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Nat Immunol. 2019 Nov;20(11):1517-1529. doi: 10.1038/s41590-019-0490-2. Epub 2019 Oct 7.

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

Author information

1
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria. tanja.schwickert@imp.ac.at.
2
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
3
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
4
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria. meinrad.busslinger@imp.ac.at.

Abstract

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.

PMID:
31591571
DOI:
10.1038/s41590-019-0490-2

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