Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.
Nat Immunol. 2019 Sep;20(9):1150-1160. doi: 10.1038/s41590-019-0445-7. Epub 2019 Jul 29.
Innate lymphoid cells (ILCs) play important functions in immunity and tissue homeostasis, but their development is poorly understood. Through the use of single-cell approaches, we examined the transcriptional and functional heterogeneity of ILC progenitors, and studied the precursor-product relationships that link the subsets identified. This analysis identified two successive stages of ILC development within T cell factor 1-positive (TCF-1) early innate lymphoid progenitors (EILPs), which we named 'specified EILPs' and 'committed EILPs'. Specified EILPs generated dendritic cells, whereas this potential was greatly decreased in committed EILPs. TCF-1 was dispensable for the generation of specified EILPs, but required for the generation of committed EILPs. TCF-1 used a pre-existing regulatory landscape established in upstream lymphoid precursors to bind chromatin in EILPs. Our results provide insight into the mechanisms by which TCF-1 promotes developmental progression of ILC precursors, while constraining their dendritic cell lineage potential and enforcing commitment to ILC fate.
先天淋巴细胞 (ILC) 在免疫和组织稳态中发挥重要作用，但它们的发育仍知之甚少。通过使用单细胞方法，我们研究了 ILC 祖细胞的转录和功能异质性，并研究了将鉴定的亚群联系起来的前体-产物关系。这项分析在 T 细胞因子 1 阳性 (TCF-1) 早期先天淋巴细胞祖细胞 (EILP) 内鉴定出 ILC 发育的两个连续阶段，我们将其命名为“指定 EILP”和“承诺 EILP”。指定的 EILP 产生树突状细胞，而这种潜力在承诺的 EILP 中大大降低。TCF-1 对于指定 EILP 的产生不是必需的，但对于承诺的 EILP 的产生是必需的。TCF-1 使用在早期淋巴祖细胞中建立的预先存在的调控景观来结合 EILP 中的染色质。我们的研究结果提供了关于 TCF-1 如何促进 ILC 前体发育进展的机制的深入了解，同时限制了它们的树突状细胞谱系潜力，并强制承诺 ILC 命运。
