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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE188933 | 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 [ChIPseq]

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