Abstract
Clonal deletion of autoreactive B cells is crucial for the prevention of autoimmunity, but the signaling mechanisms that regulate this checkpoint remain undefined. Here we characterize a previously unrecognized Ca2+-driven pathway for activation of the kinase Erk, which was proapoptotic and biochemically distinct from Erk activation induced by diacylglycerol (DAG). This pathway required protein kinase C-δ (PKC-δ) and the guanine nucleotide-exchange factor RasGRP and depended on the concentration of the Ca2+ sensor STIM1, which controls the magnitude of Ca2+ 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 PKC-δ-deficient mice, which developed B cell autoimmunity. Conversely, overexpression of STIM1 conferred a competitive disadvantage to developing B cells. Our findings establish Ca 2+-dependent Erk signaling as a critical proapoptotic pathway that mediates the negative selection of B cells.
Original language | English (US) |
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Pages (from-to) | 425-433 |
Number of pages | 9 |
Journal | Nature immunology |
Volume | 12 |
Issue number | 5 |
DOIs | |
State | Published - May 2011 |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology