Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tc17 cells are a pro-inflammatory, plastic lineage of pathogenic CD8+ T-cells that induce GVHD without anti-leukemic effects

ABSTRACT: IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORgt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNg, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft–versus–leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.

ORGANISM(S): Mus musculus

PROVIDER: GSE70931 | GEO | 2015/09/13

SECONDARY ACCESSION(S): PRJNA289964

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Tc17 cells are a pro-inflammatory, plastic lineage of pathogenic CD8+ T-cells that induce GVHD without anti-leukemic effects

Project description:IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORgt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNg, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft–versus–leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2015-09-13 | E-GEOD-70931 | biostudies-arrayexpress

ASC controls T-bet-dependent CTL differentiation and defines transplant outcome independent of the inflammasome

Project description:The adaptor protein ASC is known to facilitate caspase-1 activation essential for innate host immunity via the formation of the inflammasome complex - a multi-protein structure responsible for processing IL-1beta and IL-18 to their active moieties. Here we demonstrate that ASC-deficient CD8+ T cells fail to induce graft-versus-host disease (GVHD) and have impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects are the result of an inability to differentiate into fully cytolytic, granzyme B-expressing effector cells, with a developmental bias instead towards CD127+KLRG1- memory CD8+ T cells. These alterations in differentiation are inflammasome-independent, since GVHD lethality and CTL differentiation are not altered in recipients of caspase-1-deficient T cells. We demonstrate that ASC binds to T-bet in CD8+ T and in the absence of ASC, the binding of T-bet to the granzyme B promoter is impaired. Thus, the inhibition of ASC represents an attractive therapeutic target to manipulate transplant outcomes. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2016-04-01 | E-GEOD-78755 | biostudies-arrayexpress

Expression Profile of alloreactive CD8 and CD4 induced regulatory T cells

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

Targeting Interleukin-2-Inducible T-cell Kinase (ITK) differentiates GVL and GVHD in allo-HSCT

Project description:Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity, but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

2020-12-21 | GSE161160 | GEO

Peri-transplant Glucocorticoids Redistribute Donor T-cells to the Bone Marrow and Prevent Relapse after haploidentical SCT

Project description:Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency.

2021-10-31 | GSE184963 | GEO

ASC controls T-bet-dependent CTL differentiation and defines transplant outcome independent of the inflammasome

2016-04-01 | GSE78755 | GEO

Transcriptional analysis of beta-catenin overexpressing T cells

Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of transgenic over-expression of human β-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human β-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment

2021-08-01 | GSE180808 | GEO

RNAseq of (Dimethylfumarate)DMF-induced changes in murine Tc17 CD8+ cells

Project description:IL-17-producing CD8+ (Tc17)T cells are implicated in the pathogenesis of multiple sclerosis (MS), thereby representing a promising target for therapy. We found that dimethyl fumarate (DMF), a first-line medication for MS upregulated reactive oxygen species (ROS) by glutathione depletion in murine Tc17 cells, which limited IL-17 and diverted Tc17 cells towards cytotoxic T lymphocyte (CTL) signature. DMF enhanced PI3K-AKT-FOXO1-T-bet- as well as STAT5-signaling leading to restricted permissive histone state at the Il17 locus. T-bet-deficiency, inhibiting PI3K-AKT, STAT5 or histone deacetylases prevented DMF-ROS-mediated IL-17 suppression. In MS patients with stable response, DMF suppressed IL-17 production by CD8+ T-cells and triggered diversion from Tc17 towards CTL signature along with enriched ROS-, PI3K-AKT-FOXO1-signaling, demonstrating comparable regulation across species. Accordingly, in the mouse model for MS, DMF limited Tc17-encephalitogenicity. Our findings disclose DMF-ROS-AKT-driven pathway, which selectively modulates Tc17 fate to ameliorate MS, thus opening avenue to develop markers and targets for specific therapy.

2018-07-11 | GSE116866 | GEO

Indole-3-carboxaldehyde (ICA) mitigates morbidity and mortality in a mouse model of Graft-versus-Host-Disease

Project description:ICA-treatment following allogeneic bone marrow transplant in mice limited GvHD pathology and GVHD mortality, augmented the integrity of the intestinal mucosal barrier, and limited production of inflammatory cytokines, but did not compromise donor T cell-mediated Graft vs. Leukemia (GvL) responses. Following protracted exposure, ICA treatment also induced donor-strain-specific tolerance of engrafted T cells. We used microarray to assess gene expression changes induced by ICA in the small intestine in animals with GvHD.

2018-03-08 | GSE111512 | GEO

mRNAseq of murine PancOVA tumor cells after coculture with Tc17 conditioned -iCafs or Tc17 cells

Project description:we examined the influence of Tc17 conditioned -iCafs or Tc17 cells on the in vitro differentiation of murine PancOVA tumor cells

2023-02-10 | GSE218816 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data