Abstract
Dendritic cells (DCs) are crucial effectors of the immune system, which are formed from hematopoietic stem and progenitor cells (HSPCs) by a multistep process regulated by cytokines and distinct transcriptional mechanisms. C/EBPα is an important myeloid transcription factor, but its role in DC formation is not well defined. Using a CebpaCre-EYFP reporter mouse model, we show that the majority of splenic conventional DCs are derived from Cebpa-expressing HSPCs. Furthermore, HSPCs isolated from Cebpa knockout (KO) mice exhibited a marked reduced ability to form mature DCs after in vitro culture with FLT3L. Differentiation analysis revealed that C/EBPα was needed for the formation of monocytic dendritic progenitors and their transition to common dendritic progenitors. Gene expression analysis and cytokine profiling of culture supernatants showed significant downregulation of inflammatory cytokines, including TNFα and IL-1β as well as distinct chemokines in KO HSPCs. In addition, TNFα-induced genes were among the most dysregulated genes in KO HSPCs. Intriguingly, supplementation of in vitro cultures with TNFα at least partially rescued DC formation of KO HSPCs, resulting in fully functional, mature DCs. In conclusion, these results reveal an important role of C/EBPα in early DC development, which in part can be substituted by the inflammatory cytokine TNFα.
Highlights
Dendritic cells (DCs) are sentinels of the immune system that function via the uptake of antigens and presenting antigenic peptides to naïve T-cells, leading to T-cell priming and effector cell differentiation [1].DCs are classified based on origin, location, and function into steady state DCs, which encompass conventional DCs and plasmacytoid DCs, as well as Langerhans cells (LCs) and monocyte-derived DCs
We studied in the fact that the majority of monocytic dendritic cell progenitors (MDPs) were positive for Cebpa/EYFP expression, we vitro DC development of primary bone marrow hematopoietic stem and progenitor cells (HSPCs) isolated from inducible Cebpa knock-out (KO)
We studied in vitro DC development of primary bone marrow HSPCs isolated from inducible Cebpa knock-out (KO) mice (Mx1Cre /CebpaF/F ) and their wildtype (WT) littermates (CebpaF/F ) after FMS-related tyrosinetyrosine kinase-3kinase-3 ligand (FLT3L) stimulation [18]
Summary
DCs are classified based on origin, location, and function into steady state DCs, which encompass conventional DCs (cDCs) and plasmacytoid DCs (pDCs), as well as Langerhans cells (LCs) and monocyte-derived DCs. Apart from LCs, all types of DCs arise from bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs), which undergo sequential differentiation steps via lineage-restricted progenitors. According to the current model, steady-state DC development starts with the formation of monocytic dendritic cell progenitors (MDPs) from multipotent (MPPs) or common myeloid progenitors (CMPs) [2,3,4,5,6] through the activity of the cytokine FMS-related tyrosine. MDPs give rise to common dendritic cell progenitors (CDPs). The ETS factor PU. acts as a master regulator during the transition of MPPs to MDPs and is induced by FLT3L [7,8]. TFs such as IRF8, IRF4, and ID2 [9,10] have been shown to have effects on multiple steps of DC development
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