Journal
NATURE IMMUNOLOGY
Volume 20, Issue 11, Pages 1517-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0490-2
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Funding
- Boehringer Ingelheim
- European Research Council under the European Union [740349]
- Austrian Industrial Research Promotion Agency [FFG-852936]
- Austrian Science Fund [T838-B26]
- European Research Council (ERC) [740349] Funding Source: European Research Council (ERC)
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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 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.
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