Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.
Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.
Nat Immunol. 2019 Sep;20(9):1174-1185. doi: 10.1038/s41590-019-0449-3. Epub 2019 Aug 12.
Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2 and Id2 CDPs to Zeb2 and Id2 CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.
经典型 1 树突状细胞 (cDC1) 对于抗病毒和抗肿瘤免疫是必需的，这就需要了解它们的发育过程。cDC1 祖细胞的发育需要一个依赖 E 蛋白的增强子，该增强子位于转录因子 Irf8 的转录起始位点下游 41kb（+41-kb Irf8 增强子），但其成熟则需要依赖 Batf3 的+32-kb Irf8 增强子。为了理解这种转变，我们对共同树突状细胞祖细胞 (CDP) 进行了单细胞 RNA 测序，鉴定出一群表达影响 cDC1 发育的转录因子的细胞，如 Nfil3、Id2 和 Zeb2。这些因子之间的遗传上位性表明，Nfil3 的表达对于从 Zeb2 和 Id2 CDP 向 Zeb2 和 Id2 CDP 的转变是必需的，后者代表最早的定向 cDC1 祖细胞。这种遗传回路阻止了 E 蛋白的活性，排除了浆细胞样树突状细胞的潜能，并解释了 cDC1 发育过程中 Irf8 增强子使用的转变。
