Glycomic regulation of human B cells
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AbstractAll leukocytes are coated with a dense layer of carbohydrates called the glycocalyx. Initially believed to serve largely biophysical roles, the glycocalyx is increasingly recognized as a gatekeeper of leukocyte interactions with the cellular microenvironment, in part by mediating specific contacts with carbohydrate-binding proteins (lectins). Far from inert bystanders, the carbohydrate moieties (glycans) decorating leukocyte glycoproteins are highly dynamic and undergo significant restructuring in different immunological contexts. On T cells, which confer cell-mediated immunity, activation and differentiation are known to induce global alterations in the T cell glycan repertoire (glycome) that regulate T cell survival and homing to inflamed tissues. Yet, for B cells, which confer humoral immunity, similar alterations to the glycome have not been extensively reported.
Here, we tested the hypothesis that glycomic changes associated with B cell differentiation are critical for normal B cell function. This hypothesis was tested in two related studies. In the first study, we profiled the repertoire of asparagine (N)-linked glycans expressed by B cells at multiple stages of differentiation, including naïve, germinal center (GC), and memory B cell stages. Results from this study revealed that while all B cells expressed N-glycans replete with lactosamine chains, these lactosamine moieties were modified with I-branches in GC B cells due to upregulation of the glycosyltransferase GCNT2. Functional studies revealed that I-branches served as a selective regulator of binding of a family of immunoregulatory lectins known as galectins. In the second study, the function of one of these galectins, galectin-9, was investigated in B cells. These studies revealed that galectin-9 was highly expressed by naïve B cells and bound the glycoprotein CD45. Mechanistically, galectin-9 promoted inhibitory signaling via the Lyn-CD22-SHP-1 pathway and ultimately attenuated B cell receptor-mediated calcium signaling and activation. Perturbation of B cell-intrinsic galectin-9 revealed that galectin-9 could serve as an autologous regulator of B cell receptor signaling. In all, our study highlights a novel glycomic mechanism regulating B cell activation, and opens new avenues of investigation into the roles of galectin-9 in B cell peripheral tolerance and autoimmune disease.
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