Perspectives on the nature of BCR-mediated survival signals.

In the June 11 issue of Cell, Kraus et al. (2004) show, through conditional mutagenesis, that mature B cells have a drastically reduced life span in the absence of normal B cell antigen receptor (BCR) surface expression or tonic signal transduction. These studies support a role for signal transduction downstream of the BCR, rather than continued surface expression per se for the maintenance and survival of mature B cells in the periphery. Further, these studies exclude transient INF(gamma)-induced activation as a prerequisite to apoptosis in receptor-less cells.

Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling.

The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.

Peripheral B cell selection and homeostasis.

The size and makeup of mature B cell compartments are controlled by the proportion of immature B cells that complete differentiation, coupled with the average lifespan of mature B cells. Thus, determining the selective and homeostatic factors controlling these parameters is key to understanding how the B cell repertoire is established and maintained. Our previous work defined the developmental stages spanning immature B cell formation in the marrow and final maturation in the periphery. More recently, we have focused on the molecular basis for survival and differentiation within these developmental subsets, with emphasis on the role of BLyS and BLyS receptors. Through developmental and kinetic studies in normal and mutant mice, we have found that BLyS controls peripheral B cell numbers in two ways: by varying the proportion of cells that complete transitional B cell development and by serving as the primary determinant of mature follicular B cell lifespan. Ongoing studies are aimed at determining the mechanism of BLyS activity in these subsets, as well as how BLyS responsiveness is integrated with BcR signaling. Additionally, we have begun studies on how these selective and homeostatic processes change with age. Our results indicate that the size and dynamics of most B cell subsets shift with age, suggesting age-associated alterations in both intrinsic and microenvironmental factors that govern these processes.

Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors.

This study examines how B lymphocyte stimulator (BLyS) receptor expression and responsiveness are influenced by B cell receptor (BcR) signaling. Our results show that resting and BcR-stimulated B cells are dependent on BLyS for survival and that B cells remain BLyS responsive during BcR-induced activation. Further, BcR ligation up-regulates expression of the BLySR B cell maturation defect/BLySR3 (Bcmd/BR3), but not other known BLySRs. Finally, the coupling of BcR signaling with Bcmd/BR3 expression is limited to late transitional and mature B cells. Together, these findings establish the coupling of BcR signaling with Bcmd/BR3 expression as a fundamental aspect of follicular B cell selection, survival, and activation.