Abstract
Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.
Highlights
The bone marrow (BM) is the primary organ responsible for the formation of all blood cell lineages, and serves as a reservoir for immunological memory [1,2]
Our findings in this study take this crosstalk between hematopoietic stem and progenitor cells (HSPCs) and dendritic cells (DC) one step further, as we show that BM-resident DCs are capable of taking up fungal antigens and subsequently skew hematopoiesis towards increased production of neutrophils in a G-CSF dependent manner
We discovered that BM DCs were efficient in taking up zymosan molecules through Dectin-1 in mice and CR3 in humans; human BM DCs use CR3 rather than Decin-1, it could be that CR3 is involved in murine BM DCs, as this is highly expressed on these cells
Summary
The bone marrow (BM) is the primary organ responsible for the formation of all blood cell lineages, and serves as a reservoir for immunological memory [1,2]. It harbors a small population of resident dendritic cells (DC) that can be primed by blood borne antigens and subsequently activate naïve T cells [3,4]. The BM can act as a secondary lymphoid organ with capability of initiating adaptive immune responses. BM DCs are fully capable of activating T cells and responding to systemic infection with an inflammatory profile.
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