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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.

Original publication




Journal article


Nature immunology

Publication Date





1517 - 1529


Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.


B-Lymphocytes, Animals, Mice, Immunoglobulin D, DNA-Binding Proteins, NF-kappa B, Receptors, Antigen, B-Cell, Models, Animal, Signal Transduction, Autoimmunity, Clonal Anergy, Gene Expression Regulation, Toll-Like Receptors, Ikaros Transcription Factor, Myeloid Differentiation Factor 88