We use a mouse model in which a major placental cell type called trophoblasts express a model antigen – chicken ovalbumin – on their cell surface. Ovalbumin serves as a rejection antigen when expressed on donor organs in transplant settings. In contrast, trophoblast ovalbumin induces tolerance in ovalbumin-specific maternal T and B cells. We recently discovered that maternal B cell tolerance is at least partially mediated by the sialic acid-binding immunoglobulin-type lectin receptor (Siglec) CD22, and that trophoblast ovalbumin is decorated with glycans that are heavily sialylated. We are now poised to delineate the molecular underpinnings and in vivo phenotype of what we conceptualize as “glycosylation-dependent” antigen-specific B cell tolerance. Our current work in this area also tests the hypothesis that heavily sialylated tumor antigen induces B cell tolerance via engaging similar Siglec-dependent pathways.