Developmental-associated differences in membrane cholesterol content account for the differential responses of transitional immature and mature B cells to B cell receptor engagement (83.1)

Abstract

Abstract Tolerance-sensitive transitional immature B cells maintain significantly lower membrane unesterified cholesterol levels than mature splenic B cells. In addition, the relatively low level of plasma membrane-associated cholesterol in transitional immature B cells impairs compartmentalization of their B cell receptor (BCR) into cholesterol-enriched domains following BCR aggregation and reduces their ability to sustain certain aspects of BCR signaling as compared with mature B cells. By increasing the level of plasma membrane associated cholesterol in transitional immature B to that seen in mature B cells, we observe an decrease in apoptosis post-BCR stimulation as compared to unmanipulated transitional immature B cells. Furthermore, we have generated a stable genetic mouse model in which cholesterol is constitutively produced in B cells, thus increasing the level of plasma membrane associated cholesterol in transitional immature B cells in vivo. These studies establish an unexpected difference in the lipid composition of peripheral transitional immature and mature B cells and point to a determining role for development-associated differences in cholesterol content for the differential responses of these B cells to BCR engagement. This work was supported by Training Grant AI055428 and Grants AI43620 and AI32592 from the National Institutes of Health.