SMAD4 TGF-β-independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation

SMAD4, a mediator of TGF-beta signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using both genetic and epigenetic approaches. we revealed an unexpected mechanism by which SMAD4 prevents naive CD8(+)T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-beta receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-beta signature in naive CD8(+) T cells. Mechanistically, prior to TGF-beta signaling, SMAD4 binds to promoters and enhancers of several TGF-beta target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-beta signal, SMAD4 limits the expression of TGF-beta negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8(+) T cells for the immunoregulatory effects of TGF-beta. In addition, SMAD4 ablation conferred naive CD8(+) T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-beta control elicited chronic microbiota-driven CD8(+) T cell activation in the gut. Hence, in a TGF-beta-independent manner, SMAD4 imprints a program that preconditions naive CD8(+) T cell fate, preventing IBD.

Automated summary

SMAD4 plays an important role in preventing inflammatory bowel disease (IBD) by controlling the activation of CD8(+) T cells. This study reveals the mechanism by which SMAD4 regulates the expression of TGF-beta target genes to prevent pathogenic responses in the gut. In addition, SMAD4 deficiency enhances the retention of CD8(+) T cells in the intestinal epithelium and their response to other factors, resulting in chronic microbiota-driven CD8(+) T cell activation.