Klein Jörg, Ju Wenjun, Heyer Jörg, Wittek Britta, Haneke Torsten, Knaus Petra, Kucherlapati Raju, Böttinger Erwin P, Nitschke Lars, Kneitz Burkhard
Institute for Virology and Immunobiology, University of Würzburg, Germany.
J Immunol. 2006 Feb 15;176(4):2389-96. doi: 10.4049/jimmunol.176.4.2389.
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.
Smad2是细胞内信号转导介质的成员之一，可转导来自转化生长因子-β（TGF-β）受体和激活素受体的信号。在小鼠中靶向失活Smad2会导致原肠胚形成前的早期致死率。先前的研究表明，体内TGF-βRII缺乏会导致B细胞稳态、抗原反应性以及B细胞的IgA类别转换重组出现缺陷。为了研究Smad2介导的信号在B淋巴细胞中的重要性，我们构建了小鼠B细胞特异性失活Smad2的模型（bSmad2(-/-)）。bSmad2(-/-)小鼠脾脏中的B细胞数量正常，但边缘区B细胞群体减少。相反，bSmad2(-/-)小鼠派尔集合淋巴结中的B细胞和腹膜B-1a细胞数量增加。bSmad2(-/-)小鼠派尔集合淋巴结中表面IgA(+) B细胞和分泌IgA的细胞数量减少，血清中IgA水平降低，在用T细胞依赖性抗原免疫后，IgA反应减弱。当在体外存在TGF-β的情况下用脂多糖（LPS）刺激时，Smad2缺陷型B细胞向IgA的类别转换重组受损。在LPS刺激的B细胞中，TGF-β的生长抑制作用在Smad2缺陷型B细胞中不受影响。总之，我们的数据表明Smad2在介导TGF-β导向的向IgA的类别转换信号以及体内IgA反应的诱导中起关键作用。其他已知受TGF-βR信号调节的B细胞功能，如生长抑制信号，在Smad2缺陷型B细胞中不受影响。
