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

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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.