Analyzing dendritic cell development by inducible lineage tracing

描述(申请人提供)：树突状细胞(DC)是将病原体的先天识别与适应性免疫反应联系起来的关键免疫哨兵。DC包括两个在进化上保守的亚群，即产生I型干扰素的血浆细胞样树突状细胞(PDC)和呈递抗原的经典树突状细胞(CDCs)。这两个DC亚群共同依赖于细胞因子Flt3配体，但它们的细胞和分子特性却非常不同。目前认为，CDCs和pDCs来源于骨髓中共同的DC前体细胞(CDP)。然而，最近的一些证据与这一模型不相容，需要使用体内谱系追踪来公正地重新检查DC的发展。我们将使用表达三苯氧胺诱导的Cre重组酶(CRER)的转基因小鼠品系来标记干/祖细胞群体，并追踪它们向DC的分化。具体来说，我们将审查 造血干细胞分化为DC亚群的动力学和序列(目标1)和CDPs的分化潜力(目标2)。这些研究将产生一个基于体内血统追踪的DC发展的更新模型。它们还将产生可诱导的Cre重组的新菌株，并可用于谱系追踪和基因靶向。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are key immune sentinels that link innate recognition of pathogens to adaptive immune responses. DCs comprise two main evolutionarily conserved subsets, type I interferon- producing plasmacytoid DCs (pDCs) and antigen-presenting classical DCs (cDCs). The two DC subsets share common dependence on the cytokine Flt3 ligand, yet their cellular and molecular properties are very distinct. It is currently believed that cDCs and pDCs develop from a common DC progenitor (CDP) in the bone marrow. However, some recent evidence is not compatible with this model, warranting an unbiased re-examination of DC development using lineage tracing in vivo. We will use transgenic mouse strains expressing a tamoxifen-inducible Cre recombinase (CreER) to label stem/progenitor populations and trace their differentiation into DCs. Specifically, we will examine the kinetics and sequence of hematopoietic stem cell differentiation into DC subsets (Aim 1) and the differentiation potential of CDPs (Aim 2). These studies would generate an updated model of DC development based on in vivo lineage tracing. They would also generate novel strains for inducible Cre recombination with utility for lineage tracing and gene targeting.