Open AccessIkaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells
Author(s) -
Tanja A. Schwickert,
Hiromi Tagoh,
Karina Schindler,
Maria Fischer,
Markus Jaritz,
Meinrad Busslinger
Publication year - 2019
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-019-0490-2
Subject(s) - autoimmunity , biology , b cell receptor , breakpoint cluster region , immunology , transcription factor , microbiology and biotechnology , signal transduction , clonal anergy , immune tolerance , toll like receptor , b cell , antigen , cancer research , receptor , immune system , t cell , t cell receptor , antibody , innate immune system , gene , genetics
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.