Roles of membrane-bound lectins in the regulation of immune cells.

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CD22 is a member of the siglec family and specifically recognizes a2,6 sialic acid, whereas CD72 contains a C-type lectin domain. These membrane-bound lectin molecules contain the immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region. Upon phosphorylation, these ITIMs recruit and activate the SH2 domain containing tyrosine phosphatase 1 (SHP1), thereby down-regulate BCR signaling. We demonstrated that CD22-mediated signal regulation depends on the immunoglobulin isotypes of BCR. Indeed, CD22 negatively regulates signaling through IgM-BCR, IgD-BCR and IgA-BCR, but not signaling through IgG-BCR or IgE-BCR. In the absence of CD22-mediated signaling inhibition, IgG-BCR and IgE-BCR transmit augmented signaling, which may be involved in rapid antibody production in memory responses. The cytoplasmic regions of membrane form of IgG and IgE are involved in abrogation of CD22-mediated signal inhibition. In contrast, CD72 regulates BCR signaling regardless of Ig isotypes. SHP-1 contains two SH2 domains, and at least two out of tree ITIMs in CD22 are suggested to be essential for recruitment of SHP-1. We demonstrated that one ITIM is sufficient for recruitment of SHP-1 to CD22 and CD22-mediated signal regulation. Moreover, tyrosine at the position 783 locating in an ITIM appears to regulate phosporylation of other tyrosines in the cytoplamic region of CD22. These findings are crucial for elucidation of the function of membrane-bound lectins, and development of new strategies for controlling B cell function.