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J Immunol. 2018 Feb 1;200(3):949-956. doi: 10.4049/jimmunol.1701257. Epub 2017 Dec 29.

Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens.

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Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037; and.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.


CD22 and sialic acid-binding Ig-like lectin (Siglec)-G are members of the Siglec family of inhibitory coreceptors expressed on B cells that participate in enforcement of peripheral B cell tolerance. We have shown previously that when a BCR engages its cognate Ag on a cell surface that also expresses Siglec ligands, B cell Siglecs are recruited to the immunological synapse, resulting in suppression of BCR signaling and B cell apoptosis. Because all cells display sialic acids, and CD22 and Siglec-G have distinct, yet overlapping, specificities for sialic acid-containing glycan ligands, any cell could, in principle, invoke this tolerogenic mechanism for cell surface Ags. However, we show in this article that C57BL/6J mouse RBCs are essentially devoid of CD22 and Siglec-G ligands. As a consequence, RBCs that display a cell surface Ag, membrane-bound hen egg lysozyme, strongly activate Ag-specific B cells. We reasoned that de novo introduction of CD22 ligands in RBCs should abolish B cell activation toward its cognate Ag on the surface of RBCs. Accordingly, we used a glyco-engineering approach wherein synthetic CD22 ligands linked to lipids are inserted into the membrane of RBCs. Indeed, insertion of CD22 ligands into the RBC cell surface strongly inhibited B cell activation, cytokine secretion, and proliferation. These results demonstrate that the lack of Siglec ligands on the surface of murine RBCs permits B cell responses to erythrocyte Ags and show that Siglec-mediated B cell tolerance is restricted to cell types that express glycan ligands for the B cell Siglecs.

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