Ikaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells

被引:56
|
作者
Schwickert, Tanja A. [1 ]
Tagoh, Hiromi [1 ,2 ]
Schindler, Karina [1 ]
Fischer, Maria [1 ]
Jaritz, Markus [1 ]
Busslinger, Meinrad [1 ]
机构
[1] Vienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
[2] Univ Oxford, Ludwig Inst Canc Res, Oxford, England
基金
奥地利科学基金会; 欧洲研究理事会;
关键词
EXPRESSION; IKZF1; MICE; IGD; ASSOCIATION; LYMPHOCYTES; TOLERANCE; CHROMATIN; PROTEINS; ZFP318;
D O I
10.1038/s41590-019-0490-2
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 kappa B 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.
引用
收藏
页码:1517 / +
页数:16
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