Evolutionarily conserved effects of Notch signaling drive intestinal graft-versus-host disease in mice and non-human primates
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PROVIDER: PRJNA951719 | ENA |
REPOSITORIES: ENA
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Project description:Notch signaling promotes T-cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like ligand DLL4. To assess if Notch’s effects are evolutionarily conserved and identify key mechanisms, we studied antibody-mediated DLL4 blockade in a non-human primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved post-transplant survival with striking, durable protection from gastrointestinal GVHD, out of proportion to other disease sites. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T-cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T-cells while preserving α4β7 in regulatory T-cells, with findings suggesting increased 1 competition for 4 binding in conventional T-cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T-cells after allo-HCT. Altogether, DLL4/Notch blockade decreased effector T-cell infiltration into the gut, with increased regulatory to conventional T-cell ratios early after allo-HCT. Our results identify a conserved, biologically unique and targetable role of DLL4/Notch signaling in GVHD.
2023-07-14 | GSE228838 | GEO
Project description:Isoform-specific translational control is evolutionarily conserved in primates
| PRJNA961136 | ENA
Project description:Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 hours after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both, and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv vs. Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection, as GVHD severity was similar in recipients of wild-type Tconv combined with Notch-deprived vs. wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and T helper polarization. In contrast, Notch inhibition dampened IFN-γ and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with pathogenic effects of Notch in T cells at the earliest stages of GVHD.
2019-02-14 | GSE126518 | GEO
Project description:Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T cells while preserving α4β7 in regulatory T cells, with findings suggesting increased β1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.
| S-EPMC10896076 | biostudies-literature
Project description:graft versus host disease organoids were co-cultured with mesenchymal stem cells
2024-05-22 | PXD034822 | Pride
Project description:Effective planning for the medical response to a radiological or nuclear accident is complex. Because of limited resources for medical countermeasures, the key would be to accurately triage and identify victims most likely to benefit from treatment. We used a mouse model system to provide evidence that serum microRNAs (miRNAs) may effectively predict the impact of radiation on the long-term viability of animals. We had previously used nonhuman primates (NHPs) to demonstrate that this concept is conserved and serum miRNA signatures have the potential to serve as prediction biomarkers for radiation-induced fatality in a human population. We identified a signature of seven miRNAs that are altered by irradiation in both mice and NHPs. Genomic analysis of these conserved miRNAs revealed that there is a combination of seven transcription factors that are predicted to regulate these miRNAs in human, mice, and NHPs. Moreover, a combination of three miRNAs (miR-133b, miR-215, and miR-375) can identify, with nearly complete accuracy, NHPs exposed to radiation versus unexposed NHPs. Consistent with historical data, female macaques appeared to be more sensitive to radiation, but the difference was not significant. Sex-based stratification allowed us to identify an interaction between gender and miR-16-2 expression, which affected the outcome of radiation exposure. Moreover, we developed a classifier based on two miRNAs (miR-30a and miR-126) that can reproducibly predict radiation-induced mortality. Together, we have obtained a five-miRNA composite signature that can identify irradiated macaques and predict their probability of survival.
| S-EPMC5441546 | biostudies-literature
Project description:Alternative splicing (AS) influences the expression of human genes in diverse ways. We previously used subcellular fraction-sequencing (Frac-Seq) to reveal an unexpected connection between alternative splicing and isoform-specific mRNA translation. Here we apply comparative transcriptomics to explore alternative splicing coupled translational control (AS-TC) across 13 million years of primate evolution. We used Frac-seq to identify polyribosome associated mRNA isoforms from human, chimpanzee and orangutan induced pluripotent stem cell lines. We discovered orthologous AS-TC events with either conserved or species-specific translation patterns. Exons sequences associated with similar sedimentation profiles between species show strong sequence conservation compared to orthologous exons with divergent sedimentation profiles, suggesting exonic cis-regulatory elements influence to translational control. To test this hypothesis we created luciferase reporters from orthologous exons with divergent sedimentation profiles differing by a single nucleotide. Remarkably, single nucleotide substitutions were sufficient to drive species-specific expression of luciferase reporters. Together these data establish that cis-acting elements regulate AS-TC across primate species.
2024-04-30 | GSE230441 | GEO
Project description:Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. At the molecular level, the key components of the Notch pathway are the NOTCH-family receptors, the ligands of the DSL (Delta, Serrate, Lag-2) family and the transcription factor CSL [CBF1/RBPJ, Su(H), Lag-1]. Upon ligand binding, the NOTCH Intra-Cellular Domain (NOTCH ICD) translocates into the nucleus and forms a complex with RBPJ to activate the transcription of target genes. In the absence of NOTCH ICD, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 as a novel interactor of RBPJ. We discovered that L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and its co-factor KDM1A [lysine (K)-specific demethylase 1A] to the promoters/enhancers of Notch target genes to promote H3K4me2 demethylation and transcriptional repression. In three distinct cell contexts in which Notch signaling governs cell fate, i.e., mature T-cells as well as brain and breast tumor cells, the loss of L3MBTL3 results in the de-repression of Notch target genes. Finally, the genetic analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ/Su(H)/lag-1 and L3MBTL3/dL(3)mbt/lin-61 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.
2017-10-17 | PXD004196 | Pride