LAUSR

The protein tyrosine phosphatase CD45 plays a crucial role in B cell antigen receptor (BCR) signaling by activating Src family kinases. Cd45−/− mice show altered B cell development and a phenotype likely due to reduced steady-state signaling; however, Cd45−/− B cells show relatively normal BCR ligation–induced signaling. In our investigation of how BCR signaling was restored in Cd45−/− cells, we found that the coreceptor CD22 switched from an inhibitory to a stimulatory function in these cells. We disrupted the ability of CD22 to interact with its ligands in Cd45−/− B cells by generating Cd45−/−St6galI−/− mice, which cannot synthesize the glycan ligand of CD22, or by treating Cd45−/− B cells in vitro with the sialoside GSC718, which inhibits ligand binding to CD22. BCR ligation–induced signaling was reduced by ST6GalI deficiency, but not by GSC718 treatment, suggesting that CD22 restored BCR ligation–induced signaling in Cd45−/− mature B cells by altering cellular phenotypes during development. CD22 was required for the increase in the surface amount of IgM-BCR on Cd45−/− B cells, which augmented signaling. Because B cell survival depends on steady-state BCR signaling, IgM-BCR abundance was likely increased by the selective survival of IgM-BCRhi Cd45−/− B cells because of CD22-mediated signaling under conditions of substantially reduced steady-state signaling. Because the amount of surface IgM-BCR is increased on B cells from patients with other BCR signaling deficiencies, including X-linked agammaglobulinemia, our findings suggest that CD22 may contribute to the partial restoration of B cell function in these patients. Description The inhibitory coreceptor CD22 drives a compensatory mechanism to restore signaling in immunodeficient B cells. Restoring B cell function The protein tyrosine phosphatase CD45 activates Src family kinases to mediate signaling downstream of the B cell antigen receptor (BCR) in response to antigens. In addition, antigen-independent, steady-state signaling by the BCR is important for B cell survival and development. Loss of CD45 alters the development and function of B cells in mice, but BCR ligation–induced signaling in these cells is normal. Akatsu et al. found that the inhibitory coreceptor CD22, which normally inhibits BCR ligation–induced signaling, paradoxically enhanced this pathway in B cells lacking CD45. In mice, CD22 signaling in CD45-deficient B cells resulted in an increase in the surface abundance of the IgM class of the BCR during their development. Such changes in IgM-BCR abundance are also seen in patients with immunodeficiencies. Together, these data suggest that CD22 stimulates a compensatory mechanism by which BCR ligation–induced signaling is partially restored in immunodeficient B cells.