Galectins and Immune Responses-Just How Do They Do Those Things They Do?

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Galectins and Immune Responses—Just How Do They Do Those Things They Do? Sandra Thiemann and Linda G. Baum Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095; email: [email protected], [email protected]

Annu. Rev. Immunol. 2016. 34:9.1–9.22

Keywords

The Annual Review of Immunology is online at immunol.annualreviews.org

lactosamine, glycan ligand, CRD, lattice, glycosyltransferase

This article’s doi: 10.1146/annurev-immunol-041015-055402

Abstract

c 2016 by Annual Reviews. Copyright All rights reserved

Galectins are a family of mammalian carbohydrate-binding proteins expressed by many cell types. Galectins can function intracellularly and can also be secreted to bind to cell surface glycoconjugate counterreceptors. Some galectins are made by immune cells, whereas other galectins are secreted by different cell types, such as endothelial or epithelial cells, and bind to immune cells to regulate immune responses. Galectin binding to a single glycan ligand is a low-affinity interaction, but the multivalency of galectins and the glycan ligands presented on cell surface glycoproteins results in high-avidity binding that can reversibly scaffold or cluster these glycoproteins. Galectin binding to a specific glycoprotein counterreceptor is regulated in part by the repertoire of glycosyltransferase enzymes (which make the glycan ligands) expressed by that cell, and the effect of galectin binding results from clustering or retention of specific glycoprotein counterreceptors bearing these specific ligands.

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INTRODUCTION


As a biologist, you work with galectins every day. You may not actively think about it, but galectins are involved in virtually every process in the immune system, from holding pre-B cells in a developmental niche in the bone marrow stroma (1) to regulating the strength of TCR signaling during thymocyte selection (2) to promoting or retarding the migration of neutrophils, monocytes, and dendritic cells across endothelium and through the extracellular matrix (3, 4) to controlling cytokine secretion and cytokine receptor signaling (5, 6) to enhancing or blocking pathogen recognition and host cell attachment (7) to activating or inhibiting T and B cell death (8–10). All of these functions, for all of these cell types, in all kinds of environments—how can a family of 15 carbohydrate-binding proteins do all of this? Other lectins important for immune function often have a much more circumscribed set of functions. For example, selectins tether circulating leukocytes to inflamed endothelium to initiate the process of leukocyte migration across vascular endothelial cells into tissues (11). Tolllike receptors that recognize pathogen-associated, glycan-containing molecular patterns such as lipopolysaccharide (LPS) and lipoteichoic acid send signals to mature inflammatory dendritic cells (12, 13). Transmembrane C-type lectins, including Dectin-1 and -2 and Mincle, recognize various types of danger signals both from microbial pathogens and from damaged or altered host cells (14). Soluble lectins like ficolins, collectins, and mannose-binding protein opsonize microbial pathogens (15). Siglecs regulate leukocyte activation (16, 17). In contrast, considering all of the functions that have been reported for galectins brings to mind Ajit Varki’s landmark review on the functions of oligosaccharides (18) and suggests a paraphrase: biological roles of galectins—all of the theories are correct. If galectins have such a wide range of functions in so many cell types and environments, one might ask (as was asked of me during a scientific conversation), “But what are the rules?” There are rules, but to understand the varied and intricate roles played by galectins in immunology, one must consider several factors. The first set of factors includes galectin structure and evolution, the glycan ligands recognized by galectins, and the multivalency of galectins. The second set of factors includes the types of cells that express and secrete various galectins, the types of cell surface glycoprotein counterreceptors recognized by these galectins, and all the effects galectins can have on the counterreceptors and the cells that are bound. Finally, we discuss effects of galectins in a physiologic context.

WHAT IS A GALECTIN? Galectins are defined by a common carbohydrate recognition domain (CRD) (19, 20). The galectin CRD is composed of two extended antiparallel β-sheets that fold into a β-sandwich structure (Figure 1a; 21). This β-sandwich creates the pocket in which glycan ligands bind. The galectin β-sandwich structure is a common structure—many viral glycan-binding proteins, such as the influenza hemagglutinin, rotavirus VP4, and corona virus spike N-terminal domain and hemagglutinin-esterase proteins, share the basic galectin structural fold, leading some investigators to suggest that these viral proteins originated from host lectin (22). The galectin β-sandwich motif is also found in many leguminous plant lectins, including peanut agglutinin (23). Within the CRD, there are several highly conserved amino acids critical for glycan binding that are termed the common carbohydrate-binding cassette (21, 24). First described in the 1970s as galactoside-binding lectins (25), these molecules were also called “galaptins” and S-type lectins (24), because several galectins, including galectin-1, have unpaired cysteines in the CRD and reduced thiol residues are essential to maintain the integrity of the binding site (8, 19). The family was named galectins, a term proposed in 1994 (24), because the minimal saccharide ligand for most galectins contains galactose in a β-linkage to an N-acetylglucosamine 9.2

