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B Cell-Specific Deficiency for Smad2 In Vivo Leads to Defects in TGF--Directed IgA Switching and Changes in B Cell Fate¹

Jörg Klein^*, Wenjun Ju, Jörg Heyer, Britta Wittek^2,, Torsten Haneke, Petra Knaus^3,, Raju Kucherlapati^¶, Erwin P. Böttinger, Lars Nitschke^4,5,* and Burkhard Kneitz^4,5,

^* Institute for Virology and Immunobiology, Department of Physiological Chemistry II, Biocenter, and Department of Physiological Chemistry I, Biocenter, University of Würzburg, Würzburg, Germany; Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029; and ^¶ Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Smad2 is a member of the intracellular mediators that transduce signals from TGF- receptors and activin receptors. Targeted inactivation of Smad2 in mice leads to early lethality before gastrulation. It was shown previously that TGF-RII deficiency in vivo leads to defects in B cell homeostasis, Ag responsiveness, and IgA class switch recombination of B cells. To investigate the importance of Smad2-mediated signaling in B lymphocytes, we generated a B cell-specific inactivation of Smad2 in mice (bSmad2^–/–). bSmad2^–/– mice had normal B cell numbers in the spleen but showed a reduced population of marginal zone B cells. In contrast, B cells in Peyer’s patches and peritoneal B-1a cells of bSmad2^–/– mice were increased in numbers. bSmad2^–/– mice showed a reduced number of surface-IgA⁺ B cells and of IgA-secreting cells in Peyer’s patches, decreased levels of IgA in serum, and, after immunization with a T cell-dependent Ag, a reduced IgA response. Class switch recombination to IgA was impaired in Smad2-deficient B cells, when stimulated in vitro with LPS in the presence of TGF-. The growth-inhibitory effects of TGF- in LPS-stimulated B cells were not affected in Smad2-deficient B cells. In summary, our data indicate a crucial role of Smad2 in mediating signals for the TGF--directed class switch to IgA and the induction of IgA responses in vivo. Other B cell functions like growth-inhibitory signaling, which are known to be regulated by signals via the TGF-R, are not affected in Smad2-deficient B cells.

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The JI 2006 176: 2051-2052. [Full Text]