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Transmembrane TNF-TNFR2 axis promotes generation of human T cell precursors

ABSTRACT: The goal of this study is to understand how low level of IRF8 expression promotes the differentiation of human hematopoietic stem and progenitor cells (HSPCs) into T cell precursors. To achieve this, we utilized a construct that encodes IRF8-ERT2 fusion protein where IRF8 activity is tamoxifen-dependent. We extracted genomic DNA from HSPCs that had been co-cultured with OP9-DLL4 stromal cells and tagmented by Tn5 transposase for ATAC-sequencing. This allowed us to determine the impact of low level of IRF8 activity on the chromatin accessibility landscape of differentiating HSPCs. Our analysis found significant opening of chromatin region at the TNF core promoter in the presence of low level of IRF8 activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179534 | GEO | 2022/12/11

REPOSITORIES: GEO

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Transmembrane TNF-TNFR2 axis promotes generation of human T cell precursors

Project description:The goal of this study is to understand how low level of IRF8 expression promotes the differentiation of human hematopoietic stem and progenitor cells (HSPCs) into T cell precursors. To achieve this, we utilized a construct that encodes IRF8-ERT2 fusion protein where IRF8 activity is tamoxifen-dependent. We extracted total RNA from transduced HSPCs that had been co-cultured with OP9-DLL4 stromal cells and treated with or without 4-hydroxytamoxifen (4-OHT) for sequencing. This allowed us to determine the impact of low level of IRF8 activity on the transcriptome profile of differentiating HSPCs. Our analysis found significant increase of TNF expression in the presence of low level of IRF8 activity.

2022-12-11 | GSE179381 | GEO

Transmembrane TNF-TNFR2 axis promotes generation of human T cell precursors.

Project description:The goal of this study is to dissect the impact of soluble (sTNF) and transmembrane (tmTNF) forms of tumour necrosis factor on the differentiation of human hematopoietic stem and progenitor cells (HSPCs) into T cell precursors. To achieve this, we utilized scRNA-sequencing technologies to compare the transcriptome profiles of HSPCs that had been differentiated in the artificial thymic organoid (ATO) system in the absence (control) or presence of TNF signal (soluble or transmembrane).

2022-12-12 | GSE211400 | GEO

Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells

Project description:The IRF8-dependent subset of classical dendritic cells (cDC), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture of hematopoietic progenitors with DC growth factor Flt3 ligand (Flt3L) yields very few cDC1 (in humans) or only immature "cDC1-like" cells (in the mouse). We report that OP9 stromal cells expressing Notch ligand Delta-like 1 (OP9-DL1) optimize Flt3L-driven development of cDC1 from murine immortalized progenitors and primary bone marrow cells. Co-culture with OP9-DL1 induced IRF8-dependent cDC1 with the phenotype (CD103+ Dec205+ CD8α+) and expression profile resembling ex vivo cDC1. OP9-DL1-induced cDC1 showed preferential migration towards Ccr7 ligands in vitro and superior T cell cross-priming and antitumor vaccination in vivo. Co-culture with OP9-DL1 also greatly increased the yield of IRF8-dependent CD141+ cDC1 from human bone marrow progenitors cultured with Flt3L. Thus, Notch signaling optimizes cDC generation in vitro and yields authentic cDC1 for functional studies and therapeutic applications.

2018-06-05 | GSE110577 | GEO

Transcriptional regulation in the embryonic endocardium after NOTCH pathway manipulation

Project description:We have manipulated the NOTCH signaling pathway in mouse embryonic endocardial cells by the co-culture with OP9 stromal cells expressing Jag1 and Dll4, the culture over recombinant JAG1 and DLL4, and the use of the γ-secretase inhibitor RO4929097. We have performed RNA-seq and ATAC-seq to define the transcriptional profile and the chromatin accessibility landscape specific for each condition.

2023-12-08 | GSE223735 | GEO

Transmembrane TNF-TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression.

Project description:The double-edged sword nature by which IL-2 regulates autoimmunity and the unpredictable outcomes of anti-TNF therapy in autoimmunity highlight the importance for understanding how TNF regulates IL-2. Transmembrane TNF (tmTNF) preferentially binds TNFR2, whereas soluble TNF (sTNF) binds TNFR1. We previously showed reduced IL-2 production in TNFR1(-/-) TNFR2(-/-) CD4(+) T cells. In this study, we generated TNFR1(-/-), TNFR2(-/-), or TNFR1(-/-) TNFR2(-/-) 5C.C7 TCR Il2-GFP mice and report that CD4(+) T cell-intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. We further used tmTNF Foxp3 gfp reporter mice and pharmacological TNF blockade in wild-type mice to report a tmTNF/TNFR2 interaction for Il2 expression. IL-17 is critical for host defense, but its overabundance promotes autoimmunity. IL-2 represses Th17 differentiation, but the role for TNFR2 in this process is not well understood. We report elevated expression of TNFR2 under Th17-polarization conditions. Genetic loss-of-function experimental models, as well as selective TNF blockade by etanercept and XPro1595 in wild-type mice, demonstrate that impaired tmTNF/TNFR2, but not sTNF/TNFR1, promotes Th17 differentiation in vivo and in vitro. Under Th17-polarizing conditions, elevated IL-17 production by TNFR2-knockout CD4(+) T cells was associated with increased STAT3 activity and decreased STAT5 activity. Increased IL-17 production in TNFR2-knockout T cells was prevented by adding exogenous IL-2. We conclude that CD4(+) T cell-intrinsic tmTNF/TNFR2 promotes IL-2 production that inhibits the generation of Th17 cells in a Foxp3-independent manner. Moreover, under Th17-polarizing conditions, selective blockade of CD4(+) T cell-intrinsic TNFR2 appears to be sufficient to promote Th17 differentiation.

| S-EPMC4841279 | biostudies-literature

RNA-seq expression data from EB-HSPCs after HOXA7 overexpression

Project description:HOXA7 regulates FL-HSPC self-renewal in vitro and in vivo. We profiled EB-HSPCs after HOXA7 overexpression (EB-HOXA7), or with a control vector (EB-CTR), to assess the gene expression programs regulated by HOXA7. CD34+CD38-CD43+CD90+ HSPCs were infected with lentiviral FUGW vector either empty (FUGW-GFP) or encoding HOXA7(FUGW-GFP-HOXA7) protein. Cells were expanded on op9 for 15 days and than sorted for GFP HSPC immunophenotype.

