Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
Eur J Immunol. 2014 Mar;44(3):887-93. doi: 10.1002/eji.201343841. Epub 2013 Dec 16.
The importance of the BCR and TLR9 in autoimmunity and in the production of auto-antibodies is well established but the underlying molecular mechanism still needs to be determined. Here, we aim to characterize the BCR-TLR9 cross-talk by its effect on T-bet, as T-bet is activated and regulated by both receptors and has an important role in class-switching to pathological IgG2a in mice. Using primary mouse B cells, we demonstrate that T-bet expression is synergistically elevated by the cross-talk between the BCR and TLR9. To test the effect of this synergy on IgG2a-switching, the levels of switched B cells were checked by functional tests. We found that BCR costimulation had no additional effect on TLR9-induced IgG2a expression, however the expression of Rad51 was synergistically increased. To check the biological significance of the synergy, we compared T-bet expression in B cells from healthy and collagen-induced arthritis mice but no differences were found. Taken together, we demonstrate here that signaling cascades driven by the BCR and TLR9 have a newly identified meeting point at T-bet. The two cascades act synergistically on T-bet; however additional signals may be needed to induce prolonged functional responses such as class-switch recombination.
BCR 和 TLR9 在自身免疫和自身抗体产生中的重要性已得到充分证实，但潜在的分子机制仍有待确定。在这里，我们旨在通过其对 T-bet 的影响来描述 BCR-TLR9 的串扰，因为 T-bet 被这两种受体激活和调节，并在小鼠向病理性 IgG2a 的类别转换中具有重要作用。使用原代小鼠 B 细胞，我们证明 BCR 和 TLR9 之间的串扰协同上调 T-bet 的表达。为了测试这种协同作用对 IgG2a 转换的影响，通过功能测试检查了已转换 B 细胞的水平。我们发现 BCR 共刺激对 TLR9 诱导的 IgG2a 表达没有额外的影响，但是 Rad51 的表达协同增加。为了检查协同作用的生物学意义，我们比较了来自健康和胶原诱导性关节炎小鼠的 B 细胞中的 T-bet 表达，但未发现差异。总之，我们在这里证明，BCR 和 TLR9 驱动的信号级联在 T-bet 处具有新确定的交汇点。这两个级联在 T-bet 上协同作用；然而，可能需要额外的信号来诱导如类别转换重组等延长的功能反应。
