Antibody production results from B-cell activation and proliferation upon antigen binding. Discs large homolog 1 (Dlg1), a scaffold protein from the membrane-associated guanylate kinase family, has been shown to regulate the antigen receptor signaling and cell polarity in lymphocytes; however, the physiological function of Dlg1 in humoral responses is not completely clear. Here, we addressed this question using a conditional knockout (KO) mouse model with Dlg1 deficiency in different B-cell subsets by crossing dlg1fl/fl mice with either mb1cre/+ or aicdacre/+ mice, respectively. In both mouse models, we observed that Dlg1 deficiency in B cells (Dlg1-KO B cells) led to obvious hyper-antibody responses upon immunization, the effect of which was more obvious in antigen-recall responses. Mechanistically, we found that Dlg1-KO B cells exhibited hyper-proliferation compared with wild-type B cells upon antigen stimulation, suggesting that the hyper-antibody responses are likely induced by the hyper-proliferation of Dlg1-KO B cells. Indeed, further studies demonstrated that Dlg1 deficiency in B cells led to the down-regulation of a tumor suppressor, FoxO1. Thus, all these results reveal an unexpected function of Dlg1 in restraining hyper-antibody responses through the inhibition of FoxO1 and thus antigen-binding-induced proliferation in B cells.

中文翻译：

---

盘大同系物1调节B细胞增殖和抗体产生。

抗体的产生是由于抗原结合后B细胞的活化和增殖。盘大同系物1（Dlg1），一种来自膜相关鸟苷酸激酶家族的支架蛋白，已被证明可调节淋巴细胞中的抗原受体信号和细胞极性。但是，Dlg1在体液反应中的生理功能尚不完全清楚。在这里，我们通过将dlg1fl / fl小鼠分别与mb1cre / +或aicdacre / +小鼠杂交，使用在不同B细胞亚群中Dlg1缺乏的条件敲除（KO）小鼠模型解决了这个问题。在这两种小鼠模型中，我们观察到B细胞（Dlg1-KO B细胞）中的Dlg1缺乏导致免疫后出现明显的高抗体反应，其作用在抗原召回反应中更为明显。机械上，我们发现抗原刺激后，Dlg1-KO B细胞与野生型B细胞相比显示出过度增殖，这表明Dlg1-KO B细胞的过度增殖可能诱导了超抗体反应。确实，进一步的研究表明B细胞中Dlg1的缺乏导致肿瘤抑制因子FoxO1的下调。因此，所有这些结果揭示了Dlg1在通过抑制FoxO1从而抑制B细胞中抗原结合诱导的增殖而抑制高抗体反应中的意外功能。