2016-05-16 | E-GEOD-76684 | biostudies-arrayexpress

Interferon Regulatory Factor 8 (IRF8) Deficiency Promotes Osteoclast Transcriptional Program

Project description:Irf8 functions as negative regulator of osteoclastogenesis. Genetic deletion of Irf8 in mice results in osteoporosis, a low bone mass state caused by increased osteoclast activity. However, the effects of Irf8 ablation on genome wide regulation of osteoclast-specific genes is unknown. We performed RNA-seq analysis of Irf8-/- and Irf8+/+ bone marrow macrophages (BMMs) prior to (day 0) and after RANKL treatment (day 4 and day 8). Additionally, we have identified a novel IRF8 mutation in humans, that is associated with increased osteoclast activity and susceptibility to Multiple Idiopathic Cervical Root Resorption (MICRR). To gain insights into the functional consequences of human IRF8 mutation (hIRF8G388S) on osteoclastogenesis, we performed RNA-seq analysis of Irf8-/- BMMs transduced with hIRF8WT, hIRF8G388S, and a larger deletion construct hIRF8379-389, followed by RANKL treatment. Comparative studies in Irf8-/- and hIRF8G388S cells show that IRF8 deficiency promotes significant enhancement of osteoclast-specific transcripts.

2019-06-01 | GSE115497 | GEO

Genome wide profiling of active enhancers and IRF8-binding sites in murine mononuclear phagocyte lineage cells

Project description:To understand the mechanism underlying monocyte and dendritic cell development through the regulation of Irf8 expression by the 56 kb downstream (+56 kb) Irf8 enhancer, we performed epigenetic profiling of bone marrow cells and splenocytes from wild-type, the Irf8 +56 kb enhancer-deficient, and IRF8-deficient mice. Taken together with the transcriptome analysis of mononuclear phagocyte lineage cells in these mice, the Irf8 +56 kb enhancer-mediated high Irf8 expression in hematopoietic progenitor cells promote type 1 classical dendritic cell (cDC1) differentiation, while low Irf8 expression in progenitors led to Ly6C+ monocyte development. In addition, IRF8 ChIP-seq of mature cDC1s and monocytes suggested that IRF8 regulates enhancers in cooperation with different transcription factors in each lineage in its expression level.

2020-12-20 | GSE149757 | GEO

Gene expression analysis of human fetal liver hematopoietic stem and progenitor cells (HSPC) in culture

Project description:One of the long-standing goals in the field has been to establish a culture system that would allow maintenance of HSC properties ex vivo. In the absence of such system, the ability to model human hematopoiesis in vitro has been limited, and there has been little progress in the expansion of human HSCs for clinical application. To that end, we defined a mesenchyml stem cell co-culture system for expansion of clonally multipotent human HSPCs that are protected from apoptosis and immediate differentiation, and retain the HSPC phenotype. By performing a genome-wide gene expression analysis of purified HSPCs isolated at different stages of co-culture, we asked at the molecular level, to what degree hematopetic stem cell properties can be preserved during culture. This temporal gene expression data from in vivo derived- and ex vivo expanded human HSPCs will serve as a resource to identify novel regulatory pathways that control HSC properties, and to develop clinically applicable protocols for HSC expansion. Human CD34+ fetal liver cells were co-cultured on a subclone of OP9 stomal cells (OP9M2 sublemented with supportive cytokines (see below)). To distinguish between molecular changes acquired over prolonged culture versus immediately after exposure to culture, gene expression in isolated CD45+CD34+CD38-CD90+ HSPCs was assessed after 12 hours, 2 weeks and 5 weeks in culture. Cultured CD45+CD34+CD38-CD90+HSPCs were compared to freshly isolated CD45+CD34+CD38-CD90+HSPCs and their more differentiated CD45+CD34+CD38+CD90- downstream progenitor cells.

2013-01-31 | E-GEOD-34972 | biostudies-arrayexpress

Expression data from immunophenotypic HSPCs isolated from different stages of human hematopoiesis, in vivo and in vitro

Project description:The derivation of functional, transplantable HSCs from an pluripotent stem cells in vitro holds great promise for clinical therapies, but is unachieved. In order to achieve full functionality of HSCs, it is vital to determine the extent to which PSCs can currently be differentiated to the HSC program in vitro and identify the remaining dysregulated genetic pathways. Microarrays were used to compare the transcritomes of ESC-derived immunophenotypic HSPCs to endogenous HSPCs from various stages of development to determine the programs important for human HSC development and function, and which programs were lacking in ESC-derived hematopoietic cells. CD34+CD38-CD43+CD90+ HSPCs were sorted from human placenta and embryoid bodies, and CD34+CD38-CD45+CD90+ HSPCs sorted from fetal liver and embryoid bodies co-cultured on OP9-M2 stroma, the RNA was extracted, library created and hybridized to the Affymetrix microarray

2016-05-16 | E-GEOD-64865 | biostudies-arrayexpress

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