A new pathway for central B cell tolerance: interaction of AID, MyD88, and BCR (IRC3P.467)

Abstract

Abstract Expression of activation-induced cytidine deaminase (AID) in immature and transitional B cells in mice and humans is genetically linked to the first tolerance checkpoint. In the absence of AID, autoreactive immature/transitional-1 (T1) B cells are inefficiently purged and exhibit increased resistant to receptor-induced apoptosis. These substantial effects are surprising given that AID expression in the immature/T1 B cells is only 3% of that in germinal center B cells. We now show that in immature/T1 B cells, but not mature B cells, B-cell antigen receptor and Toll-like receptor (TLR) signaling synergize to elicit high levels of AID expression. This synergy is restricted to intracellular TLR ligands, requires the phospholipase D-dependent compartmentalization of intracellular TLR and activation of the TLR through acidification, and acts to ensure self-tolerance through a process that requires Myd88. In a 3H9 mouse model, we show that suppression of intracellular acidification by administration of chloroquine increased the generation of immature/T1 B cells in proportion to small pre-B cells, suggesting that chloroquine treatment support the survival of autoreactive 3H9 immature/T1 B cells in bone marrow. These findings identify a novel mechanism for central B-cell tolerance and resolve several weaknesses of current models for the first tolerance checkpoint. We suggest that this AID mediated pathway may be the primary mechanism for central B-cell tolerance by deletion.