CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1

Recognition of antigen by the B cell antigen receptor (BCR) determines the subsequent fate of a B cell and is regulated in part by the involvement of other surface molecules, termed coreceptors. CD22 is a B cell-restricted co receptor that gets rapidly tyrosyl-phosphorylated and recruits various sign aling molecules to the membrane following BCR ligation. Although CD22 conta ins three immunoreceptor tyrosine-based inhibitory motifs (ITIMs), only the two carboxyl-terminal ITIM tyrosines are required for efficient recruitmen t of the SHP-1 phosphatase after BCR ligation. Furthermore, Grb2 is inducib ly recruited to CD22 in human and mu- rine B cells. Unlike SHP-1, Grb2 recr uitment to CD22 is not inhibited by specific doses of the Src family kinase -specific inhibitor PP1. The tyrosine residue in CD22 required for Grb2 rec ruitment (Tyr-828) is distinct and independent from the two ITIM tyrosines required for efficient SHP-1 recruitment (Tyr-843 and Tyr-863). Individuall y both Lyn and Syk are required for maximal phosphorylation of CD22 followi ng ligation of the BCR, and together Lyn and Syk are required for all of th e constitutive and induced tyrosine phosphorylation of CD22. We propose tha t the cytoplasmic tail of CD22 contains two domains that regulate signal tr ansduction pathways initiated by the BCR and B cell fate.