Role of Smad4-deficient T cells in Gastrointestinal Inflammatory Disease (59.7)

Abstract

Abstract Selective loss of Smad4 signaling in T cells leads to spontaneous gastrointestinal inflammation and cancer. However, the mechanism underlying the pathogenesis of these diseases is not completely understood. Here, we report that Smad4 is essential for TGF-β conversion of naïve T cells into Foxp3+ regulatory T (Treg) cells and for TGF-β suppression of effector T cells activity. We show that Smad4 deficient (Smad4KO) T cells do not generate Foxp3-expressing cells in inducible Treg (iTreg) differentiation condition. In suppression assays, iTreg cells from naïve WT T cells suppress T cell proliferation but Smad4KO T cells lack suppressive activity. In Smad4KO mice at 6 months of age, FoxP3+ Treg cells among CD4+ T cells are significantly reduced in the colon, but not in the thymus or spleen compared to those of WT. Moreover, TGF-β suppresses the proliferation of WT CD4+ T cells via cell cycle arrest and reduces the production of pro-inflammatory cytokines including INF-γ and IL-6, but TGF-β fails to suppress T cell proliferation and pro-cytokine production of Smad4 KO T cell. As expected, CD4+ and CD8+ T cells in the colon of Smad4KO mice are highly activated and produce pro-inflammatory cytokines, such as INF-γ and IL-6 greater compared with those of WT. Taken together, our results suggest the important role of Smad4 dependent TGF-β signaling in T cells in the maintenance of mucosal immune homeostasis and the pathogenic mechanism underlying gastrointestinal disease.