CD19 Function in Early and Late B Cell Development: I. Maintenance of Follicular and Marginal Zone B Cells Requires CD19-Dependent Survival Signals

Abstract

Loss of membrane-bound Ig results in the rapid onset of apoptosis in recirculating B cells. This observation implies that a competent B cell receptor (BCR) is not only required for Ag-dependent differentiation, but also for continued survival in the peripheral immune system. Expression of the B cell coreceptor, CD19, is likewise essential for key B cell differentiative events including the formation of B-1, germinal center, and marginal zone (MZ) B cells. In this study, we report that CD19 also exerts a role before Ag encounter by promoting the survival of naive recirculating B cells. This aspect of CD19 signaling was first suggested by the analysis of mixed bone marrow chimeras, wherein CD19−/− B cells fail to effectively compete with wild-type B cells to reconstitute the peripheral B cell compartment. Consistent with this observation, Bromodeoxyuridine- and CFSE-labeling studies reveal a shorter in vivo life span for CD19−/− B cells vs their wild-type counterparts. Moreover, we find that CD19 is necessary for propagation of BCR-induced survival signals and thus may contribute to homeostatic mechanisms of tonic signaling. To determine whether provision of a constitutive survival signal could compensate for the loss of CD19 in vivo, Bcl-2-transgenic mice were bred onto the CD19−/− background. Here, we observe an increase in follicular B cell numbers and selective recovery of the MZ B cell compartment. Together these findings suggest that maintenance of the follicular and MZ B cell compartments require CD19-dependent survival signals.

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

“…In addition, we found that BAFF is required for normal CD21 expression in B cells and for the generation of marginal zone B cells. Importantly, a Bcl-2 transgene rescued the marginal zone B cell deficiency in CD19 -/-mice, ruling out the hypothesis that these cells could be unresponsive to Bcl-2 [33].…”

“…The balance between marginal zone versus follicular B cell development is also regulated by Aiolos and Btk [21], whereas CD19 is important for the survival and differentiation of several B cell populations, including B1 and marginal zone B cells [33]. Inactivation of the repressor activity of RBP-J by Notch signaling promotes marginal zone B cell formation, whereas the Notchantagonizing protein MINT prevents it [40,41].…”

Heparan Sulfate and Heparin Enhance ERK Phosphorylation and Mediate preBCR-Dependent Events during B Lymphopoiesis

“…This suggests that heparin is either recruiting coreceptors that can reduce the signaling threshold of the preBCR, or that heparin is modifying the cell surface milieu and allowing the antiAb to be more effective. These findings prompted us to compare the results when cells are pretreated with an activating, anti-CD19 Ab because CD19 has been reported to establish signaling thresholds of the preBCR (25)(26)(27)(28). Activating the CD19 pathway before anti-stimulation resulted in increased pERK levels, similar to when cells were pretreated with heparin.…”

“…In fact, heparin or heparan sulfate in combination with anti-treatment of cells causes a similar response by pERK compared with anti-CD19 and anti-. Current models suggest CD19 lowers the threshold of activation of the preBCR and BCR, and establishes critical signaling thresholds (25)(26)(27)(28). In its absence, there is an impaired proB to preB cell transition and a severe reduction in mature B cells.…”

Expression of complement receptors 1 (CR1/CD35) and 2 (CR2/CD21), and co-signaling molecule CD19 in cattle

“…The presence of CD19 on the cell surface is essential for B lymphocyte activation; under--expression of CD19 is associated with fewer peritoneal B cells, decreased B cell proliferative responses to mitogen, greatly reduced concentrations of serum immunoglobulin (Engel et al, 1995), decreased responses to T--cell--dependent B cell antigens, absent germinal center formation and afBinity maturation (Rickert et al, 1995). CD19 provides tonic survival signals to recirculating naive B lymphocytes; the B cell compartment in CD19 --/--mice can be partially rescued by over--expression of apoptosis survival genes (Otero et al, 2003).…”