Murine regulatory T cells stimulated by death receptor 3 agonistic antibody
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Yasuhisa Yokoyama
PROVIDER: E-GEOD-83743 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft and host disease (GVHD) in murine models of allogeneic hematopoietic cell transplantation. It was reported that a single treatment of the agonistic antibody to Death receptor 3 (DR3) in donor mice resulted in the expansion of donor derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. We analyzed the gene expression profile, immune phenotype, and function of DR3-activated Treg in a murine model of allogeneic hematopoietic cell transplantation.
2016-06-28 | GSE83743 | 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:We hypothesize that nuclear factors co-occupying the genetic elements with regulatory T (Treg) cell lineage–specifying factor Foxp3 play critical roles in transcriptional regulation of Treg immune suppression function, thus, offering a unique approach to investigate the factors and their mechanisms controlling Treg-mediated immune tolerance involved in self-tolerance and antitumor immunity. We seek to identify the proteins occupying Foxp3 targets in the resting state or after cells receiving stimulation. To this end, we projected the spatial information (PSI) of Foxp3, Histone H3, or Stat5 onto their adjacent proteins with peroxidase–catalyzed biotin-phenoxyl radicals and identify these biotinylated proteins with tandem mass tag (TMT)–based quantitative mass spectrometry (MS).
2024-06-08 | PXD019050 | Pride
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
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:Graft-versus-Host Disease (GvH) is the excessive inflammatory response by mature T cells contained in the graft during bone marrow transplantation. The allogeneic T cells recognize self-antigens as foreign and systemically attack multiple organs mostly with epithelial structures such as the skin, liver and gastrointestinal tract. We could show that IL-33 administration during allogeneic hematopoietic cell transplantation (alloHCT) increased regulatory T cell (Treg) numbers and ameliorated the outcome of GvHD. Furthermore, it is known that IL-33 also has an impact on myeloid cell compartments and we showed that IL-33 delivery together with a loss of FoxP3 positive Treg led to a massive expansion of myeloid cells. With the underlying experiment we wanted to further characterize the myeloid cells when Treg are lost, therefore mice were treated with IL-33 and one group had a loss in FoxP3 cells. CD11b+F4/80+Gr-1lo myeloid cells were sorted and analyzed in the microarray. The examined myeloid cell population shows strong activation of the IFNg transcriptome and are prone to M1 macrophage polarization. Therefore, Treg restrain myeloid cell expansion and polarization during IL-33 delivery.
2016-06-27 | E-MTAB-4677 | biostudies-arrayexpress
Project description:Graft-versus-host disease (GvHD) is still one of the major complications following allogeneic stem cell transplantation (SCT) triggered by alloreactive donor T cells. Whereas murine data have clearly shown the beneficial effects of regulatory T cells (Tregs) on the development of GvHD, data from the human system are rare mainly due to low cell numbers of circulating or organ-infiltrating Tregs in lymphopenic patients. Here, we present a comparative analysis of Tregs from patients with and without acute/ chronic GvHD designed as a dynamical approach studying the whole genome profile over the first 6 months after SCT. For this purpose, blood samples were collected monthly for FACS-based isolation of CD4+CD25highCD127low/- Tregs. The Treg transcriptome showed a high stability in the first half year representing the most sensitive time window for tolerance induction. However, the comparison of the Treg transcriptome from patients with and without GvHD uncovered regulated gene transcripts that point to a reduced suppressive function of Tregs with diminished migration capacity to the target organs likely contributing to the development of GvHD. These findings highlight the critical role of human Tregs in the pathophysiology of GvHD and identify novel targets for the manipulation of Tregs to optimize cellular immune intervention strategies. Keywords: cell type comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of 2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.
2010-12-31 | E-GEOD-23332 | biostudies-arrayexpress
Project description:Comparative analysis of four murine Treg subsets differentially affected by pre-transplant conditioning and acute gastrointestinal GvHD following allogeneic hematopoietic stem cell transplantation.
2023-03-27 | GSE227929 | GEO
Project description:CD4+Foxp3+ Treg cells are essential for maintaining self-tolerance and preventing excessive immune responses. In the context of Th1 immune responses, co-expression of the Th1 transcription factor T-bet with Foxp3 is essential for Treg cells to control Th1 responses. T-bet-dependent expression of CXCR3 directs Tregs to the site of inflammation, however, the suppressive mediators enabling effective control of Th1 responses at this site are unknown. In this study, we determined the signature of CXCR3+ Treg cells arising in Th1 settings and defined universal features of Treg cells in this context using multiple Th1-dominated models. Our analysis defined a set of Th1-specific co-inhibitory receptors that are specifically expressed in Treg cells during Th1 immune responses. Among these, we identified the novel co-inhibitory receptor CD85k as a functional mediator of the enhanced suppression of Th1 effector cells by CXCR3+ Treg cells.
2018-06-30 | E-MTAB-6156 | biostudies-arrayexpress
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. Keywords: Normal vs Activated
2009-08-31 | GSE16210 | GEO