title: B cell-specific deficiency for Smad2 in vivo leads to defects in TGF-beta-directed IgA switching and changes in B cell fate.
abstract: Smad2 is a member of the intracellular mediators that transduce signals from TGF-beta receptors and activin receptors. Targeted inactivation of Smad2 in mice leads to early lethality before gastrulation. It was shown previously that TGF-betaRII 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-beta. The growth-inhibitory effects of TGF-beta 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-beta-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-betaR, are not affected in Smad2-deficient B cells.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Klein
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ju
authors.forename: Jörg
authors.initials: J
authors.lastname: Heyer
authors.forename: Britta
authors.initials: B
authors.lastname: Wittek
authors.forename: Torsten
authors.initials: T
authors.lastname: Haneke
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Böttinger
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kneitz
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051899:Smad2 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D007070:Immunoglobulin A; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta