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ADAM10 shapes myeloid antigen-presenting cell homeostasis in the splenic marginal zone

ABSTRACT: The spleen contains phenotypically and functionally distinct cDC1 and cDC2 subpopulations, which each can be divided into several smaller and less-well characterized subsets. Despite advances in understanding the complexity of DC ontogeny and function by transcriptional programming, the significance of post-translational modifications in controlling tissue-specific cDC (subset) immunobiology remains elusive. Here, we identified the cell surface-expressed A-disintegrin-and-metalloproteinase 10 (ADAM10) as an essential regulator of cDC1 and cDC2 homeostasis in the splenic marginal zone (MZ). Mice with a CD11c-specific deletion of ADAM10 (ADAM10ΔCD11c) exhibited a complete loss of splenic ESAMhi cDC2A, because ADAM10 controlled their commitment, differentiation, survival, and EBI2-mediated localization within the MZ. Moreover, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as this unbalanced cDC2A homeostasis in the absence of ADAM10 was compensated for by the emergence of a novel Clec12a+ cDC2B subset, closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10ΔCD11c mice terminal differentiation of cDC1 was abrogated, resulting in reduced numbers of Langerin+ cDC1.

ORGANISM(S): Mus musculus

PROVIDER: GSE154309 | GEO | 2023/06/27

REPOSITORIES: GEO

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ADAM10 shapes myeloid antigen-presenting cell homeostasis in the splenic marginal zone

Project description:The spleen contains phenotypically and functionally distinct cDC1 and cDC2 subpopulations, which each can be divided into several smaller and less-well characterized subsets. Despite advances in understanding the complexity of DC ontogeny and function by transcriptional programming, the significance of post-translational modifications in controlling tissue-specific cDC (subset) immunobiology remains elusive. Here, we identified the cell surface-expressed A-disintegrin-and-metalloproteinase 10 (ADAM10) as an essential regulator of cDC1 and cDC2 homeostasis in the splenic marginal zone (MZ). Mice with a CD11c-specific deletion of ADAM10 (ADAM10ΔCD11c) exhibited a complete loss of splenic ESAMhi cDC2A, because ADAM10 controlled their commitment, differentiation, survival, and EBI2-mediated localization within the MZ. Moreover, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as this unbalanced cDC2A homeostasis in the absence of ADAM10 was compensated for by the emergence of a novel Clec12a+ cDC2B subset, closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10ΔCD11c mice terminal differentiation of cDC1 was abrogated, resulting in reduced numbers of Langerin+ cDC1.

2021-09-06 | GSE154767 | GEO

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

Project description:To characterize the changes that had occurred in splenic pre-cDCs in the absence of ADAM10, we performed RNA sequencing on sorted pre-cDC1 and 2 from the spleens of wild-type and ADAM10ΔDC mice. Unsupervised hierarchical clustering and principal component analysis of all four groups demonstrated that distinct transcriptomic changes had taken place in ADAM10ΔDC pre-cDC2, while minimal changes were observed for pre-cDC1

2019-11-12 | GSE131264 | GEO

RNA sequencing of primary isolated unstimulated murine splenic DC1 and DC2 from specific pathogen free (SPF), Germ free (GF) and Interferon alpha/beta receptor 1 (Ifnar) knock out mice

Project description:The transcriptomes of primary isolated unstimulated murine splenic cDC1 and cDC2 from specific pathogen free (SPF) were compared to cDC1 and cDC2 from Germ Free (GF) and Interferon alpha/beta receptor 1 (Ifnar) knock out mice. Total RNA was prepared from sort-purified cDC1 and cDC2 (for each sample 3 individual mice were pooled) using Trizol reagent (Invitrogen) in combination with the miRNeasy Micro Kit (Qiagen) according to the manufacturer’s instructions. For poly-A-dependent cDNA synthesis and a first amplification step 10 ng of total RNA was used as input in the Smart-Seq v4 mRNA Ultra Low Input RNA Kit (Clontech) and processed according to the manufacturer’s instructions. 1 ng of the purified cDNA was used for tagmentation and library completion with the Nextera XT library preparation kit (Illumina). In the following, 2x75nt paired-end sequencing was performed on a NextSeq 500.

2020-03-30 | E-MTAB-8883 | biostudies-arrayexpress

pDC-like cells are pre-DC2 and require Klf4 to control homeostatic CD4 T cells

Project description:Plasmacytoid dendritic cells (pDCs) have been shown to play an important role during immune responses, ranging from initial viral control through the production of type I interferons (IFNs) to antigen presentation. However, recent evidence uncovered unexpected heterogeneity among pDCs. Notably we identified a new subset, referred to as pDC-like cells, that resembles pDCs but shares cDC features. Here we show that this subset is a circulating progenitor distinct from common DC progenitors (CDP), with prominent cDC2 precursor potential. This precursor subset responds to homeostatic cytokines, such as macrophage colony stimulating factor (M-CSF) by expanding and differentiating into cDC2 that efficiently prime Th17 cell. Development of pDC-like cells into CX3CR1+ESAM- cDC2b but not CX3CR1- ESAM+ cDC2a requires the transcription factor KLF4. Finally, we show that under homeostatic conditions this developmental pathway regulates the immune threshold at barrier sites, by controlling the pool of Th17 cells within the skin draining lymph nodes.

2023-02-24 | GSE223100 | GEO

Expression data from splenic cDC1, cDC2, and pDC from WT and Bcl6cKO mice

Project description:We used microarray gene analysis to compare the transcriptional profiles between WT and Bcl6cKO splenic cDC1, cDC2, and pDCs.

