CD22 (also known as Siglec-2) is a member of the Siglec family preferentially expressed in B cells. CD22 specifically recognizes α2,6 sialic acid by the extracellular lectin domain and recruits the protein tyrosine phosphatase SHP-1 at the cytoplasmic tail, thereby negatively regulating signaling through the B cell antigen receptor (BCR). CD22 constitutively interacts with multiple different sialylated endogenous ligands, mostly those expressed on the same cell (cis-ligands). Analysis using mice deficient in α2.6 sialic acid, and synthetic sialosides that inhibit ligand binding of CD22 revealed that ligand interaction of CD22 differentially regulates BCR ligation-induced signaling and tonic signaling, the low-level signaling generated by the BCR in the absence of ligation, probably because CD22 is regulated by different cis-ligands depending on the level of CD22 phosphorylation. This differential regulation is involved in quality control of signaling-competent B cells. Interaction of CD22 with ligands, especially BCR, lowers tonic signaling required for B cell survival, thereby removing signaling-incompetent cells during B cell development. In contrast, recognition of other CD22 molecules as a cis-ligand enhances signaling upon BCR ligation. Interaction of CD22 with multiple different sialylated ligands therefore plays a crucial role in the maintenance of efficient B cell responses to antigens.