Abstract
Migration of B cells within lymphoid follicles is controlled by the chemokine receptors CXCR5 and CCR7 and the G-protein-coupled receptor EBI2 (GPR183). Whereas CXCR5 and CCR7 are known to mediate migration toward their respective chemokine ligands, it is unclear whether EBI2 acts by modulating these processes or by directly mediating chemotaxis toward its own spatially restricted ligand. It is also unknown how signals from these three receptors are integrated to control B cell localization. To answer these questions, we generated compound knockout mice deficient in expression of EBI2, CXCR5, or CCR7. Analysis of these mice revealed that EBI2 mediates B cell migration toward the outer areas of follicles and to bridging channels of the spleen independent of both CXCR5 and CCR7. Migratory signals delivered by EBI2 were shown to control B cell organization within the spleen and to be particularly important for positioning activated B cells in the early stages of Ab responses. An additional minor role for EBI2 was identified in the organization and affinity maturation of B cells in germinal centers. Thus, EBI2-mediated chemotaxis provides a third dimension to B cell migration that balances and integrates with the inputs from CXCR5 and CCR7 to determine B cell positioning.