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

• Published in: The EMBO journal Vol. 18; no. 5; pp. 1280 - 1291
• Main Authors: Yang, Xiao, Letterio, John J., Lechleider, Robert J., Chen, Lin, Hayman, Russ, Gu, Hua, Roberts, Anita B., Deng, Chuxia
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.1999
• Subjects: Animals; B-Lymphocytes - metabolism; bacterial infections; Chemotaxis - drug effects; DNA-Binding Proteins - genetics; Gene Targeting; Immunity, Mucosal - genetics; Immunoglobulin A - metabolism; inflammation; Intestinal Mucosa - pathology; L-Selectin - analysis; Mice; Mice, Knockout; Neutrophils - metabolism; Signal Transduction - genetics; Smad2 Protein; SMAD3; Smad3 Protein; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; TGF-β signaling; Trans-Activators - genetics; Transforming Growth Factor beta - pharmacology
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/18.5.1280

SMAD3 is one of the intracellular mediators that transduces signals from transforming growth factor‐β (TGF‐β) and activin receptors. We show that 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 adjacent to mucosal surfaces. Mutant T cells exhibit an activated phenotype in vivo, and are not inhibited by TGF‐β1 in vitro. Mutant neutrophils are also impaired in their chemotactic response toward TGF‐β. Chronic intestinal inflammation is infrequently associated with colonic adenocarcinoma in mice older than 6 months of age. These data suggest that SMAD3 has an important role in TGF‐β‐mediated regulation of T cell activation and mucosal immunity, and that the loss of these functions is responsible for chronic infection and the lethality of Smad3‐null mice.