Galectin-Glycan Interactions as Regulators of B Cell Immunity

Abstract

Cell surface glycans and their glycan-binding partners (lectins) have generally been recognized as adhesive assemblies with neighbor cells or matrix scaffolds in organs and the blood stream. However, our understanding of the roles for glycan-lectin interactions in immunity has expanded substantially to include regulation of nearly every stage of an immune response, from pathogen sensing to immune contraction. In this Mini-Review, we discuss the role of the ß-galactoside-binding lectins known as galectins specifically in the regulation of B-lymphocyte (B cell) development, activation, and differentiation. In particular, we highlight several recent studies revealing new roles for galectin (Gal)-9 in the modulation of B cell receptor-mediated signaling and activation in mouse and man. The roles for cell surface glycosylation, especially I-branching of N-glycans synthesized by the glycosyltransferase GCNT2, in the regulation of Gal-9 binding activity are also detailed. Finally, we consider how dysregulation of these factors may contribute to aberrant immune activation and autoimmune disease.

Keywords: B cell activation; B cell receptor; B cells; GCNT2; I-antigen; I-branch; galectin.

Figure 1

Galectin-9 regulates B cell receptor signaling in human and murine B cells through analogous but distinct mechanisms. Naïve B cell activation is antagonized by Gal-9 through binding to the receptor tyrosine phosphatase CD45 on human B cells that activates a Lyn-CD22-SHP-1 dependent circuit and inhibits calcium accumulation downstream of the BCR [Left, orange asterisks (*)]. In murine B cells, Gal-9 similarly regulates BCR signaling by altering the nanoscale organization of signaling molecules. Specifically, Gal-9 has been found to bind CD45 but also IgM BCR, preventing exclusion of CD45 and CD22 upon B cell activation and leading to impaired signal transduction following BCR ligation [Left, blue asterisks (*)]. In humans, Gal-9 binding activity is differentially regulated between naïve and germinal center (GC) B cells via concerted alterations in N-glycosylation. Specifically, Gal-9 binding has been shown to be greatly diminished in germinal center (GC) B cells via upregulation of the glycosyltransferase GCNT2, which catalyzes I-branch formation on glycan ligands of Gal-9 (poly-LacNAcs), and attenuates Gal-9 binding (56, 57).

Figure 2

Galectins regulate B cell development, activation, and differentiation. Depicted are published roles of galectins at various stages of differentiation, as well as reported expression of galectins and galectin-binding glycans. Orange asterisks (*) indicate findings described in human B cells, and blue asterisks (*) indicate findings observed in mice. Bone marrow B cells (–34, 37, 60); naïve B cells (38, 43, 45, 56, 57); anergic B cells (37, 68); GC B cells (45, 51); memory B cells (, , –50, 58); plasmablasts and plasma cells (37, 39, 59, 60).