Watanabe Hitomi, Hidaka Reiko, Hayashi Rinako, Hayatsu Norihito, Fujiwara Kentaro, Kuwata Rei, Uehata Takuya, Ochi Yotaro, Takenaka Makoto, Kawaguchi Risa Karakida, Ikuta Koichi, Takeuchi Osamu, Ogawa Seishi, Hozumi Katsuto, Holländer Georg A, Kondoh Gen, Akiyama Taishin, Miyazaki Masaki
Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan.
Genes Dev. 2025 Mar 3;39(5-6):384-400. doi: 10.1101/gad.352111.124.
External signals from the thymic microenvironment and the activities of lineage-specific transcription factors (TFs) instruct T-cell versus innate lymphoid cell (ILC) fates. However, mechanistic insights into how factors such as Notch1-Delta-like-4 (Dll4) signaling and E-protein TFs collaborate to establish T-cell identity remain rudimentary. Using multiple in vivo approaches and single-cell multiome analysis, we identified a feedback amplifier circuit that specifies fetal and adult T-cell fates. In early T progenitors (ETPs) in the fetal thymus, Notch signaling minimally lowered E-protein antagonist levels, and high abundance favored the differentiation of ETPs into ILCs. Conversely, in the adult thymus, Notch signaling markedly decreased abundance in ETPs, substantially elevating E-protein DNA binding and in turn promoting the activation of a T-cell lineage-specific gene expression program linked with V(D)J gene recombination and T-cell receptor signaling. Our findings indicate that, in the fetal versus the adult thymus, a simple feedback amplifier circuit dictated by Notch-mediated signals and abundance enforces T-cell identity and suppresses ILC development.
来自胸腺微环境的外部信号以及谱系特异性转录因子（TFs）的活性决定了T细胞与固有淋巴细胞（ILC）的命运。然而，对于Notch1-δ样4（Dll4）信号传导和E蛋白TFs等因子如何协同作用以确立T细胞身份的机制性见解仍很初步。利用多种体内方法和单细胞多组学分析，我们鉴定出了一个决定胎儿和成年T细胞命运的反馈放大回路。在胎儿胸腺中的早期T祖细胞（ETP）中，Notch信号传导使E蛋白拮抗剂水平轻微降低，而高丰度则有利于ETP分化为ILC。相反，在成年胸腺中，Notch信号传导显著降低了ETP中的丰度，大幅提高了E蛋白与DNA的结合，进而促进了与V(D)J基因重排和T细胞受体信号传导相关的T细胞谱系特异性基因表达程序的激活。我们的研究结果表明，在胎儿胸腺与成年胸腺中，由Notch介导的信号和丰度所决定的一个简单反馈放大回路强化了T细胞身份并抑制了ILC的发育。
