The First B-Cell Tolerance Checkpoint in Mice and Humans: Control by AID

Activation-induced cytidine deaminase (AID) expression in the germinal center response drives the immunoglobulin class-switch recombination and V(D)J hypermutation necessary for efficacious, high-affinity antibody responses. That AID is expressed in developing lymphocytes is less well known, but represents an evolutionarily conserved pattern of lymphocyte development that is represented in all vertebrate species. Here we review the role of early, developmentally regulated AID expression in mice and humans and its role in establishing the first B-cell tolerance checkpoint. This newly recognized component of central tolerance requires coordinate signaling by poly- or autoreactive B-cell antigen receptors and endosomal Toll-like receptors. These signals synergize to upregulate AID expression in immature and transitional B cells to levels that approach that of germinal center B cells with the result of caspase 3-mediated cell death. In this review, we discuss the origins and mechanism of this interesting collaboration between adaptive and innate receptors to purge the primary B-cell repertoire of self-reactivity and how it may be related to receptor editing, the other major mechanism for central tolerance.