The periphery is the dominant site of B-cell deletion in a polyclonal repertoire

The concerted actions of multiple tolerance checkpoints limit the possibility of immune attack against self-antigens. For B cells, purging of autoreactivity from the developing repertoire has been almost exclusively studied using B-cell receptor transgenic models. Analyses have generally agreed that central and peripheral tolerance occurs in the form of deletion, receptor editing and anergy. However, when and where these processes occur in a normal polyclonal repertoire devoid of B-cell receptor engineering remain unclear. Here, employing sensitive tools that alleviate the need for B-cell receptor engineering, we track the development of self-reactive B cells and challenge whether deletion plays a meaningful role in B-cell tolerance. We find self-reactive B cells can mature unperturbed by ubiquitous self-antigen expression but, even in the presence of T-cell help, are robustly anergic in the periphery. These studies query the prominence attributed to central and peripheral deletion by most BCR transgenic studies and suggest that other mechanisms predominantly govern B cell tolerance.