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Developmental self-reactivity determines the pathogenic Tc17 differentiation potential of naive CD8+ T cells by adjusting endogenous SMAD3 expression

ABSTRACT: Developmental self-reactivity determines the pathogenic Tc17 differentiation potential of naive CD8+ T cells by adjusting endogenous SMAD3 expression

PROVIDER: PRJNA1003805 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25582001_1.fastq.gz	Fastqsanger.gz
	SRR25582001_2.fastq.gz	Fastqsanger.gz
	SRR25582002_1.fastq.gz	Fastqsanger.gz
	SRR25582002_2.fastq.gz	Fastqsanger.gz
	SRR25582003_1.fastq.gz	Fastqsanger.gz

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Developmental self-reactivity determines the pathogenic Tc17 differentiation potential of naive CD8+ T cells by adjusting endogenous SMAD3 expression

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

Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8<sup>+</sup> T cells in murine models of inflammation.

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 a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (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.

| S-EPMC10994929 | biostudies-literature

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

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

2015-09-13 | GSE70931 | 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

Expression data from CTL and Tc17 cell

Project description:Goal of this study was to compare transcriptional changes in CTL cells compared to Tc17 cells We used microarray to detail the global programme of gene expression underlying CTL and Tc17 cell differentiation and identified distinct classes of upregulated genes thereby

2018-02-09 | GSE110346 | GEO

TGF-beta/Smad3-dependent gene expression analysis in naive CD4 T cells

Project description:Investigation of transcript level modulation in unstimulated and TGF-beta treated (with or without superimposed T-cell receptor and CD28 stimulation) naive CD4 T cells from wild type or Smad3-deficient littermate mice. Smad3 is a critical signaling molecule and transcription factor downstream of TGF-beta and mediates several of the TGF-beta dependent tolerogenic effects in T cells. This study was undertaken to unveil the transcriptionnal program controled by the TGF-b/Smad3 axis. Microarray study using RNA recovered after 6 hours of culture in either serum free media, serum-free media + TGF-beta (2.5ng/ml) or serum-free media + TGF-beta and anti-CD3e and anti-CD28 stimulation (3 conditions). Naive CD4 T cells (TCRb+, CD4+, CD62L+ and CD44-) were sorted from either wild type or Smad3 deficient littermates and submitted to the 3 culture conditions. Three biological replicates were obtained (each from at least 2 different mice). Thus a total of 18 Nimblegen 365K chip were used.

2012-08-31 | E-GEOD-40494 | biostudies-arrayexpress

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

TGF-beta/Smad3-dependent gene expression analysis in naive CD4 T cells

2012-08-31 | GSE40494 | GEO

ChIPseq Smad3-JMJD3

Project description:ChIPseq Smad3-JMJD3

| PRJEB2739 | ENA