CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor.

Mature B cells coexpress both IgM and IgD B-cell antigen receptor (BCR) classes, which are organized on the cell surface in distinct protein islands. The specific role of the IgD-BCR is still enigmatic, but it is colocalized with several other receptors on the B-cell surface, including the coreceptor CD19. Here, we report that the chemokine receptor CXCR4 is also found in proximity to the IgD-BCR. Furthermore, B cells from IgD-deficient mice show defects in CXCL12-mediated CXCR4 signaling and B-cell migration, whereas B cells from IgM-deficient mice are normal in this respect. CXCR4 activation results in actin cytoskeleton remodeling and PI3K/Akt and Erk signaling in an IgD-BCR-dependent manner. The defects in CXCR4 signaling in IgD-deficient B cells can be overcome by anti-CD19 antibody stimulation that also increases CXCL12-mediated B-cell migration of normal B cells. These results show that the IgD-BCR, CD19, and CXCR4 are not only colocalized at nanometer distances but are also functionally connected, thus providing a unique paradigm of receptor signaling cross talk and function.