BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Masayuki Kuraoka, Pilar B. Snowden, Takuya Nojima, Laurent Verkoczy, Barton F. Haynes, Daisuke Kitamura, Garnett Kelsoe
Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs.

Graphical abstract

Teaser

AID is essential for purging autoreactive developing B cells. Kuraoka and colleagues find that BCR and TLR signals synergize to elicit high AID expression in immature B lymphocytes through phospholipase-D activation, endosomal acidification, and MyD88. Inhibition of these pathways results in accumulation of autoreactive clones. The BCR+TLR pathway thus coordinately establishes central B cell tolerance.


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