Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta

SMAD3 is one of the intracellular mediators that transduces signals from tr ansforming growth factor-beta (TGF-beta) and activin receptors. We show tha t SMAD3 mutant mice generated by gene targeting die between 1 and 8 months due to a primary defect in immune function. Symptomatic mice exhibit thymic involution, enlarged lymph nodes, and formation of bacterial abscesses adj acent to mucosal surfaces. Mutant T cells exhibit an activated phenotype in vivo, and are not inhibited by TGF-beta 1 in vitro. Mutant neutrophils are also impaired in their chemotactic response toward TGF-beta, Chronic intes tinal inflammation is infrequently associated with colonic adenocarcinoma i n mice older than 6 months of age. These data suggest that SMAD3 has an imp ortant role in TGF-beta-mediated regulation of T cell activation and mucosa l immunity, and that the loss of these functions is responsible for chronic infection and the lethality of Smad3-null mice.