The Glycoscience of Immunity

Abstract

Carbohydrates, or glycans, are as integral to biology as nucleic acids and proteins. In immunology, glycans are well known to drive diverse functions ranging from glycosaminoglycan-mediated chemokine presentation and selectin-dependent leukocyte trafficking to the discrimination of self and non-self through the recognition of sialic acids by Siglec (sialic acid-binding Ig-like lectin) receptors. In recent years, a number of key immunological discoveries are driving a renewed and burgeoning appreciation for the importance of glycans. In this review, we highlight these findings which collectively help to define and refine our knowledge of the function and impact of glycans within the immune response.

Figure I. The Human and Mouse Siglec Family

Siglec nomenclature is based on the human Siglecs, numbered 1 to 16 (Siglec-1, Siglec-2, etc.). The Siglecs conserved across humans and mice retain the number designation (Siglec-1, Siglec-2, Siglec-3, Siglec-4, and Siglec-15), although key differences in the domains of Siglec-3 renders it inhibitory in humans and activating in mice. Mouse Siglecs without a conserved counterpart in humans are given letter designations (Siglec-E, Siglec-F, Siglec-G, Siglec-H). Most Siglecs fall into an inhibitory category, carrying one or more ITIM sequences, while others are activating receptors in which their transmembrane domain contains a charged residue that leads to association with DAP12, which carries ITAMs. Siglec-1 has no defined ability to transmit signals, and contains an unusual number of Ig domains (16 in total), while Siglec-4 contains a cytoplasmic domain with a Fyn kinase phosphorylation site. Finally, several Siglecs are known by other names. Siglec-1 is also called sialoadhesin or CD169. Siglec-2 is also called CD22. Siglec-3 is also called CD33.

Figure 1

Examples of Glycan Function in the Immune System. (A) The ABO(H) and some of the Lewis blood group antigens are shown, illustrating their glycan structures. The Lewis antigens are also known to be sulfated in multiple patterns not shown. (B) The complement pathway is broken into the Classical, Alternative, and Lectin pathways. Shown is a very simplified schematic of where glycan binding by Mannose Binding Lectin (MBL) and Ficolin drives the lectin pathway of activation and cellular cytotoxicity. (C) Selectins are C-type Lectins which drive leukocyte trafficking to sites of infection and/or inflammation. The process of tethering, rolling, and ultimately adhesion to the endothelium is predominantly dependent upon sialyl-Lewis^X binding by selectins. Symbols: fucose, red triangles; galactose, yellow circles; N-acetylglucosamine, blue squares; N-acetylgalactosamine, yellow squares; sialic acid, red diamonds.

Figure 2

Highlighted Glycan-Influenced Pathways. (A) Recognition of MUC1 by Siglec-9 or GBS capsule by Siglec-E on macrophages leads to the differentiation into tumor-associated inhibitory macrophages (TAM) and reduces phagocytosis, respectively, leading to immune evasion. (B) CD22 is a Siglec that leads to B cell tolerance when ligated in trans while the B cell receptor (BCR) is also engaged, but can also function to promote adherence to high endothelial venules (HEV). (C) The sialyltransferase ST6Gal1 can sialylate Fc-localized IgG glycans outside of the B cell, within the blood stream, but the degree to which B cells also sialylate IgG in the Golgi apparatus prior to secretion remains debatable. (D) The binding of HIV broadly neutralizing antibody PGT145 requires both protein-protein and glycan-protein contacts with high mannose glycans present on the HIV envelope trimer (coordinates from PDB# 5v8l). Green spheres are mannose residues and blue cubes are N-acetylglucosamine (GlcNAc) residues. The image was created using VMD software with a GLYCAM plugin for glycan visualization and rendered in POV-Ray.