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Lymph node medulla is a quorum sensing niche for developing dendritic cells [preDC]

ABSTRACT: Conventional dendritic cells (cDC) and macrophages form complex networks that are essential for tissue homeostasis and immune defence. While the differentiation and residency of macrophages is regulated within distinct tissue niches, it is unclear whether DC development in tissues follows similar principles given their short life-span. By studying cDC development using fate mapping and depletion/reconstitution approaches, we found that preDC undergo distinct developmental stages. This development that preceded DC maturation was guided within the medullary cords of LNs. Intravital imaging and in situ photoconversion showed that preDC homed via medullary vessels and used them as guiding structures for their migration to the LN parenchyma. Infection-induced relocation of cDCs changed the availability of lymphocyte-derived Flt3l in the medulla which accelerated preDC development to ensure their local replenishment and responsiveness. Uncovering these principles of the spatiotemporal development of cDC and their complex cellular networks may guide novel angles for immunotherapy against cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE204815 | GEO | 2023/05/22

REPOSITORIES: GEO

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Project description:Dendritic cells (DCs) in lymphoid tissue comprise conventional DCs (cDCs) and plasmacytoid DCs (pDCs) that develop from common DC progenitors (CDPs). CDPs are Flt3+c-kitintM-CSFR+ and reside in bone marrow. Here we describe a two-step culture system that recapitulates DC development from c-kithiFlt3-/lo multipotent progenitors (MPPs) into CDPs and further into cDC and pDC subsets. MPPs and CDPs are amplified in vitro with Flt3 ligand, stem cell factor, hyper-IL-6 and insulin- like growth factor-1. The four-factor cocktail readily induces self-renewal of MPPs and their progression into CDPs and has no self-renewal activity on CDPs. The amplified CDPs respond to all known DC poietins and generate all lymphoid tissue DCs in vivo and in vitro. Additionally, in vitro CDPs recapitulate the cell surface marker and gene expression profile of in vivo CDPs and possess a DC-primed transcription profile. Transforming growth factor-Î²1 (TGF-Î²1) impacts on CDPs and directs their differentiation towards cDCs. Genome-wide gene expression profiling of TGF-Î²1-induced genes identified transcription factors, such as interferon regulatory factor-4 (IRF-4) and RelB, that are implicated as instructive factors for cDC subset specification. TGF-Î²1 also induced the transcription factor inhibitor of differentiation/DNA binding 2 (Id2) that suppresses pDC development. Thus, TGF-Î²1 directs CDP differentiation into cDC by inducing both cDC instructive factors and pDC inhibitory factors. 20 samples in total. Multipotent progenitor - MPP_1 - MPP_2 Common dendritic cell progenitor - CDP_1 - CDP_2 Plasmacytoid dendritic cell - pDC_1 - pDC_2 Conventional dendritic cell - cDC_1 - cDC_2 In vivo common dendritic cell progenitor - In vivo CDP_1 - In vivo CDP_2 Untreated common dendritic cell progenitor (CDP) - CDP_0h_1 - CDP_0h_2 TGF-beta1 treated (4 hours) CDP - CDP_4h_1 - CDP_4h_2 TGF-beta1 treated (8 hours) CDP - CDP_8h_1 - CDP_8h_2 TGF-beta1 treated (12 hours) CDP - CDP_12h_1 - CDP_12h_2 TGF-beta1 treated (24 hours) CDP - CDP_24h_1 - CDP_24h_2

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Lymph node medulla is a quorum sensing niche for developing dendritic cells [preDC]

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