Regulation of tissue resident macrophage development by IL-7R signaling

最近发现成人造血（血液）干细胞（HSC）不产生所有免疫细胞 尽管维持整个生命周期的血液生产从根本上挑战了我们对 免疫发育和功能。连续转移研究和命运绘图实验 表明组织驻留巨噬细胞仅在胎儿发育期间被指定，不能被 在成年期产生或者再生。与它们的成人HSC衍生的对应物相比，胎儿衍生的 组织驻留巨噬细胞在其驻留组织内驻留和自我更新，在那里它们执行不同的功能。 自我平衡和免疫监视功能。组织驻留巨噬细胞的胎儿起源的发现 提出了许多关于它们的规范、在整个生命周期中的持久性和独特功能的新问题。 这项建议的长期目标是确定独特的发展机制， 组织驻留巨噬细胞在整个生命周期中的功能能力，以阐明它们在 成人组织内环境稳定和疾病。本实验室最近的工作鉴定了白细胞介素-7受体（IL-7R）， 信号转导作为一种新的机制调节建立组织驻留巨噬细胞在胎儿 发展IL-7R信号传导仅限于调节成人造血中的淋巴谱系。的 胎儿骨髓特化对IL-7 R信号的依赖性表明胎儿造血利用了替代的 分化途径，以便赋予胎儿来源的巨噬细胞不同的特征。在这 建议，我们将利用这一新的监管机制的发现，深入研究这些 不同的免疫细胞在发育过程中从胎儿前体中指定。在目标1中，我们将使用遗传 确定胎儿骨髓特化过程中IL 7 R信号传导需求的方法。我们将 特异性地缺失一系列处于不同发育阶段的祖细胞和成熟细胞中的受体亚链IL 7。 以确定IL 7r α在胎儿发育期间如何调节骨髓特化。在目标2中，我们 首次定义了IL-7R信号传导如何在骨髓细胞中发生-包括下游信号转导 和转录靶点-以及由IL-7R信号调节的特定发育过程 在胎儿巨噬细胞建立期间。在目标3中，我们将建立IL-7作为胎儿骨髓小生境的功能， 因子，并定义对IL-7的需求以及哪些细胞亚群负责产生IL-7。 驻留组织以支持巨噬细胞发育。总之，拟议研究的工作将阐明 胎儿造血过程中的替代分化途径如何赋予不同的功能特征， 胎儿来源的组织驻留巨噬细胞，从而阐明了特定的个体发育亚群的作用， 正常组织和疾病过程中的巨噬细胞。

The recent discovery that adult hematopoietic (blood) stem cells (HSCs) do not produce all immune cells despite sustaining blood production across the lifespan has fundamentally challenged our understanding of both immune development and function. Adoptive transfer studies and fate mapping experiments have demonstrated that tissue-resident macrophages are only specified during fetal development and cannot be generated or regenerated in adulthood. As compared to their adult HSC-derived counterparts, fetal-derived tissue resident macrophages reside and self-renew within their resident tissues, where they perform distinct homeostatic and immune surveillance functions. The discovery of a fetal origin of tissue-resident macrophages has raised many new questions about their specification, persistence across the lifespan, and distinct function. The long-term objective of this proposal is to define the developmental mechanisms underlying the unique functional capacity of tissue resident macrophages across the lifespan in order to illuminate their distinct role in both adult tissue homeostasis and disease. Recent work in our lab has identified interleukin-7 receptor (IL-7R) signaling as a novel mechanism regulating the establishment of tissue resident macrophages during fetal development. IL-7R signaling is restricted to regulation of the lymphoid lineage in adult hematopoiesis. The reliance of fetal myeloid specification on IL-7R signaling suggests that fetal hematopoiesis exploits alternate differentiation pathways in order to confer distinct characteristics on fetal-derived macrophages. In this proposal, we will capitalize on the discovery of this new regulatory mechanism to dig deeper into how these distinct immune cells are specified from fetal precursors during development. In Aim 1, we will use genetic approaches to determine the requirement for IL7R signaling during fetal myeloid specification. We will specifically delete the receptor sub-chain IL7raain a range of progenitors and mature cells at different stages of development to define how IL7rα regulates myeloid specification during fetal development. In Aim 2, we will define for the first time how IL-7R signaling occurs in myeloid cells - including downstream signal transducers and transcriptional targets- and the specific developmental processes that are regulated by IL-7R signaling during fetal macrophage establishment. In Aim 3, we will establish the function of IL-7 as a fetal myeloid niche factor and define both the requirement for IL-7 and which cell subsets are responsible for producing IL-7 within resident tissues to support macrophage development. Together, work from the proposed studies will illuminate how alternative differentiation pathways during fetal hematopoiesis impart distinct functional characteristics on fetal-derived tissue resident macrophages, and thereby illuminate the role of specific ontogenetic subsets of macrophages in normal tissue and disease processes.