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

SMAD4, a mediator of TGF-ß 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-ß receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-ß signature in naive CD8+ T cells. Mechanistically, prior to TGF-ß signaling, SMAD4 binds to promoters and enhancers of several TGF-ß target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-ß signal, SMAD4 limits the expression of TGF-ß negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-ß. 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-ß control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-ß-independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.

Common and Exclusive Features of Intestinal Intraepithelial γδ T Cells and Other γδ T Cell Subsets.

Murine peripheral lymph node TCR γδ T cells have been divided into type 1 and type 17 functional categories based on phenotypic and functional markers. Localized in the gut epithelial barrier, intestinal intraepithelial lymphocytes (iIEL) γδ T cells constitute a peculiar subset of T lymphocytes involved in intestinal homeostasis. However, whether iIEL γδ T cells obey the type 1/type 17 dichotomy is unclear. Using both global transcriptional signatures and expression of cell surface markers, we reveal that murine iIEL γδ T cells compose a distinct population, expressing ∼1000 specific genes, in particular genes that are responsible for cytotoxicity and regulatory functions. The expression of the transcription factor Helios is a feature of iIEL γδ T cells, distinguishing them from the other TCR γδ T subsets, including those present in the epithelia of other tissues. The marked expression of Helios is also shared by the other iIELs, TCRαßCD8αα lymphocytes present within the intestinal epithelium. Finally, we show that Helios expression depends in part on TGF-ß signaling but not on the microbiota. Thus, our study proposes iIEL γδ T cells as a distinct subset and identifies novel markers to differentiate them from their peripheral counterparts.