Extracellular ST6Gal-1 calibrates B cell IgG production by cell non-autonomous extrinsic sialylation

Abstract

Abstract Cell surface glycans are well-positioned to modify receptor interactions and their downstream biological outcomes. Although canonical glycosylation occurs intracellularly, glycosyltransferases also exist in the blood and can catalyze extracellular reactions with platelet-derived sugars. We have recently reported that such extrinsic glycosylation by the sialyltransferase ST6Gal-1 enhances survival and BCR signaling in immature B cells. Here, we report that mice lacking extrinsic ST6Gal-1 had reduced total and antigen-specific IgG after bone marrow transplantation, despite unaltered IgG half-life and reconstitution of mature B cells and plasma cells. Rather, this deficiency was accompanied by reduced IgG+ splenic B cells and impaired per-cell IgG secretion after BCR stimulation. In vitro, extrinsic sialylation of immature B cells with recombinant ST6Gal-1 enhanced expression of IgM, IgD, and CD86, and potentiated IgG production upon stimulation. Surprisingly, this was not associated with increased IgG germline transcripts or isotype switching, but more robust antigen-induced proliferation, generating more IgG-producing cells. In vivo, hydrodynamic transfection with St6gal1 DNA resulted in an increase in total serum IgG. Finally, infusion of recombinant ST6Gal-1 enlarged splenic follicles and the follicular B cell population, highlighting therapeutic potential in modifying B cell development. Currently, vaccine adjuvants rely on mechanical or inflammatory properties to trigger an immune response. Our results suggest the manipulation of a bloodborne sialyltransferase may be a novel B cell-targeted, biological strategy to boost vaccine-induced and overall IgG production.