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Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host-disease-associated autoimmunity

ABSTRACT: We report application of RNA-seqencing to investigate PSGL1hi and PSGL1lo CD4+T cells transcriptional difference in the GVHD target tissues of spleen, liver and lung at day 30 after HCT.

ORGANISM(S): Mus musculus

PROVIDER: GSE157566 | GEO | 2020/12/31

REPOSITORIES: GEO

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Evolutionarily conserved effects of Notch signaling drive intestinal graft-versus-host disease in mice and non-human primates

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

Effect of hBD-2 treatment on gene expression in the colon of acute graft-versus-host disease (GVHD) mice

Project description:Wildtype (WT) BALB/c mice were treated with allogeneic hematopoietic cell transplantation (allo-HCT) in order to induce acute GVHD. C57BL/6 mice were used bone marrow (BM) and T cell donor mice. We studied the effect of oral hBD-2 treatment versus vehicle (PBS) control treatment on the gene expression in the colon, as main GVHD target organ.

2022-12-23 | GSE190796 | GEO

Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease-associated autoimmunity.

Project description: Not available

| S-EPMC7773409 | biostudies-literature

ROCK1 inhibition reduces steroid-refractory acute graft-versus-host disease

Project description:To identify kinases in immune cells of patients with SR-GVHD we isolated leukocytes and specifically enriched kinases via kinet-beads-technology. Rho Kinase Type 1 (ROCK1) was identified as the most abundant kinase in SR-GVHD.

2023-12-19 | PXD012036 | Pride

Acute graft-versus-host disease (gene expression profiling)

Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for high-risk hematological malignancies, yet a major complication associated with this therapy is acute graft-versus-host disease (GVHD). Despite a well-defined pathophysiological mechanism, there are no definitive markers for predicting acute GVHD development or progression to advanced stages. In the current study, we enrolled four acute GVHD and four acute GVHD-free recipients of allogeneic HSCT and collected peripheral blood just prior to onset of clinical acute GVHD for analysis on Affymetrix GeneChip Human Genome U133 Plus 2.0 microarrays. We noted significant differences in expression of 1,658 genes between control and acute GVHD patients, based on an analysis of covariance (ANCOVA) by type of transplant, a pooled error estimate, and a false discovery rate (FDR) of 10%. In conclusion, we offer the first report of a preliminary molecular signature of acute GVHD in allogeneic HSCT patients.

2008-04-09 | GSE7510 | GEO

Defining TCF1+ progenitor allogeneic CD8 T cell subset in acute graft-versus-host disease

Project description:The goals of this study were to gain a better understanding of the heterogeneity and gene signatures of allogeneic PD-1+ CD8 T cells isolated from the spleen of GvHD B6 recipients of Balb/c T cells.

2022-10-14 | GSE215315 | GEO

Single cell RNA sequencing of mouse donor T cells after graft-versus-host disease (GVHD) model

Project description:Lethally irradiated mice were transferred with bone marrow cells together with allogeneic Treg cells isolated from CD226+/+ TIGIT+/+, CD226-/- TIGIT+/+, CD226+/+ TIGIT-/-, or CD226-/- TIGIT-/- mice, followed by allogeneic wild-type Tconv cells two days later to induce acute GVHD. We performed scRNA sequencing of donor T cells isolated from the spleen of recipient mice eight days after GVHD induction.

2021-05-18 | GSE155250 | GEO

Transcriptome analysis of acute graft-versus-host disease in children

Project description:Steroid-refractory gastrointestinal graft-versus-host disease (GI GVHD) is a major barrier to successful hematopoietic stem cell transplant (HSCT). Poor understanding of the pathophysiology of GI GVHD contributes to continued poor outcomes and high mortality rates. We therefore obtained rectosigmoidal mucosal biopsies from post-HSCT patients with GI GVHD and submitted them to RNA-sequencing in order to transcriptomally characterize GI GVHD. These were compared to patients undergoing endoscopy for routine clinical indications. Using single end, 50bp reads processed using Kallisto using genome annotations from Gencode v24 with transcripts per million as the output. We included 14,239 trancsripts in our analysis, where we compared GVHD vs non-GVHD with significance defined as FDR<0.05 and FC 1.5 using R package DESeq2. We identified 164 key genes, of which 141 were upregulated in GVHD, and were ontologically related to microbial response, key immune effectors, and cell migration/chemotaxis. Down-regulated genes were related to nutrient metabolism. Additionally, we performed WGCNA that highlighted ERK as a key upregulated pathway in GI GVHD.

2022-03-07 | GSE168116 | GEO

Integrated Analysis of T-cell Repertoire and Transcriptome Shed Light into the Mechanisms of Regulatory T cell (Treg) Suppression of Acute Graft-versus-Host-Disease

Project description:CD4+ FOXP3+ regulatory T (Treg) cells are currently under clinical evaluation as an immunoregulatory cellular therapy for graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCR) sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. We show that both Treg and Tcon underwent clonal expansion and that Treg did not interfere with the activation of alloreactive Tcon clones. Transcriptomic analysis revealed that Treg predominantly affected CD4 Tcon and to a lesser extent CD8 Tcon transcriptome, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. Our results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach.

2022-07-15 | GSE205375 | GEO

Donor regulatory T cells rapidly adapt to recipient tissues to control acute graft-versus-host disease [TCR-seq]

Project description:Adoptive transfer of donor regulatory T cells (Treg) is a promising treatment option for Graft-versus-Host disease (GvHD), but has not yet found its way into routine clinical practice. To map distinctive properties of protective Treg (generated by either polyclonal or allogeneic in vitro expansion), we followed their fate in recipient organs (spleen, liver, colon) in a prophylactic mouse model of MHC-mismatched bone-marrow transplantation (BMT). Using comprehensive gene expression and T cell receptor profiling, we show that both in vitro expansion protocols generated Treg products that preserved hallmark Treg properties, ameliorated GvHD symptoms, retained their phenotypic plasticity and rapidly acquired organ-specific gene expression profiles after BMT, comparable to their tissue-resident counterparts. When co-transplanted with GvHD-inducing T cells, Treg enabled hallmark suppressive and cytotoxic features, most evidently in the colon. Dominant Treg T cell receptor clonotypes were evenly distributed between organs and across recipients, suggesting a major role of ubiquitous alloantigen-specific Treg in controlling GvHD. Effective protection inversely correlated with the relative abundance of organ-specific Treg, that were transcriptionally distinct, less “activated” and preferentially accumulated in the colon of recipients receiving polyclonally expanded Treg. In summary, we provide a detailed atlas of Treg selection and adaptation in the prophylactic therapy of GvHD.

2024-01-01 | GSE223797 | GEO

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