Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA325451 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:AhR signaling reprograms newly activated CD4+ T cells promoting combinatorial expression of regulatory genes to suppress murine GVHD [72 hr]
| PRJNA325450 | ENA
Project description:AhR signaling reprograms newly activated CD4+ T cells promoting combinatorial expression of regulatory genes to suppress murine GVHD
| PRJNA325446 | ENA
Project description:AhR activation during the first 3 days of an immune response is sufficient to reprogram CD4+ T cells, resulting in prevention of GVHD. To identify the early transciptional signature of AhR activation in CD4+ T cells, we performed analyses on mice treated with 2 different AhR ligands, TCDD and Cl-BBQ, in comparison with vehicle treated mice. Transcriptional responses were measured by global microarray analysis of donor alloresponding CD4+ T cells from spleen and lymph nodes.
2016-09-01 | GSE83258 | GEO
Project description:AhR activation during the first 3 days of an immune response is sufficient to reprogram CD4+ T cells, resulting in prevention of GVHD. To identify the early transciptional signature of AhR activation in CD4+ T cells, we performed analyses on mice treated with 2 different AhR ligands, TCDD and Cl-BBQ, in comparison with vehicle treated mice. Transcriptional responses were measured by global microarray analysis of donor alloresponding CD4+ T cells from spleen and lymph nodes.
2016-09-01 | GSE83257 | GEO
Project description:Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemic (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4 iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8 iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT. Indeed, the combinational therapy was superior to CD4 or CD8 iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4 and CD8 effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8 iTregs possess elevated expression of multiple cytolytic molecules compared to CD4 iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4 and CD8 iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.
2016-11-17 | GSE75118 | GEO
Project description:Graft-versus-host disease (GVHD) and long-term systemic anti-GVHD treatment-associated aggressive immunosuppression remain a major barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Living cell therapy for immune regulation could achieve long-lasting effects and provide a more nuanced regulatory activity. However, novel approaches that can produce immune regulatory cells, which can robustly expand in culture, persist in vivo after infusion, and sustain immune modulatory function in vivo, remain an unmet need. Here, we demonstrate that IFN-a2- and PD-L1-overexpressing human T cells (ap-T cells) have a potent capacity to inhibit xenogeneic GVHD (x-GVHD) but preserve the ability to eliminate human xenograft leukemia in NOD/SCID/IL2Rg−/− (NSG) mice. In culture, these CD4+ ap-T cells robustly expanded and stably maintained expression of PD-L1 and IFN-a during expansion. These properties allowed generation of adequate number of immune suppressor cells without large-scale purification for the therapy purpose. Following infusion into NSG mice, CD4+ ap-T cells survived, persisted, and infiltrated into peripheral tissues, where they repressed GVHD. Notably, CD4+ αp-T cells created a synergistic reinforcing regulatory loop to suppress expansion and survival of GVHD T cells, in which IFN-a promoted the generation of PD-1+TIM3+ terminal exhaustion-like T cells, thereby sensitizing them to PD-L1-mediated suppression. Furthermore, CD4+ ap-T cell treatment preserved the graft-versus-tumor effect, significantly improving the survival of human xenograft leukemia-bearing NSG mice. Our findings identify that CD4+ ap-T cell therapy may represent a novel translational strategy to improve the safety and efficacy of allo-HSCT.
2026-08-30 | GSE292397 | GEO
Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.
2009-09-15 | E-GEOD-16210 | biostudies-arrayexpress
Project description:Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality and is characterized by a wide spectrum of impaired maternal and fetal vascular function. Aryl hydrocarbon receptor (AhR, a ligand-activated transcription factor) plays a critical role in regulating vascular development and function. Endogenous AhR ligands can induce endothelial dysfunction. However, the underlying protein phospho-signaling mechanisms remain unknown. To determine if endogenous AhR ligands dysregulate the phosphoproteomes and proteomes in endothelial cells, primary human umbilical vein endothelial cells (HUVECs) (n = 4; 2 cell preparations/cell sex) were cultured in endothelial cell media (ECM). After 16 hr serum starvation, subconfluent cells were treated with 1 µM 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, an endogenous AhR ligand) or DMSO (vehicle) for 4 and 24 hr. The cell proteins were subjected to a bottom-up phosphoproteomic analysis to determine acute and prolonged effects of ITE on protein phosphorylation.
2025-02-10 | PXD047834 | Pride
Project description:Lymphocyte subsets (CD8, CD4 Tconv, CD4 Treg) were sorted from patients' peripheral blood obtained 180 days after matched-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy) as a single agent GVHD prophylaxis (NCT00809276). Cohort of patients developed GVHD, or remained GVHD-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD.
2021-09-28 | GSE182678 | GEO
Project description:Lymphocyte subsets (CD8, CD4 Tconv, CD4 Treg) were sorted from patients' peripheral blood obtained on day 28 after matched-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy) as a single agent GVHD prophylaxis (NCT00809276). Cohort of patients developed GVHD, or remained GVHD-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD.
2021-09-28 | GSE182610 | GEO