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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 transforming growth factor-beta (TGF-beta) 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-beta1 in vitro. Mutant neutrophils are also impaired in their chemotactic response toward TGF-beta. 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-beta-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.

Pubmed ID: 10064594

Authors

  • Yang X
  • Letterio JJ
  • Lechleider RJ
  • Chen L
  • Hayman R
  • Gu H
  • Roberts AB
  • Deng C

Journal

The EMBO journal

Publication Data

March 1, 1999

Associated Grants

None

Mesh Terms

  • Animals
  • B-Lymphocytes
  • Chemotaxis
  • DNA-Binding Proteins
  • Gene Targeting
  • Immunity, Mucosal
  • Immunoglobulin A
  • Intestinal Mucosa
  • L-Selectin
  • Mice
  • Mice, Knockout
  • Neutrophils
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • T-Lymphocytes
  • Trans-Activators
  • Transforming Growth Factor beta