Dominant, hierarchical induction of peripheral tolerance during foreign antigen-driven B cell development

Abstract

We created mice expressing transgene-encoded BCRs with "dual reactivity" for the hapten Ars and nuclear autoantigens. Expression of transgene-encoded BCRs was not evident in the memory compartment despite observation of transgene-expressing B cells in germinal centers following Ars immunization. In contrast, dual reactive mAbs were readily obtained from mice with enforced expression of Bcl-2 following secondary Ars immunization. However, while these mAbs were hypermutated and displayed increased affinity for Ars, all had reduced avidity for DNA and intracellular autoantigens. Thus, Bcl-2 alters dominant-negative selection of dual reactive B cells during the Ars response, but this is restricted to those with lowered autoreactivity, demonstrating a hierarchy of peripheral tolerance during memory B cell development.