SMAD4 TGF-?-independent function dictates naive CD8+ T cell fate and prevents gut inflammation
IGALOUZENE R. 1, HERNANDEZ-VARGAS H. 1, GUYENNON A. 1, BENECH N. 1, BAUCH╔ D. 1, BARRACHINA C. 1, DUBOIS E. 1, MARIE J. 1, SOUDJA S. 1
1 Centre de Recherche en cancÚrologie de Lyon, Lyon, France
Characterizing naïve T cells as being completely "naïve" may not accurately reflect their true nature and functionality. SMAD4, a key mediator of TGF-β signaling, plays a crucial role in T cells preventing chronic intestinal inflammation. In spite of this, the mechanisms underlying this control remain obscure. Using different genetic and epigenetic approaches, we reveal that SMAD4 in naïve CD8 T cells prevents microbiota-mediated chronic intestinal inflammation in a TGF-β-independent manner by preconditioning their fate prior to their activation. Mechanistically, SMAD4 acts as a basal repressor of TGF-β-target genes by histone deacetylations in naïve CD8 T cells. Inversely to TGF-β signaling, SMAD4 endows naïve CD8 T cells with a robust effector program and limits their potential differentiation into gut intraepithelial lymphocytes. In addition, in a feedforward mechanism, SMAD4 inhibits the expression of TGF-β-signaling-repressors, predisposing CD8 T cells to an efficient TGF-β mediated immunosuppression. Hence, in a TGF-β-independent manner, SMAD4 both blocks the TGF-β signature in naïve CD8 T cells and restrains their future epithelial localization and intestinal pathology. Our findings unveil SMAD4 as a critical regulator of CD8 T cell differentiation, programming the fate of CD8 T cells during their naive stage, ultimately shaping their behavior and function in subsequent immune responses. These insights provide an original avenue for modulating future immune responses.