Fucosylation

Abstract: Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen–antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate–carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions.

Abstract: There is much interest in developmentally regulated molecules which may have function in cell interactions and sorting during embryogenesis and differentiation. Numerous antisera have been raised which detect antigens that are expressed in early embryonic cells and become restricted during differentiation, being expressed in only a minority of adult cells (reviewed in refs 1–3). The precise antigenic determinants recognized by such antisera have not been defined. However, studies using a hybri-doma antibody against mouse spleen cells4 and monoclonal autoantibodies of patients with cold agglutinin disease5 have shown that two defined carbohydrate antigen systems, the Forssman and the li antigens, have stage-specific expression in early mouse embryos. We now describe evidence that the stage-specific embryonic antigen SSEA-1 (ref. 6) involves the carbohydrate sequence Galβ1 → 4GlcNAc ↑1,3 Fucα This determinant is formed by α 1 → 3 fucosylation of blood group I or i antigens which are branched or linear oligosaccharides, respectively7–9, built of Galβ1 →4GlcNAc units and known as type 2 precursor chains10 of the major blood group antigens. Thus, we introduce the concept of simple glycosylation changes as a basis for stage-specific expression of embryonic antigens.

Abstract: Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation.