BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells

•The BCR serves as a ‘master regulator’ of co-receptor signals.•Dual BCR and BAFF-R or CD40 signals drive survival of T1 and T2 B cells.•Dual BCR and TLR signals promote either apoptosis or survival of T1 and T2 B cells.•Excess signals facilitate the positive selection of autoreactive T1 and T2 B cells.•Signaling variants impact the autoreactivity profile of the mature repertoire.

The establishment of a diverse B cell repertoire requires fine-tuning of antigen receptor selection during development in order to permit sufficient diversity while reducing the potential for autoimmunity. In this review, we highlight recent studies demonstrating the central role of the B cell antigen receptor (BCR), in coordination with other key pro-survival signals mediated by CD40, BAFF-R, TACI and/or TLRs, in regulating both negative and positive selection of autoreactive B cells. In particular, we show how altered antigen or co-stimulatory signaling can facilitate positive selection of transitional B cells with self-reactive BCRs, ultimately leading to their entry into the mature, naive B cell compartment. We propose a model wherein altered receptor signals (due to inherited genetic changes) leads: first, to enhanced positive selection of autoreactive cells into the naïve B cell repertoire; subsequently, to an increased probability of pathogenic germinal center responses in individuals with a broad range of autoimmune disorders.