Analyzing dendritic cell development by inducible lineage tracing

描述（由申请人提供）：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包含两个主要的进化上保守的亚群，I型干扰素产生性浆细胞样DC（pDC）和抗原呈递经典DC（cDC）。这两个DC亚群对细胞因子Flt 3配体具有共同的依赖性，但它们的细胞和分子特性非常不同。目前认为cDC和pDC从骨髓中的共同DC祖细胞（CDP）发育而来。然而，最近的一些证据与该模型不相容，从而阻碍了使用体内谱系追踪对DC发育进行无偏见的重新检查。我们将使用转基因小鼠株表达他莫昔芬诱导Cre重组酶（CreER）标记干/祖细胞群体和跟踪其分化为DC。具体来说，我们将研究 造血干细胞分化为DC亚群的动力学和顺序（Aim 1）以及CDPs的分化潜能（Aim 2）。这些研究将基于体内谱系追踪生成DC发育的更新模型。他们还将产生用于可诱导Cre重组的新型菌株，其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.