Stim1, PKCδ and RasGRP proteins set a threshold for pro-apoptotic Erk signaling during B cell development

Clonal deletion of autoreactive B cells is crucial to prevent autoimmunity, but the signaling mechanisms that regulate this checkpoint remain undefined. Here we characterized a previously unrecognized Ca(2+)-driven Erk activation pathway, which was pro-apoptotic and biochemically distinct from DAG-induced Erk activation. This pathway required PKCδ and RasGRP proteins and depended on Stim1 concentrations, which control the magnitude of Ca(2+) entry. Developmental regulation of these proteins was associated with selective activation of the pathway in B cells prone to negative selection. This checkpoint was impaired in PKCδ-deficient mice, which developed B cell autoimmunity. Conversely, Stim1 overexpression conferred a competitive disadvantage to developing B cells. These findings establish Ca(2+)-dependent Erk signaling as a critical pro-apoptotic pathway that mediates B cell negative selection.