The impact of transcriptomic imprinting on the functional specialization of monocytes during health and disease

单核巨噬细胞系由树突状细胞(DC)、单核细胞和巨噬细胞组成，在启动、维持和控制免疫反应中起着至关重要的作用。此外，在诱导和维持耐受性的过程中，关键的角色已经被分配给这一血统的成员。利用单细胞mRNA测序、飞行时间细胞术(CyToF)、流式细胞术和体内转移等前沿技术的最新进展，使我们能够深入了解DC亚群的起源和功能特化及其发展。然而，尽管单核细胞是小鼠和人类中最大和功能最多样化的细胞室之一，但仍然缺乏特征。在单核细胞生命周期的每个阶段都可以观察到表型和功能的特化，目前还不清楚这种不同的细胞亚群是如何在转录、发育和功能上进行调节的。因此，建议的中心问题将是健康和疾病期间小鼠(Ly6c+)和人类(CD14+)单核细胞亚群功能特化的转录和发育调节。该提案将详细研究人类和小鼠单核细胞在稳定状态下跨越淋巴和非淋巴组织的功能专门化，以确定在Ly6c+单核细胞功能专门化过程中自然与后天的影响。此外，还将在各种炎症模型，如疫苗诱导的炎症和肠道炎症中，研究单核细胞依赖的训练性免疫的调节和转录基础。这项提议将利用尖端技术，如单细胞mRNA测序、CyToF和多色流式细胞术，并结合功能表征，首次描绘健康和疾病期间人类和小鼠单核细胞亚群的功能专门化。

The mononuclear phagocyte lineage consists of dendritic cells (DCs), monocytes and macrophages and is crucial for initiation, maintenance and control of immune responses. Additionally, crucial roles during the induction and maintenance of tolerance have been assigned to members of the this lineage. Recent advances using cutting edge technologies, such as single cell mRNA sequencing, cytometry by time of flight (CyToF), flow cytometry and in vivo transfers enabled us to get an in depth understanding of the origin and functional specialization of DC subsets and the development thereof. Monocytes however, albeit one of the largest and functional most diverse cell compartments in mouse and man remain poorly characterized. Phenotypic and functional specialization can be observed at every stage of the monocyte life cycle and it is not well understood how such a heterogeneous cell subset is transcriptomically, developmentally, and functionally regulated. Therefore the proposals central question will be the transcriptional and developmental regulation of the functional specialization of mouse (Ly6c+) and human (CD14+) monocyte subsets during health and disease. In detail the proposal will investigate the functional specialization of human and mouse monocytes during steady state, across lymphoid and non-lymphoid tissues, to determine the impact of Nature vs. Nurture during the functional specialization of Ly6c+ monocytes. Moreover the regulation and transcriptional basis of monocyte dependent trained immunity will be investigated during various inflammatory models such as vaccination induced inflammation and intestinal inflammation. This proposal will utilize cutting edge technologies such as single cell mRNA sequencing, CyToF and multicolour flow cytometry paired with functional characterization to delineate for the first time the functional specialization of human and mouse monocyte subsets during health and disease.