SMAD4 governs a feedforward regulation of the TGF-beta effects in CD8 T cells that contributes to preventing chronic intestinal inflammation

Abstract

SMAD4, a key mediator of TGF-{beta} signaling, plays a crucial role in T cells to prevent chronic gut inflammation. However, the molecular mechanisms underlying this control remain elusive. Using different genetic and epigenetic approaches, we unexpectedly reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation by a feedforward mechanism that is TGF-{beta}-independent. Prior to any TGF-{beta}-receptor engagement, SMAD4 acts as an active and basal repressor of epigenetic, transcriptional and functional TGF-{beta} imprinting in CD8 T cells. Thus, in sharp opposition to total TGF-{beta} signaling deletion, SMAD4 deletion impairs naive CD8 T cell effector predisposition but promotes CD8 T cell accumulation and epithelial retention by promoting their response to IL-7 and their expression of integrins such as Itgae. Besides, SMAD4 deletion unleashes the induction of a wide range of TGF-{beta}-signaling-repressors such as Smad7, Ski, Skil, and Smurf2 and hampers TGF-{beta}-mediated CD8 T cell immunosuppression. Mechanistically, prior to any TGF-{beta} signal, SMAD4 binds to the loci of several TGF-{beta}-target genes, and by regulating histone acetylation, represses their expression. The massive gut epithelial colonization, associated with their escape from the immunoregulatory TGF-{beta} effects overtakes their poor effector preconditioning and elicits microbiota-driven chronic epithelial CD8 T cell activation. Hence, in an anticipatory manner, independently of TGF-{beta}, SMAD4 governs a feedforward regulation of TGF-{beta} effects in CD8 T cells, preventing chronic intestinal inflammation.