B cell defects in SLP65/BLNK-deficient mice can be partially corrected by the absence of CD22, an inhibitory coreceptor for BCR signaling.

Abstract

CD22 is an inhibitory coreceptor for B cell receptor (BCR) signaling. The inhibition is most likely mediated by activation of SHP-1. We found that SLP65/BLNK reaches maximal tyrosine-phosphorylation at earlier time points in CD22(-/-) than in wild type B cells upon BCR cross-linking, suggesting that SLP65/BLNK is a substrate of SHP-1. However, in contrast to the defective Ca(2+) mobilization of SLP65/BLNK(-/-) B cells, there was a clear Ca(2+) response in SLP65/BLNKxCD22 double-deficient B cells. This implies that SLP65/BLNK is not the sole target of SHP-1 in the regulation of the Ca(2+) signaling strength. While SLP65(-/-) mice show several blocks of B cell differentiation, in SLP65/BLNK x CD22 double-deficient mice the maturation block of B cells in the spleen was partially rescued. However, the proliferative responses of B cells from both SLP65/BLNK(-/-) and double-deficient mice were defective after IgM- or CD40-stimulation. These results show that SLP65/BLNK is not absolutely essential for Ca(2+) induction in B cells, because the deficiency of this adapter can be by-passed by the additional deletion of an inhibitory receptor. Furthermore, these experiments suggest that B cell maturation in the spleen is directly dependent on the strength of BCR-derived Ca(2+) signals.