Siglecs and B Cell Regulation

Abstract

Sialic acid-binding immunoglobulin-like lectins (Siglecs) constitute a family of mammalian membrane proteins mostly expressed in immune cells. Most of the members contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region and negatively regulate cell activation. B lymphocytes (B cells) express a few members of the Siglec family, among which, CD22 has been the most extensively studied. CD22 negatively regulates signaling through B cell antigen receptor (BCR) by recruiting SH2-containing protein tyrosine phosphatase 1 (SHP-1) at the ITIMs, thereby inhibiting B cell activation. Although CD22 recognizes a2,6 sialic acids, CD22 regulates B cell responses to antigens regardless of whether they contain sialic acids. Ligand recognition rather plays a role in interaction of CD22 with the sialic acid-containing molecules expressed on B cells (cis ligand), which regulate signal inhibitory function of CD22. Human and mouse CD22 prefer distinct forms of a2,6 sialic acid. Human and mouse CD22 prefer 6-sulfo-Nacetyllactosamine-containing a2,6 sialylated and Neu5Gc-containing glycans, respectively. Interestingly, these specific ligands are not expressed in B cells in the germinal center (GC) in which antigen-activated B cells extensively proliferate and differentiate to memory B cells and long-lived plasma cells to establish immunological memory. Lack of preferred ligand for CD22 may regulate signaling and activation of GC B cells. B cells also express other Siglecs such as Siglec10. Siglec10 negatively regulates B cell activation especially in B-1 cells, which constitute a distinct B cell subset located in peritoneal and pleural cavities and involved in first line of defense by secreting polyreactive antibodies. Thus, Siglec-mediated B cell regulation is regulated in a manner dependent on B cell subpopulations and their differentiation stages.