Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA117149 | ENA |
REPOSITORIES: ENA
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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: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
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. CD4+Foxp3+ Treg were sorted from the mice stimulated with anti-DR3 or control antibody using fluorescence-activated cell sorter for RNA extraction and hybridization on Affymetrix microarrays.
2016-06-28 | E-GEOD-83743 | biostudies-arrayexpress
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: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: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
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 | GSE223798 | GEO
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
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 | GSE223796 | GEO
Project description:Expression data of Naïve Treg and Tumor associated Treg cells
| PRJNA109769 | ENA