Glycobiology of immune responses

Abstract

Unlike their protein "roommates" and their nucleic acid "cousins," carbohydrates remain an enigmatic arm of biology. The central reason for the difficulty in fully understanding how carbohydrate structure and biological function are tied is the nontemplate nature of their synthesis and the resulting heterogeneity. The goal of this collection of expert reviews is to highlight what is known about how carbohydrates and their binding partners-the microbial (non-self), tumor (altered-self), and host (self)-cooperate within the immune system, while also identifying areas of opportunity to those willing to take up the challenge of understanding more about how carbohydrates influence immune responses. In the end, these reviews will serve as specific examples of how carbohydrates are as integral to biology as are proteins, nucleic acids, and lipids. Here, we attempt to summarize general concepts on glycans and glycan-binding proteins (mainly C-type lectins, siglecs, and galectins) and their contributions to the biology of immune responses in physiologic and pathologic settings.

Figure 1

Schematic of the N- and O-linked glycosylation pathway in mammals. (Top) The asparagine (N)-linked pathway begins in the endoplasmic reticulum (ER), where OST (oligosaccharyltransferase) moves the core N-glycan from the dolichol precursor to an asparagine residue with the N-X-S/T consensus sequence. This structure is trimmed by glucosidases (Glc I and Glc II) within the ER, which assist in the folding quality control system mediated by the calnexin/calreticulin pathway. Once released from this quality control, the nascent glycoprotein traffics to the Golgi apparatus where further trimming occurs initially, which is then followed by the creation of significant diversity through addition of other saccharides by a variety of transferases (“T” in the abbreviations) in a nontemplate-driven process. Another key addition are 2,3-linked and 2,6-linked terminal sialic acids, which are critical for a number of biological functions. Finally, the LacNAc disaccharide unit (N-acetyllactosamine) is a key recognition site for a number of glycan-binding molecules, including some of the galectin family. (Bottom) The serine/threonine (O)-linked glycosylation pathway is distinct from the N-linked pathway in a number of ways. The nature of the linkage and the enzymes involved are separate, and the resulting structures are quite divergent, although some similarities exist, such as the presence of the LacNAc unit. The O-linked glycans are broken down into core subgroups and carry names like “Tn antigen” and “Sialyl-Lewis^x” that are common in the literature. These have been labeled for reference.

Figure 2

Lectin-glycan interactions in innate immunity: Discrimination of non-self, altered-self, and self by antigen-presenting cells (APCs). GBPs (e.g., DC-SIGN, Dectin-1, siglec-1, galectin-3 (Gal-3), galectin-9 (Gal-9)) can function as pattern recognition receptors (PRR) through the recognition of non-self glycans exposed on different pathogens, including viruses, bacteria, yeasts, and parasites. In particular those CLRs with glycan specificity for Lewis and mannose glycans (such as DC-SIGN) have been shown to bind a multitude of pathogens such as HIV-1 and other viruses, bacteria such as Mycobacterium tuberculosis and Helicobacer pylori, helminths such as Schistosoma mansoni, and yeasts such as Candida albicans. On the other hand, Gal-3 and Gal-9 play key roles as soluble PPRs by discriminating Leishmania species. Also, CLRs (e.g., MGL, DC-SIGN) can detect changes in glycosylation of certain tumor-associated antigens, such as the carcinoma embryonic antigen (CEA) and MUC1 occurring during onco-transformation and tumor progression. These changes include increased expression of the Lewis blood group family of antigens, particularly Le^x, and Le^y, that are often associated with poor prognosis of the tumor. This recognition allows antigen internalization, presentation to CD4⁺ T cells, cross-presentation to CD8⁺ T cells, and potentiation of antitumor immunity, although in some cases these interactions can also lead to inhibition of T cell responses. In addition, GBPs may play important roles in self-recognition in a variety of cellular processes, including (among others) cell adhesion (DC-SIGN-ICAM1/3 interactions), T cell signaling (MGL interactions with GalNAc-expressing CD45 glycoforms), discrimination of danger signals (interactions among siglec-G, CD24, and the HMGB1 alarmin), and modulation of immunogenic or tolerogenic APC programs (e.g., interactions between galectins and APC glycoproteins, such as Tim-3 and CD43).