The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online 29 April 2002 doi:10.1084/jem.20011783
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© Rockefeller University Press, 0022-1007/2002/5/1207/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 9, May 6, 2002 1207-1213

Brief Definitive Report

The Ligand-binding Domain of CD22 Is Needed for Inhibition of the B Cell Receptor Signal, as Demonstrated by a Novel Human CD22-specific Inhibitor Compound

Soerge Kelm1, Judith Gerlach3, Reinhard Brossmer2, Claus-Peter Danzer3 and Lars Nitschke3

1 Centre for Biomolecular Interactions Bremen, University Bremen, Department for Biology and Chemistry, 28334 Bremen, Germany
2 Biochemistry Center Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany
3 Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany

Address correspondence to Lars Nitschke, Institute for Virology and Immunobiology, University of Würzburg, Versbacherstr.7, 97078 Würzburg, Germany. Phone: 49-931-201-49957; Fax: 49-931-201-49243; E-mail: nitschke{at}vim.uni-wuerzburg.de

CD22 is a B cell–specific transmembrane protein of the Siglec family. It binds specifically to {alpha}2,6-linked sialic acid (Sia) residues, which are also present on glycoproteins on the B cell surface. CD22 acts as a negative regulator in B cell receptor–mediated signaling by recruitment of Src homology 2 domain–containing tyrosine phosphatase (SHP)-1 to its intracellular tail. To analyze how ligand-binding of CD22 influences its intracellular signaling domain, we designed synthetic sialosides as inhibitors for the lectin domain of CD22. One of these compounds inhibited binding of human CD22-Fc to target cells over 200-fold better than Sia and was highly selective for human CD22. When Daudi cells or primary B cells were stimulated with anti-immunoglobulin (Ig)M in presence of this sialoside inhibitor, a higher Ca2+ response was observed, similar to CD22-deficient B cells. Accordingly, a lower tyrosine-phosphorylation of CD22 and SHP-1 recruitment was demonstrated in presence of the sialoside. Thus, by interfering with ligand binding of CD22 on the B cell surface, we have shown for the first time that the lectin domain of CD22 has a direct, positive influence on its intracellular inhibitory domain. Also, we have developed a novel low molecular weight compound which can enhance the response of human B cells.

Key Words: B lymphocytes • CD22 • Siglecs • sialic acid • Ca2+ flux


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