Ly6D+ Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+ Ly6D+ intermediary stage
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PROVIDER: PRJEB52646 | ENA |
REPOSITORIES: ENA
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Project description:Plasmacytoid and conventional dendritic cells (pDC, and cDC) are generated from distinct lymphoid and myeloid progenitor cells in murine bone marrow. Despite the early separation of pDC and cDC lineages, CD11c+ MHCII-/lo Siglec-H+ CCR9lo pDC-like precursor cells are able to differentiate into both pDC and cDC. Single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis revealed the heterogeneity and commitment of subsets in this compartment. While Ly6D– cells within this fraction were cDC-committed and B220hi Ly6Dhi Zbtb46– cells were immediate precursors of pDCs, B220lo Ly6Dhi Zbtb46– cells still had the potential to generate cDCs in addition to pDCs. Transition to cDCs occurred via an intermediary stage marked by coexpression of Siglec-H, Ly6D and Zbtb46. Type I IFN stimulation limited cDC and promoted pDC output from these precursors, demonstrating their plasticity in response to inflammation. Thus, flexibility to divert to cDCs is retained in the pDC lineage at later differentiation stages.
2021-12-01 | GSE189780 | GEO
Project description:Plasmacytoid dendritic cell precursors give rise to conventional dendritic cells via a Siglec-H+ Zbtb46+ Ly6D+ intermediary stage
| PRJNA784517 | ENA
Project description:Plasmacytoid and conventional dendritic cells (pDC and cDC) are generated from progenitor cells in the bone marrow and commitment to pDCs or cDC subtypes may occur in earlier and later progenitor stages. Cells within the CD11c+MHCII−/loSiglec-H+CCR9lo DC precursor fraction of the mouse bone marrow generate both pDCs and cDCs. Here we investigate the heterogeneity and commitment of subsets in this compartment by single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis: Within the CD11c+MHCII−/loSiglec-H+CCR9lo DC precursor pool cells expressing high levels of Ly6D and lacking expression of transcription factor Zbtb46 contain CCR9loB220hi immediate pDC precursors and CCR9loB220lo (lo-lo) cells which still generate pDCs and cDCs in vitro and in vivo under steady state conditions. cDC-primed cells within the Ly6DhiZbtb46– lo-lo precursors rapidly upregulate Zbtb46 and pass through a Zbtb46+Ly6D+ intermediate stage before acquiring cDC phenotype after cell division. Type I IFN stimulation limits cDC and promotes pDC output from this precursor fraction by arresting cDC-primed cells in the Zbtb46+Ly6D+ stage preventing their expansion and differentiation into cDCs. Modulation of pDC versus cDC output from precursors by external factors may allow for adaptation of DC subset composition at later differentiation stages. The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.
| S-EPMC9200809 | biostudies-literature
Project description:Tumor-angiogenesis and -immunity play critical roles in cancer progression and outcome. The existence of an inverse correlation hints at common regulatory mechanism(s) controlling these two processes. Here, we report that Zbtb46, a repressive transcription factor and widely accepted marker for classical dendritic cells (DCs), constitutes one such regulatory mechanism in the tumor microenvironment (TME) and is downregulated in both DCs and endothelial cells (ECs) by tumor-derived factors to facilitate robust tumor growth. This downregulation leads to the development of hallmark features of a pro-tumor environment, including dysfunctional vasculature and immunosuppressive cell accumulation. Analysis of cancer patient data revealed a similar association of a low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, upon enforced Zbtb46 expression, the hallmark TME features are mitigated, and tumor growth is restricted. Mechanistically, Zbtb46-deficient ECs were highly angiogenic, and Zbtb46-deficient bone-marrow precursors upregulated Cebpb and showed enhanced myeloid lineage output. Conversely, Zbtb46-maintenance normalizes ECs and, by suppressing Cebpb, skews the polarization of bone-marrow precursors towards more DCs and fewer macrophages, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in pre-clinical models. These findings identify Zbtb46 as a common regulatory mechanism for angiogenesis and for non-hematopoietic-stem-cell-mediated myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.
2024-02-24 | GSE226087 | GEO
Project description:Nine different cell types (common dendritic progenitor (CDP), pre-conventional dendritic cell (pre-cDC), common dendritic progenitor (CDPr, according to Rodrigues et al., but this population was flawed in sorting purity), Flt3+ CD11c+ Siglec-H+ CCR9-low B220-low progenitor cell (lo-lo), Flt3 + CD11c+ Siglec-H+ CCR9-low B220-high progenitor cell (lo-hi), plasmacytoid dendritic cell (pDC), Ly6D+ lymphoid progenitor (SP), Ly6D+ Siglec-H+ lymphoid progenitor (DP) and common lymphoid progenitor (CLP)) were sorted to allow for analysis of their transcriptomic relation and/or similarity. The pDC_precursor_scvelo.h5ad file is a processed file ready for direct downstream analysis with scvelo.
2022-05-21 | E-MTAB-11752 | biostudies-arrayexpress
Project description:Tumor-angiogenesis and -immunity play critical roles in cancer progression and outcome. An inverse correlation of these two1 hints at common regulatory mechanism(s). Here, we report that Zbtb46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2,3, constitutes one such regulatory mechanism. Zbtb46 was downregulated in both DCs and endothelial cells (ECs) by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive cell accumulation. Analysis of cancer patient data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression brought dynamic changes in the TME landscape to mitigate the pro-tumor features and to enhance anti-tumor immune components, restricting tumor growth. Mechanistically, Zbtb46-deficient ECs were highly angiogenic, and Zbtb46-deficient bone-marrow progenitors upregulated Cebpb and diverted the DC program to myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone-marrow precursors towards more DC generation over macrophages, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in pre-clinical models. These findings identify Zbtb46 as a common regulatory mechanism for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.
2024-07-05 | GSE264124 | GEO
Project description:We unexpectedly identify one unique subset of group 3 innate lymphoid cells (ILC3s) that co-expresses Zbtb46, a transcription factor that specifies conventional dendritic cells (cDCs). Zbtb46 is robustly expressed by CCR6+ lymphoid tissue inducer (LTi)-like ILC3s that are developmentally and phenotypically distinct from cDCs. To determine the function of Zbtb46 in ILC3s, we performed RNA sequencing on CCR6+ ILC3s sorted from the large intestine of Zbtb46 f/f and Rorc Cre Zbtb46 f/f mice at steady state.
2022-05-02 | GSE181865 | GEO
Project description:Expression data from Zbtb46- CDPs, Zbtb46+ CDPs, and pre-CD8 DCs
| PRJNA509678 | ENA
Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed
2016-03-16 | E-GEOD-79248 | biostudies-arrayexpress
Project description:Zbtb46 represses G-CSFR and LifR in cDCs Zbtb46 does not significantly affect gene expression in erythroid progenitors
2012-05-21 | GSE37028 | GEO