2019-10-01 | GSE135904 | GEO

RNA-seq of dendritic cell subsets

Project description:Comparison of cDC1, cDC2, mcDC transcriptome Conventional dendritic cells (cDCs) are classically subdivided in two subsets, named cDC1 and cDC2. We demonstrated that mcDC are a new subset of cDCs. To understand their transcriptomic relatedness, we perform a RNA sequencing on cDC1, cDC2 and mcDCs sorted from mouse spleens. We demonstrate that cDC1, cDC2 and mcDCs all cluster independently in a PCA analysis and an unbiased hierarchical cluster analysis reveals unique gene profile for all three cDC subsets. As mcDC cluster slightly more towards cDC1 than cDC2, we next aimed to more closely examine the transcriptomic relatedness between mcDC and cDC2. We compared the DC subsets gene expression signatures based on a selected gene set known to define cDC2. Both the PCA and hierarchical cluster analysis show that mcDC exhibit a different signature to cDC2. Altogether, we demonstrate that mcDC are a distinct subsets of cDCs with a specific transcriptomic signature.

2020-04-30 | GSE147458 | GEO

Retinoic acid directs the development and transcriptional programming of intestinal dendritic cells

Project description:This file contains gene microarray data from bone marrow pre-ul DC, in vitro derived CD103+CD11b+ and CD103+CD11b- cDC with or without retinoic acid. We analyze transcript expression data from bone marrow pre-uDC, Splenic and SI cDC1 and cDC2 (GSE15907 - 18 samples), in vitro derived CD103+CD11b+ and CD103+CD11b- cDC from C57Bl/6 mice. The complete dataset is linked below as a supplementary file.

2015-08-01 | E-GEOD-68399 | biostudies-arrayexpress

Tissue-specific factors differentially regulate the expression of antigen-processing enzymes during dendritic cell ontogeny

Project description:Dendritic cells (DC) form a collection of antigen-presenting cells that are distributed throughout the body. Conventional DC (cDC) which include the cDC1 and cDC2 subsets, and plasmacytoid DC (pDC) constitute the two major ontogenically distinct DC populations. The pDC complete their differentiation in bone-marrow (BM) while the cDC subsets derive from pre-committed bone-marrow (BM) precursors, the pre-cDC, that seed lymphoid and non-lymphoid tissues where they further differentiate into mature cDC1 and cDC2. Within different tissues, cDC express distinct phenotype and function. Notably cDC in the thymus are exquisitely efficient at processing and presenting antigens in the class II pathway, while in the spleen they do so only upon maturation induced by danger signals. To appraise this functional heterogeneity, we examined the regulation of the expression of distinct antigen-processing enzymes during DC ontogeny. We analyzed the expression of cathepsin S (CTSS), cathepsin L (CTSL) and thymus specific serine protease (TSSP), three major antigen-processing enzymes regulating class II presentation in cDC, by DC BM precursors and immature and mature cDC from spleen and thymus. We found that pre-cDC in the BM express relatively high levels of these different proteases. Then, their expression is modulated in a tissue-specific and subset–specific manner with immature and mature thymic cDC expressing overall higher levels than immature splenic cDC. On the other hand, TSSP expression level is selectively down-regulated in spleen pDC while CTSS and CTSL are both increased in thymic and splenic pDC. Hence tissue-specific factors program the expression levels of these different proteases during DC differentiation thus conferring tissue-specific function to the different DC subsets.

2020-01-29 | GSE144421 | GEO

Optimization of the Irf8 +32 kb enhancer disrupts dendritic cell lineage segregation

Project description:Autoactivation of lineage-determining transcription factors (TFs) mediates bistable expression to generate distinct cell phenotypes essential for complex body plans. Classical dendritic cells type 1 (cDC1) and type 2 (cDC2) provide non-redundant functions required for defense against distinct immune challenges. Interferon Regulatory Factor 8 (IRF8), the cDC1 lineage-determining TF, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32 kb enhancer, responsible for IRF8 autoactivation, has been tuned to possess low-affinity IRF8 binding sites. Increasing these affinities in vivo induces erroneous IRF8 autoactivation in specified cDC2 progenitors, causing their redirection towards cDC1 and a novel hybrid DC subset with mixed lineage phenotypes. These developmental alterations critically impair both cDC1- and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of classical dendritic cells required for normal immune function.

2024-02-01 | GSE241341 | GEO

scRNAseq of sorted splenic MHCII+ cells from 9 day-old female Clec9a-Cre/Cre Rosa-tdTomato/tdTomato mice after exclusion of CD19+ B cells and autofluorescence+F4/80hi macrophages

Project description:We use scRNA sequencing of MHCII+ cells in the neonatal spleen to elucidate the heterogeneity in young cDC populations and their potential ontogenetic relationship with MHCII-expressiong ILCs. Additionally, we aim to uncover the transcriptomic differences of TOM+ cDC2 and TOM- DC2 in the single cell level. Our data reveal that the neonatal spleen consists of the same cDC1 and cDC2 subsets that comprise the adult cDC compartment. Additionallu, ILCs do not seem to relate otogenetically with TOM- DC2.In the cDC2 clusters, TOM+/- cells are evenly distributed indicative of their transciptomic resemblance. A unique and distinct cluster of TOM- DC2 is observed.

2020-11-06 | GSE151592 | GEO

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