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TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE188934 | GEO | 2022/03/15

REPOSITORIES: GEO

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TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [RNAseq]

Project description:SMAD4, a key mediator of TGF-beta signaling, plays a crucial role in T cells to prevent chronic intestinal inflammation through unknown mechanisms. We reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation primarily in a TGF-beta-independent manner. Mechanistically, SMAD4, in CD8 T cells, acts as a basal and tonic repressor of TGF-beta-target genes at the transcriptional and epigenetic level, prior to any TGF-beta signal. SMAD4 deletion affects aberrantly a wide range of TGF-beta-target genes, thereby promoting accumulation and epithelial retention of CD8.alpha.beta T cells inversely to total TGF-beta signaling disruption. Moreover, SMAD4 deletion unleashes the expression of TGF-beta-signaling-repressors and hampers TGF-β-mediated CD8 T cell immunosuppression, eliciting their chronic activation. Hence, in a feedforward mechanism, SMAD4 both blocks the TGF-beta signature in CD8 T cells and pre-sensitizes them to TGF-beta.

2022-03-15 | GSE188933 | GEO

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [ChIPseq]

2022-03-15 | GSE188932 | GEO

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation.

Project description:TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation.

| PRJNA780795 | ENA

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [ChIPseq]

Project description:TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [ChIPseq]

| PRJNA780804 | ENA

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [RNAseq]

Project description:TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [RNAseq]

| PRJNA780803 | ENA

Microbiota-driven arginase 1 expression impedes the resolution of intestinal inflammation

Project description:Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. Patients with inflammatory bowel disease (IBD) show an enhanced expression and activity of Arg1 in the intestinal (sub-)mucosa, but the function of Arg1 in IBD remains poorly characterized. Here, we found that Arg1 expression correlates with the degree of inflammation in colitic tissues of IBD patients. In mice with - experimental colitis Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in the intestinal microbiota, diminished infiltration by myeloid cellsand an accumulation of intraluminal polyamines that are associated with epithelial healing. Dietary L-arginine restriction abolished the protective effect of Arg1-deletion, suggesting that protection is related to an increased availability of L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wildtype recipients restored the protective, anti-inflammatory phenotype while transfers from wildtype littermates into Arg1-deficient mice prevented the accelerated recovery from colitis. Thus, altered intestinal microbiota and metabolic products in Tie2-Cre+/-Arg1fl/fl mice account for the accelerated resolution from colitis in the absence of Arg1. Subsequently, L-arginine serves as novel therapeutic and diagnostic target for clinical intervention in IBD patients.

2020-06-07 | GSE151931 | GEO