Foxo3 promotes apoptosis of B cell receptor-stimulated immature B cells, thus limiting the window for receptor editing

Kristina Ottens, Rochelle M. Hinman, Evan Barrios, Brian Skaug, Laurie S. Davis, Quan Zhen Li, Diego H. Castrillon, Anne B. Satterthwaite

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Central tolerance checkpoints are critical for the elimination of autoreactive B cells and the prevention of autoimmunity. When autoreactive B cells encounter their Ag at the immature B cell stage, BCR cross-linking induces receptor editing, followed by apoptosis if edited cells remain autoreactive. Although the transcription factor Foxo1 is known to promote receptor editing, the role of the related factor Foxo3 in central B cell tolerance is poorly understood. We find that BCR-stimulated immature B cells from Foxo3-deficient mice demonstrate reduced apoptosis compared with wild type cells. Despite this, Foxo32/2 mice do not develop increased autoantibodies. This suggests that the increased survival of Foxo32/2 immature B cells allows additional rounds of receptor editing, resulting in more cells “redeeming” themselves by becoming nonautoreactive. Indeed, increased Igl usage and increased recombining sequence recombination among Igl-expressing cells were observed in Foxo32/2 mice, indicative of increased receptor editing. We also observed that deletion of high-affinity autoreactive cells was intact in the absence of Foxo3 in the anti-hen egg lysozyme (HEL)/membrane-bound HEL model. However, Foxo3 levels in B cells from systemic lupus erythematosus (SLE) patients were inversely correlated with disease activity and reduced in patients with elevated anti-dsDNA Abs. Although this is likely due in part to increased B cell activation in these SLE patients, it is also possible that low-affinity B cells that remain autoreactive after editing may survive inappropriately in the absence of Foxo3 and become activated to secrete autoantibodies in the context of other SLE-associated defects.

Original languageEnglish (US)
Pages (from-to)940-949
Number of pages10
JournalJournal of Immunology
Volume201
Issue number3
DOIs
StatePublished - Aug 1 2018

ASJC Scopus subject areas

  • Immunology

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