Differences in CXCR4-mediated signaling in B cells.

Among all chemokine receptors CXCR4 possesses a unique response profile and distinguishes itself through a prolonged signaling capacity. Here, we investigated the signaling capacity of CXCR4 to its so far known unique ligand CXCL12 in B cell lines and primary CD19(+) B lymphocytes. During lymphopoiesis, CXCR4 is continuously expressed on the surface of B cells. However, its signaling profile changes inasmuch preB and proB cells migrate towards CXCL12, mobilize intracellular calcium and activate the small GTPases Rac1 and Cdc42, whereas mature B cells do not show these responses, albeit the cells retain the capability to migrate in response to CXCL13 and CCL21. By contrast, stimulation of B cells with CXCL12 at all stages of development results in the activation of the MAP-kinase cascade and in rapid CXCR4 internalization. The pathways leading to ERK1/2 activation are different in preB and mature B cell lines. In either case, ERK1/2 activation is pertussis toxin sensitive, but only in mature B-cells inhibition of PI3-kinase causes an almost complete block of ERK1/2 activation. Taken together, the results show that CXCR4 changes its coupling to downstream signal-transduction pathways in B cells, suggesting that receptor activity may depend on accessory proteins.