Lectins as pattern recognition molecules: The effects of epitope density in innate immunity

Glycobiology vol. 20 no. 3 pp. 270–279, 2010 doi:10.1093/glycob/cwp186 Advance Access publication on November 24, 2009 REVIEW Lectins as pattern recognition molecules: The effects of epitope density in innate immunity∗ Tarun K Dam and C Fred Brewer1 Department of Molecular Pharmacology and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA Received on October 20, 2009; revised on November 19, 2009; accepted on November 19, 2009 The innate immune response of multicellular organisms is initiated by the binding of soluble and membrane-bound host molecules including lectins to the surface of pathogenic organisms. Until recently, it was believed that the epitopes recognized by host molecules were uniquely associated with the pathogenic organisms. Hence, the term pattern recognition receptors (PRRs) was used to describe their binding specificities. However, with an expanding number of lectin classes including C-type lectins, siglecs, and galectins recognized as PRRs, it is apparent that many of the glycan epitopes recognized on foreign pathogens are present in the host and involved in cellular functions. Hence, the molecular basis for pattern recognition by lectins of carbohydrate epitopes on pathogens is in question. A number of studies indicate that the density and number of glycan epitopes in multivalent carbohydrates and glycoprotein receptors determine the affinity of lectins and their effector functions. This paper reviews lectins that are involved in innate immunity, mechanisms of enhanced affinity and cross-linking of lectins with density-dependent glycan epitopes, density-dependent recognition of glycan receptors by lectins in host systems and lectin–glycan interactions in foreign pathogens. Evidence indicates that lectin pattern recognition in innate immunity is part of a general mechanism of density-dependent glycan recognition. This leads to a new definition of lectin receptor in biological systems, which considers the density and number of glycan epitopes on the surface of cells and not just the affinity of single epitopes. Keywords: epitope density/glycans/immunosurveillance/innate immunity/lectins Introduction The innate immune response of metazoans involves binding of soluble and membrane-bound host molecules to the surface of pathogenic organisms including viruses, bacteria, parasites, and fungi. These interactions can lead to signaling for further immune responses or neutralization of the infectivity of the whom correspondence should be addressed: Tel: +1-718-430-2227; Fax: +1-718-430-8922; e-mail: ∗ Dedicated to the memory of George A. Orr and Carol K. Demitz 1 To pathogen (van Kooyk and Rabinovich 2008; Vasta 2009). Host molecules involved in innate immunity include glycan binding receptors (lectins), Toll-like receptors (some of which recognize glycans), nucleotide-binding oligomerization domains (NODs) and NK cell receptors (Medzhitov and Janeway 2000, Vasta 2009). Until recently, innate immune receptors were believed to recognize epitopes uniquely associated with pathogenic organisms (Medzhitov and Janeway 2002). Hence, the term pathogenassociated molecular patterns (PAMPs)1 was used to describe these epitopes (Medzhitov and Janeway 2002). In turn, pattern recognition receptors (PRRs) are used to describe host molecules that recognize PAMPs (Medzhitov and Janeway 2000). However, with an expanding number of lectin classes including C-type lectins, siglecs, and galectins recognized as PPRs (van Kooyk and Rabinovich 2008; Vasta 2009), it is apparent that many of the glycan epitopes recognized on foreign pathogens are present in the host and involved in functions that include development, immune regulation and homeostasis (Marth and Grewal 2008; Varki et al. 2009). Therefore, the molecular basis for pattern recognition of carbohydrate epitopes on pathogens and hosts by lectins is in question. Recent studies have shown that the density and number of glycan epitopes in multivalent carbohydrates and glycoprotein receptors are important determinants of the binding and crosslinking activities of lectins and their effector functions. This paper provides a review of lectins that are involved in innate immunity, mechanisms of enhanced affinity and cross-linking activity of lectins with density-dependent glycan epitopes, densitydependent recognition of glycan receptors by lectins in host systems and lectin–glycan interactions in foreign pathogens. The molecular basis for pattern recognition by lectins in innate immunity is discussed in terms of density-dependent glycan recognition. Lectins in innate immunity At least three classes of lectins, C-type lectins, siglecs, and galectins, are described as PRRs in the literature (Vasta 2009). C-type lectins are calcium-dependent proteins and comprise a large number of receptors (60–80) that are divided into subfamilies (Zelensky and Gready 2005). Most C-type lectins possess more than one carbohydrate recognition domain (CRD) and hence are multivalent receptors (Drickamer 1993). The majority of C-type lectins are membrane-associated receptors, while a subclass of C-type lectins, the collectins, is soluble molecules. The specificity of C-type lectins can be generally divided into two categories: (1) the mannose (Man)-specific C-type lectins, such as DC-SIGN, that possess specificity for Man- and/or fucose (fuc) terminated glycans, (2) and galactose (Gal)-specific c The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:  270 Epitope density in immune recognition C-type lectins, such as macrophage galactose lectin, that recognize Gal- and N-acetylgalactosamine (GalNAc) terminated glycans (Weis et al. 1998). The Man-specific C-type lectins are known to bind to multivalent N-linked high mannose and Fuc-containing oligosaccharides possessing the Lewisa,b,x,y determinants, while the Gal-specific C-type lectins bind to multivalent glycans possessing GalNAc residues (van Kooyk and Rabinovich 2008). These glycan structures are expressed in mammalian glycoproteins such as the intracellular adhesion molecule ICAM-2, ICAM-3, Mac-1, carcinoembryogenic antigen (CEA), CEA-related cell adhesion molecule (CEACAM1), butyrophilin, CD45, and human milk bile-salt stimulated lipase (BSSL) (van Kooyk and Geijtenbeek 2003). Many of these glycan epitopes are also found in pathogens such as the N-linked high mannose oligosaccharides in yeast, viral glycoproteins, Leishmania pifanoi lipophosphoglycans, the di- and tri-Man structures of ManLAM in Mycobacteria tuberculosis, and Lewisx glycan structures in Helicobactor pylori and Schistosoma mansoni (van Kooyk and Geijtenbeek 2003). Affinity increases of C-type lectins for polyvalent displays of specific glycans have been posited for their binding to glycan receptors involved in pathogen and self-recognition (Feinberg et al. 2007; van Kooyk and Rabinovich 2008; Garcia-Vallejo and van Kooyk (...truncated)