FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2992086695> ?p ?o ?g. }

• W2992086695 endingPage "588" @default.
• W2992086695 startingPage "588" @default.
• W2992086695 abstract "Notch signaling drives graft-versus-host-disease (GVHD) pathogenesis in preclinical models of allogeneic hematopoietic cell transplantation (allo-HCT). Short-term systemic blockade of the Notch ligands Delta-like1 (Dll1) and Delta-like4 (Dll4) within two days of allo-HCT conferred long-term protection from acute GVHD lethality in mice, with a dominant impact of Dll4. Surprisingly, critical Notch ligands in GVHD were provided by radioresistant non-hematopoietic fibroblastic stromal cells lineage traced by a Ccl19-Cre transgene in secondary lymphoid organs (SLO) (Chung, JCI 2017). Our discovery revises prevailing GVHD models and identifies a pathogenic role for a stromal cell niche expressing Notch ligands in SLOs. However, little is known about the distribution and regulation of Dll1/Dll4-expressing cells among SLO stromal cells. To address this question, we deployed genetic and biochemical tools to map expression of Notch ligands in SLO stromal cells, characterize the transcriptional landscape of these cells, and identify putative regulators of Notch ligand expression. To map Dll1 and Dll4 expression, we combined a Ccl19-Cre transgene with a ROSA26-YFP Cre-activated allele and Dll1-mCherry or Dll4-mCherry BAC reporters. Using this model, we fluorescently traced all cells derived from Ccl19-Cre+ cells which contain the essential Dll1/Dll4 source in GVHD, while detecting Dll1 vs. Dll4 expression with high sensitivity. Within the lymph node (LN) Ccl19-Cre+ROSA26-YFP+ compartment, Dll4-mCherry was present predominantly among CD157hi CD45-Ter119-CD31-gp38+ fibroblastic stromal cells, including fibroblastic reticular cells (FRCs), marginal reticular cells (MRCs) and follicular dendritic cells (FDCs). In the spleen, Dll4-mCherry was detected among both CD157+ cells (predominant in the T-zone) and CD157- cells. In contrast, Dll1-mCherry was abundant among spleen CD157+ and CD157- cells, but not detected in the corresponding LN compartments. Thus, Dll1 and Dll4 are expressed with a non-overlapping distribution pattern in different SLOs and stromal cell subsets. Next, we studied expression of the dominant Dll4 ligand after MHC-mismatched allo-HCT (BALB/c into C57BL/6). Although Dll4-mCherry fluorescence did not increase, we detected a rise in surface Dll4 protein, peaking 12 hrs after allo-HCT in LN Ccl19-Cre+ CD157hi FRCs, MRCs and FDCs. Increased Dll4 abundance coincided with the critical timing of pathogenic Notch signals within days after allo-HCT and required irradiation conditioning as well as infusion of allogeneic T cells, suggesting a crosstalk between alloreactive T cells and Dll4+ stromal cells. The mechanisms underlying increased surface Dll4 abundance are under investigation, but could involve post-transcriptional effects as the Dll4-mCherry transcriptional reporter did not change. We next characterized transcriptomic features of Dll4+ fibroblastic stromal cells. We performed RNA-Seq on rare SLO stromal cells sort-purified from LNs at baseline and 12 hrs after allo-HCT. We compared CD157hi FRCs that do or do not express Dll4-mCherry, while including CD157lo FRCs that do not express Dll4-mCherry and lymphatic endothelial cells that express Dll4 at high levels as controls. These populations were sort-purified for RNA-Seq analysis, using the data to produce a comprehensive picture of gene expression and regulatory machinery in the SLO niche in alloimmunity, as well as identify new putative regulators of Notch ligand expression. Interestingly, we found only 13 differentially expressed genes between Ccl19-Cre-expressing CD157hi fibroblastic stromal cells that do and do not express the Dll4-mCherry reporter 12 hrs after transplant (log-fold change ≥ 1, corrected p ≤ 0.01). The list of up-regulated transcripts included Cxcl13, encoding a chemokine produced by FDCs, and Rankl, encoding a TNF-family member important in LN development and homeostasis. In summary, our data uncover key new features of the specialized fibroblastic stromal cells expressing Delta-like Notch ligands in SLOs. Ongoing work is testing how qualitative and quantitative differences in Dll1 and Dll4's effects during GVHD may relate to their distribution, regulated expression, or biochemical properties as they interact with Notch receptors in T cells. Our ultimate goal is to design strategies that target Notch ligand expression in SLOs as new prophylactic approaches in GVHD. Disclosures Blazar: Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc.: Research Funding; Tmunity: Other: Co-Founder; KidsFirst Fund: Research Funding; Childrens' Cancer Research Fund: Research Funding; Leukemia and Lymphoma Society: Research Funding; Abbvie Inc: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees. Maillard:Genentech: Consultancy; Regeneron: Consultancy." @default.
