CD22 serves as a receptor for soluble IgM

Abstract

CD22 (Siglec-2) is a B-cell membrane-bound lectin that recognizes glycan ligands containing a2,6-linked sialic acid (a2,6Sia) and negatively regulates signaling through the B-cell Ag receptor (BCR). Although CD22 has been investigated extensively, its precise function remains unclear due to acting multiple phases. Here, we demonstrate that CD22 is efficiently activated in trans by complexes of Ag and soluble IgM (sIgM) due to the presence of glycan ligands on sIgM. This result strongly suggests sIgM as a natural trans ligand for CD22. Also, CD22 appears to serve as a receptor for sIgM, which induces a negative feedback loop for B-cell activation similar to the Fc receptor for IgG (FccRIIB).Key words: B cells . CD22 . Fc receptor . IgM . Siglec-2 Supporting Information available online Introduction CD22 is a 140 kDa glycoprotein on the surface of B cells that negatively regulates signaling through the B-cell Ag receptor (BCR) [1][2][3]. There are six tyrosine residues within the cytoplasmic portion of CD22, four of which are located within ITIMs [4]. These tyrosine residues are phosphorylated upon BCR cross-linking, leading to recruitment of SHP-1 [4,5]. SHP-1 subsequently dephosphorylates the BCR-proximal signaling molecules, resulting in downmodulation of BCR signaling. Consistent with this, B cells from CD22-deficient mice are hyperactive [6][7][8][9]. The extracellular portion of CD22 is composed of seven immunoglobulin (Ig)-like domains, the most distal of which is a V-set Ig-like domain that recognizes a2,6-linked sialic acid (a2,6Sia)-containing glycoconjugates [3,10]. a2,6Sia is common at the terminal of N-linked glycans and is abundantly expressed on various kinds of cells, including erythrocytes, monocytes, B cells, and T cells. a2,6Sia also exists on soluble plasma proteins such as serum-soluble IgM (sIgM) [11]. CD22 is a member of the sialic acid-binding Ig-like lectin (Siglec) family, Results and discussion sIgM binds to CD22 on the cells in a b-galactoside a2,6-sialyltransferase I-dependent manner Since sIgM has been shown to bind to recombinant CD22 fusion protein [11], we tested whether sIgM binds to CD22-expressing cells. The mouse myeloma line J558L fails to express the CD22 glycan ligand a2,6Sia at the terminal of N-glycan due to a lack of b-galactoside a2,6-sialyltransferase I (ST6GalI) expression. Introduction of a ST6GalI expression vector can restore a2,6Sia on cell-surface glycoproteins and we showed previously that the soluble CD22 fusion protein (CD22-Fc) bound to J558L cells expressing ST6GalI (J558L/ST6) but not to J558L cells [16]. Since sIgM has been identified as a potential glycan ligand for CD22 [11], we examined whether sIgM binds to these cells. (4-Hydroxy-3-nitrophenyl) acetyl (NP)-specific sIgM bound to Ag NP-PE (Ag/sIgM) was able to bind to CD22-expresssing (J558L/CD22) cells but not to CD22-deficient (J558L) cells (Fig. 1A). Double staining with anti-CD22 mAb is shown in Supporting Information Fig. 1. This binding was not prevented by the presence of FCS containing a2,6Sia,...

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