Abstract
CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause autoimmune diseases and blood cancers. Here we report the crystal structure of human CD22 at 2.1 Å resolution, which reveals that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin as a unique mode of recognition across sialic acid-binding immunoglobulin-type lectins. The CD22 ectodomain adopts an extended conformation that facilitates concomitant CD22 nanocluster formation on B cells and binding to trans ligands to avert autoimmunity in mammals. We structurally delineate the CD22 site targeted by the therapeutic antibody epratuzumab at 3.1 Å resolution and determine a critical role for CD22 N-linked glycosylation in antibody engagement. Our studies provide molecular insights into mechanisms governing B-cell inhibition and valuable clues for the design of immune modulators in B-cell dysfunction.
Highlights
CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check
The biology of sialic acid (Sia) ligands binding to CD22 is complex; for example, it remains unclear how the availability of Sia ligands in their various glycoforms modulate CD22 function, in both health and disease
Two common animal Sias exist: Neu5Ac and Neu5Gc. They differ by a hydroxyl at the 5′-position that is irreversibly added to Neu5Ac by cytidine monophospho-N-acetyl neuraminic acid hydroxylase (CMAH)[36]
Summary
CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. Sialic acid-binding immunoglobulin-like lectin (Siglec) receptors are a family of 14 cell surface transmembrane proteins that bind to sialic acid (Sia)-containing glycans, facilitating cell adhesion and/or cell signaling[1]. Siglecs are found primarily in vertebrates on a wide range of immune cells including granulocytes, neutrophils, monocytes, dendritic cells, eosinophils, mast cells, T cells, and B cells[2] Their functions are determined by their cellular distribution and ligand specificity. Cell surface sialylated glycans can be modified, typically at the 4, 6, 7, or 9 hydroxyl positions, which can alter their binding specificities to CD227, 8. Some of these changes are associated with cellular dysregulation. Constitutive CD22 clathrin-mediated endocytosis[20] allows for the targeted
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