Blk-haploinsufficiency impairs the development, but enhances the functional responses, of marginal zone B cells (153.22)

Abstract

Abstract Blk was identified two decades ago as a B cell-specific Src family kinase. Surprisingly, despite its restricted expression, Blk was found to have a non-essential role in B cell development and activation. Recent studies, however, have discovered that Blk is expressed in many cell types outside of the B lineage, including IL-17-producing γδ T cells and pancreatic β-cells. The discovery that Blk has a broader expression pattern than previously reported prompted us to perform a more comprehensive analysis of Blk expression patterns in hematopoietic cells. During this analysis, while using B cell subsets as positive controls, we found that Blk is differentially expressed in mature splenic B cell subsets, with marginal zone (MZ) B cells expressing high levels, and follicular (FO) B cells expressing low levels, of Blk. To determine whether this difference in Blk expression levels reflected a differential requirement for Blk in MZ and FO B cell development, we analyzed the effects of reducing Blk levels on splenic B cell development in mice expressing one functional allele of Blk (Blk+/-). We report that reducing Blk levels impaired the generation of MZ B cells but not FO B cells. Moreover, although there were fewer MZ B cells in Blk+/- mice compared to Blk+/+ mice, Blk+/- MZ B cells were hyper-responsive to BCR stimulation, both in vitro and in vivo. Thus, this study has revealed a previously unappreciated role for Blk in the development and activation of MZ B cells.