• W2992086695 created "2019-12-13" @default.
• W2992086695 creator A5005196958 @default.
• W2992086695 creator A5014339064 @default.
• W2992086695 creator A5031118170 @default.
• W2992086695 creator A5036097834 @default.
• W2992086695 creator A5048706550 @default.
• W2992086695 creator A5052242638 @default.
• W2992086695 creator A5058268746 @default.
• W2992086695 creator A5058651388 @default.
• W2992086695 creator A5066485275 @default.
• W2992086695 creator A5076989555 @default.
• W2992086695 creator A5084923564 @default.
• W2992086695 date "2019-11-13" @default.
• W2992086695 modified "2023-09-30" @default.
• W2992086695 title "Dll1 and Dll4 Notch Ligands Prime T Cell Alloimmunity and Are Expressed in Non-Overlapping Populations of Fibroblastic Stromal Cells in Spleen and Lymph Nodes at the Onset of Gvhd" @default.
• W2992086695 doi "https://doi.org/10.1182/blood-2019-123533" @default.
• W2992086695 hasPublicationYear "2019" @default.
• W2992086695 type Work @default.
• W2992086695 sameAs 2992086695 @default.
• W2992086695 citedByCount "0" @default.
• W2992086695 crossrefType "journal-article" @default.
• W2992086695 hasAuthorship W2992086695A5005196958 @default.
• W2992086695 hasAuthorship W2992086695A5014339064 @default.
• W2992086695 hasAuthorship W2992086695A5031118170 @default.
• W2992086695 hasAuthorship W2992086695A5036097834 @default.
• W2992086695 hasAuthorship W2992086695A5048706550 @default.
• W2992086695 hasAuthorship W2992086695A5052242638 @default.
• W2992086695 hasAuthorship W2992086695A5058268746 @default.
• W2992086695 hasAuthorship W2992086695A5058651388 @default.
• W2992086695 hasAuthorship W2992086695A5066485275 @default.
• W2992086695 hasAuthorship W2992086695A5076989555 @default.
• W2992086695 hasAuthorship W2992086695A5084923564 @default.
• W2992086695 hasConcept C109159458 @default.
• W2992086695 hasConcept C143689837 @default.
• W2992086695 hasConcept C161879069 @default.
• W2992086695 hasConcept C16930146 @default.
• W2992086695 hasConcept C203014093 @default.
• W2992086695 hasConcept C2778324207 @default.
• W2992086695 hasConcept C2779282312 @default.
• W2992086695 hasConcept C2780931953 @default.
• W2992086695 hasConcept C28328180 @default.
• W2992086695 hasConcept C502942594 @default.
• W2992086695 hasConcept C62478195 @default.
• W2992086695 hasConcept C86803240 @default.
• W2992086695 hasConcept C8891405 @default.
• W2992086695 hasConcept C95444343 @default.
• W2992086695 hasConceptScore W2992086695C109159458 @default.
• W2992086695 hasConceptScore W2992086695C143689837 @default.
• W2992086695 hasConceptScore W2992086695C161879069 @default.
• W2992086695 hasConceptScore W2992086695C16930146 @default.
• W2992086695 hasConceptScore W2992086695C203014093 @default.
• W2992086695 hasConceptScore W2992086695C2778324207 @default.
• W2992086695 hasConceptScore W2992086695C2779282312 @default.
• W2992086695 hasConceptScore W2992086695C2780931953 @default.
• W2992086695 hasConceptScore W2992086695C28328180 @default.
• W2992086695 hasConceptScore W2992086695C502942594 @default.
• W2992086695 hasConceptScore W2992086695C62478195 @default.
• W2992086695 hasConceptScore W2992086695C86803240 @default.
• W2992086695 hasConceptScore W2992086695C8891405 @default.
• W2992086695 hasConceptScore W2992086695C95444343 @default.
• W2992086695 hasIssue "Supplement_1" @default.
• W2992086695 hasLocation W29920866951 @default.
• W2992086695 hasOpenAccess W2992086695 @default.
• W2992086695 hasPrimaryLocation W29920866951 @default.
• W2992086695 hasRelatedWork W149881189 @default.
• W2992086695 hasRelatedWork W1543576317 @default.
• W2992086695 hasRelatedWork W1895989020 @default.
• W2992086695 hasRelatedWork W193476542 @default.
• W2992086695 hasRelatedWork W2038751426 @default.
• W2992086695 hasRelatedWork W2045966942 @default.
• W2992086695 hasRelatedWork W2076188533 @default.
• W2992086695 hasRelatedWork W2111091418 @default.
• W2992086695 hasRelatedWork W2119511363 @default.
• W2992086695 hasRelatedWork W2141799161 @default.
• W2992086695 hasVolume "134" @default.
• W2992086695 isParatext "false" @default.
• W2992086695 isRetracted "false" @default.
• W2992086695 magId "2992086695" @default.
• W2992086695 workType "article" @default.