Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
Nat Immunol. 2019 Nov;20(11):1517-1529. doi: 10.1038/s41590-019-0490-2. Epub 2019 Oct 7.
The establishment of a diverse B cell antigen receptor (BCR) repertoire by V(D)J recombination also generates autoreactive B cells. Anergy is one tolerance mechanism; it renders autoreactive B cells insensitive to stimulation by self-antigen, whereas Toll-like receptor (TLR) signaling can reactivate anergic B cells. Here, we describe a critical role of the transcription factor Ikaros in controlling BCR anergy and TLR signaling. Mice with specific deletion of Ikaros in mature B cells developed systemic autoimmunity. Ikaros regulated many anergy-associated genes, including Zfp318, which is implicated in the attenuation of BCR responsiveness by promoting immunoglobulin D expression in anergic B cells. TLR signaling was hyperactive in Ikaros-deficient B cells, which failed to upregulate feedback inhibitors of the MyD88-nuclear factor κB signaling pathway. Systemic inflammation was lost on expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B cells. Thus, Ikaros acts as a guardian preventing autoimmunity by promoting BCR anergy and restraining TLR signaling.
通过 V(D)J 重组建立多样性的 B 细胞抗原受体 (BCR) repertoire 也会产生自身反应性 B 细胞。失能是一种耐受机制；它使自身反应性 B 细胞对自身抗原的刺激不敏感，而 Toll 样受体 (TLR) 信号可以使失能的 B 细胞重新激活。在这里，我们描述了转录因子 Ikaros 在控制 BCR 失能和 TLR 信号中的关键作用。在成熟 B 细胞中特异性缺失 Ikaros 的小鼠会发生全身性自身免疫。Ikaros 调控许多与失能相关的基因，包括 Zfp318，它通过促进失能 B 细胞中免疫球蛋白 D 的表达来减弱 BCR 反应性。Ikaros 缺陷的 B 细胞中 TLR 信号过度活跃，无法上调 MyD88-核因子 κB 信号通路的反馈抑制剂。在 Ikaros 缺陷的 B 细胞中表达非自身反应性 BCR 或缺失 MyD88 时，全身性炎症就会消失。因此，Ikaros 通过促进 BCR 失能和抑制 TLR 信号来充当保护者，防止自身免疫。
