RUNX:CBFb complex constrains fetal-restricted innate T cell generation from adult lymphopoietic progenitors

摘要 在宫内发育期间，免疫系统产生的细胞亚群将定植于粘膜屏障。这一过程 仅限于胎儿/新生儿窗口，因为成年细胞无法补充粘膜淋巴细胞。尽管如此， 时间限制，支持成人和胎儿造血潜力的分子机制尚未完全阐明 已澄清。我们认为，一组特定的胎儿因子的表达受转录因子的剂量控制 复杂的RUNX：CBF2负责获得胎儿的发育潜力。我们制造了意想不到的东西 发现CBF2单倍体功能不全使成人造血干细胞具有重建原型的能力 产生T17细胞的3型细胞因子。CbF-2杂合子成人造血祖细胞的转录分析 小鼠发现，通常在胚胎中活跃的基因上调，可能直接受到RUNX：CbF2复合体的控制。 我们认为，胚胎造血中心的转录因子(TF)的集合可以指导成年祖细胞 以获得胎儿的淋巴生成潜能。为了验证这一假设，我们将利用子宫内移植试验。 忠实地概括了胎儿的利基环境。常规或转基因前体细胞在子宫内的发育分析 将有助于剖析黏膜先天淋巴样细胞生成过程中的细胞和转录需求。 我们还建议利用cbf2单倍体不足带来的发育可塑性来重新连接成人调节。 在成年祖细胞中采用胚胎发育潜力的回路。候选胎儿因子受以下因素调节 RUNX：Cbf2将在成年祖细胞中过表达，因为他们有能力与受限的胎儿产生免疫亚群 起源。在目标1中，我们将确定cbf2杂合子成体的整体染色质景观。 并允许增强胎儿型先天淋巴细胞的重建。在目标2中，我们将识别基因 将成人造血祖细胞重新编程为胎儿淋巴生成潜能所需。我们的长期目标是 绘制允许造血祖细胞产生组织驻留的高粒度转录变化图 胎儿/新生儿来源的免疫细胞。

Summary During intrauterine development the immune system generates cell subsets that will colonize mucosal barriers. This process is restricted to a fetal/neonatal window as adult cells are unable to replenish mucosal lymphocytes. Despite this sharp temporal constraint, the molecular mechanisms underpinning adult versus fetal hematopoietic potential has not been fully elucidated. We propose that the expression of a specific set of fetal factors controlled by the dosage of the transcriptional complex RUNX:CBF2 is responsible for the acquisition of fetal developmental potential. We made the unexpected discovery that CBF2 haploinsufficiency confers adult hematopoietic stem cells the ability to reconstitute the prototypical type 3 cytokine producing T17 cells. Transcriptional analysis of adult hematopoietic progenitors in CBF2 heterozygous mice revealed the upregulation of genes usually active in embryos and likely controlled directly by RUNX:CBF2 complex. We propose that an ensemble of transcription factors (TFs) central to embryonic hematopoiesis can instruct adult progenitors to acquire fetal lymphopoietic potential. To test this hypothesis we will take advantage of the in utero transplantation assay that faithfully recapitulate the fetal niche. Developmental assays of conventional or genetically altered precursors in utero will help dissect the cellular and transcriptional requirements during the generation of mucosal innate-like lymphoid cells. We also propose to exploit the developmental plasticity imposed by CBF2 haploinsufficiency to rewire adult regulatory circuits in adult progenitors to adopt an embryonic developmental potential. Candidate fetal factors that are regulated by RUNX:CBF2 will be overexpressed in adult progenitors for their ability to generate immune subsets with a restricted fetal origin. In Aim 1, we will determine the overall chromatin landscape that characterizes CBF2 heterozygous adult progenitors and permit enhanced reconstitution of fetal-type innate lymphocytes. In Aim 2, we will identify the genes required for reprogramming adult hematopoietic progenitors towards fetal lymphopoietic potential. Our long term goal is to map with high granularity transcriptional changes that license hematopoietic progenitors to give rise to tissue resident fetal/neonatal-derived immune cells.