RNAseq of (Dimethylfumarate)DMF-induced changes in murine Tc17 CD8+ cells
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PROVIDER: PRJNA480462 | ENA |
REPOSITORIES: ENA
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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
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 | GSE116865 | GEO
Project description:RNAseq of (Dimethylfumarate)DMF-induced changes in human CD8+ memory cells
| PRJNA480463 | ENA
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
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
Project description:The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in inflammatory disease models. The differential ability of Tc17 differentiation was not related to T-cell receptor (TCR) diversity and antigen specificity but was inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon was linked to differential levels of intrinsic TCR sensitivity and basal SMAD3 expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.
2023-08-15 | GSE240440 | GEO
Project description:CD8+ T cells are pre-programmed for cytotoxic differentiation. However, a subset of effector CD8+ T cells (‘Tc17’) produce IL-17 and fail to express cytotoxic genes. Here, we show that the transcription factors directing IL-17 production inhibit cytotoxicity despite persistent Runx3 expression. Cytotoxic gene repression did not require the transcription factor Thpok. We further show that STAT3 restrained cytotoxic gene expression in CD8+ T cells and that RORgt represses cytotoxic genes by inhibiting the functions but not the expression of the ‘cytotoxic’ transcription factors T-bet and Eomesodermin. Thus, the transcriptional circuitry directing IL-17 expression inhibits cytotoxic functions.
2017-11-27 | GSE104143 | GEO
Project description:CD8+ T cells are pre-programmed for cytotoxic differentiation. However, a subset of effector CD8+ T cells (‘Tc17’) produce IL-17 and fail to express cytotoxic genes. Here, we show that the transcription factors directing IL-17 production inhibit cytotoxicity despite persistent Runx3 expression. Cytotoxic gene repression did not require the transcription factor Thpok. We further show that STAT3 restrained cytotoxic gene expression in CD8+ T cells and that RORgt represses cytotoxic genes by inhibiting the functions but not the expression of the ‘cytotoxic’ transcription factors T-bet and Eomesodermin. Thus, the transcriptional circuitry directing IL-17 expression inhibits cytotoxic functions.
2017-11-27 | GSE104144 | GEO
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.
2015-09-13 | GSE70931 | GEO
Project description:Gene expression profiling of Tc1 and Tc17 CD8+ T cells
| PRJNA411815 | ENA