CD22(Siglec-2) and regulation of its glycan ligand expression
	CD22 CD22/Siglec-2 is a member of the Siglec family lectin(1) expressed on the surface of B cells. The extracellular domain of CD22 prominently recognizes the 2,6-linked sialylated glycan as a cis-ligand, which is expressed on the surface of the same cell. The intracellular cytoplasmic domain of CD22 has ITIM (immunoreceptor tyrosine inhibitory motif), which often negatively regulate the signal transduction by recruiting SH2 domain containing the tyrosine phosphatase SHP-1 upon phosphorylation. As a result, CD22 is thought to negatively regulate B cell receptor signaling (Figure 1).
Fig.1
	Glycan ligand for CD22 CD22 recognizes the Sia (sialic acid) 2,6-LacNAc (N-aceyllactosamine) structure. This glycan is biosynthesized by the action of sialyltransferase ST6Gal I in B cells. Mouse CD22 prefers N-glycolylneuraminic acid (Neu5Gc) for Sia species whereas human CD22 binds both Neu5Gc and N-acetylneuraminic acid (Neu5Ac) equally. CD22 ligand binding is also sensitive to 9-O-acetylation of the Sia molecule, which is another common modification of Sia that blocks the recognition by masking the Sia molecule(2). Recently, it has been suggested that the carrier protein of the CD22 ligand is CD22 itself for cis-ligand(3). Taken together, CD22 ligand expression could be regulated by Sia modification reaction, de-modification reaction, sialyltransferase reaction and carrier protein expression.
	Regulation of CD22 ligand expression Biochemical characteristics of CD22 cis-ligand on B cells have been addressed as stated above. However, it was not known how the ligand expression of CD22 is regulated in the events, such as activation, that affect B cell fate. Recently, it was shown that CD22 ligand expression is specifically repressed in the germinal center B cells that are undergoing rapid activation-dependent proliferation, somatic hyper-mutation and class-switch recombination. Among the enzymes involved in the biosynthetic pathway enzymes for CD22 ligand formation, the CMP-Neu5Ac hydroxylase reaction that gives rise to CMP-Neu5Gc in the cytosol, was specifically suppressed in the activated B cells(4) (Figure 2). Therefore, CD22 ligand expression is not static, but rather a regulated event duration of the B cell activation. Consistently, it was reported that CD22 is unmasked from cis-ligand when human B cells are activated(5).
Fig.2
	Function of CD22 ligand Functional aspects of the CD22 ligand were addressed using a mouse system. St6gal1 knockout mouse lost the CD22 ligand on splenocytes and had attenuated calcium influx upon BCR ligation(6). This attenuation was canceled in the double knockout B cells with Cd22(7), indicating either that CD22 had a dominant effect on calcium influx or that CD22 is required for the attenuation of calcium influx caused by St6gal1 deletion. When the ligand-binding domain of CD22 was mutated in the genome, mutant Cd22 knock-in mouse B cells showed no significant change in the calcium influx upon BCR ligation(8). Therefore, the event in which the CD22 ligand is involved in the CD22 function of B cell biology remains in debate and requires more defined experiments to figure out the properness of the currently existing model.
	Hiromu Takematsu (Graduate School of Biostudies, Kyoto University)
	References (1) Crocker, P. R. & Varki, A. (2001) Siglecs in the immune system. Immunology.,103, 137-45. (2) Sjoberg, E. R., Powell, L. D., Klein, A. & Varki, A. (1994) Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids. J Cell Biol.,126, 549-62. (3) Han, S., Collins, B. E., Bengtson, P. & Paulson, J. C. (2005) Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking. Nat Chem Biol.,1, 93-97. (4) Naito, Y., Takematsu, H., Koyama, S., Miyake, S., Yamamoto, H., Fujinawa, R., Sugai, M., Okuno, Y., Tsujimoto, G., Yamaji, T., Hashimoto, Y., Itohara, S., Kawasaki, T., Suzuki, A. & Kozutsumi, Y. (2007) Germinal Center Marker GL7 Probes Activation-Dependent Repression of N-Glycolylneuraminic Acid, a Sialic Acid Species Involved in the Negative Modulation of B-Cell Activation. Mol Cell Biol.,27,3008-22. (5) Razi, N. & Varki, A. (1998) Masking and unmasking of the sialic acid-binding lectin activity of CD22 (Siglec-2) on B lymphocytes. Proc Natl Acad Sci USA.,95, 7469-74. (6) Hennet, T., Chui, D., Paulson, J. C. & Marth, J. D. (1998) Immune regulation by the ST6Gal sialyltransferase.Proc Natl Acad Sci U S A.,95, 4504-9. (7) Collins, B. E., Smith, B. A., Bengtson, P. & Paulson, J. C. (2005) Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling.Nat Immunol.,7, 199-206. (8) Poe, J. C., Fujimoto, Y., Hasegawa, M., Haas, K. M., Miller, A. S., Sanford, I. G., Bock, C. B., Fujimoto, M. & Tedder, T. F. (2004) CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms. Nat Immunol.,5, 1078-87.
May 11, 2007