Abstract
Functionally distinct plasmacytoid and conventional dendritic cells (pDC and cDC) shape innate and adaptive immunity. They are derived from common dendritic cell progenitors (CDPs) in the murine bone marrow, which give rise to CD11c+ MHCII− precursors with early commitment to DC subpopulations. In this study, we dissect pDC development from CDP into an ordered sequence of differentiation events by monitoring the expression of CD11c, MHC class II, Siglec H and CCR9 in CDP cultures by continuous single cell imaging and tracking. Analysis of CDP genealogies revealed a stepwise differentiation of CDPs into pDCs in a part of the CDP colonies. This developmental pathway involved an early CD11c+ SiglecH− pre-DC stage and a Siglec H+ CCR9low precursor stage, which was followed rapidly by upregulation of CCR9 indicating final pDC differentiation. In the majority of the remaining CDP pedigrees however the Siglec H+ CCR9low precursor state was maintained for several generations. Thus, although a fraction of CDPs transits through precursor stages rapidly to give rise to a first wave of pDCs, the majority of CDP progeny differentiate more slowly and give rise to longer lived precursor cells which are poised to differentiate on demand.
Highlights
Cells have the capacity to generate mature plasmacytoid dendritic cells (pDCs) or cDC subsets in the steady state depending on the environmental cues provided in different tissues[22,28]
Apoptosis occurred in only 3.7% and 0.9% of the cells and 17.2% and 16.6% of the Common DC progenitors (CDP) progeny were lost to tracking due to movement outside of the imaging position or migration under the stromal cell layer
Continuous imaging of CDP in the EL08/Flt3L co-culture system allows the generation of CDP genealogies, which reveal heterogeneous behaviour of CDP progeny with regard to number of divisions and acquisition of cell type defining markers
Summary
Cells have the capacity to generate mature pDCs or cDC subsets in the steady state depending on the environmental cues provided in different tissues[22,28]. Recent work suggested that Siglec H+ pre-DCs are derived from CDPs and constitute an early pre-DC stage which gives rise to pDCs and pre-cDCs17,31 It was unclear so far, if the Siglec H+ CCR9low population truly is a CDP-derived precursor of pDCs or if it develops in parallel as an immature subset of pDCs. To clearly delineate the ontogeny and cell fate of this pDC-like precursor population and to understand the extent of lineage commitment at the CDP and pre-DC stages, we chose to study the development of individual CDP progeny in vitro by single cell imaging and tracking[32]. We could show that pDCs develop from CDPs sequentially via intermediate stages of early CD11c+ SiglecH− pre-DC and SiglecH+ CCR9low precursors
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