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OH

b HO

O HO b1,4

HO

O OH


Galactose

HO

O OH NH O

N-acetylglucosamine

Lactosamine Synonyms: N-acetyl-D-lactosamine, Galβ1-4GlcNAc, LacNAc

Figure 1 Ribbon diagram of a dimeric galectin and the structure of the minimal galectin ligand lactosamine. (a) Two extended antiparallel β-sheets ( pink and green) fold into a β-sandwich binding pocket, creating the carbohydrate recognition domain (CRD), which binds glycan ligands. Lactose (red ) is inserted into each CRD. (Panel a obtained with permission from Z. Li and J.M. Rini and adapted from Reference 21) (b) Structure of lactosamine, a disaccharide consisting of galactose ( yellow circle) and N-acetylglucosamine (blue square).

residue, Gal-GlcNAc, also called lactosamine (lactose is a disaccharide of galactose and glucose) (Figure 1b; 26). However, the CRDs of various galectins differ in amino acid sequence outside of the conserved minimal set of residues involved in glycan recognition (19, 24, 27, 28), so that different galectin CRDs can preferentially recognize different glycan ligands. The fine glycan specificities of different CRDs contribute to the different effects that various galectins can have on a single cell type, as the preferred complex glycan ligands recognized by different galectins can be displayed on different glycoproteins (19, 29–31). Thus, galectin-1 and galectin-3 bind to glycans on CD45 on T cells, but galectin-9 does not (32, 33). Structurally, there are three subfamilies of mammalian galectins (Figure 2; 19, 34). The first family consists of galectins that are synthesized as monomers that can associate into noncovalent homodimers. Galectin-1 is the prototype member of this family. Most of the molecule is the βsandwich fold, and the dimerization occurs on the back of the CRD, away from the glycan-binding site. These galectins typically dimerize in an antiparallel manner. When in a dimer, the centers of the galectin-1 CRDs are roughly 50 A˚ apart, a distance that can influence the glycan types or structures that the dimer can cross-link (35). The second subfamily, called chimera-type galectins, consists only of galectin-3 in mammals. Galectin-3 is called a chimeric galectin because it has a C-terminal CRD and an extended Nterminal domain of about 120–160 amino acids, depending on the mammalian species (24, 36). Although galectin-3 can dimerize via interactions of the C-terminal CRD (37), it can also multimerize via interactions of the N-terminal domain (38), giving galectin-3 CRDs a relatively large space across which glycan ligands can be bound. Galectin-3 multimerization via the N-terminal domain results in pentamers, and the multimerization process is promoted by galectin-3 binding to multivalent glycan ligands on a surface (39), such as the cell surface. Thus, the extensive crosslinking of galectin-3 with glycan ligands on glycoproteins will be favored on the surface of a cell or on extracellular matrix, rather than in solution. The third subfamily consists of the tandem-repeat or bivalent galectins. These molecules have two distinct CRDs connected by a flexible peptide linker. Some tandem-repeat galectins, such www.annualreviews.org • Galectins and Immune Responses


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a

Prototype Galectin-1, -2, -5, -7, -10, -11, -13, -14, -15

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Chimera Galectin-3

Tandem-repeat Galectin-4, -6, -8, -9, -12

Figure 2 Schematic representation of the three groups of galectins. (a) Prototype galectins contain one carbohydrate recognition domain (CRD; top) and dimerize (bottom). (b) Chimera-type galectin-3 (top) contains one CRD and oligomerizes through its N terminus upon binding glycan ligands (bottom). (c) Tandem-type galectins contain two distinct CRDs (top) covalently linked through a flexible linker and can oligomerize via their N and C termini into large multimers (bottom).

as galectin-9, can be synthesized with peptide linkers of varying length (40), due to cell-specific alternative splicing of RNA encoding the linker domain (41). The two CRDs in dimeric galectins recognize overlapping but distinct sets of glycan ligands (42, 43), so that dimeric galectins may cross-link a variety of glycan ligands on different glycoproteins. A critical feature of galectins is that the molecules oligomerize, allowing binding of multiple glycan ligands on the same or a different glycoprotein (Figure 2) or glycolipid backbones. As mentioned above, the monomeric galectins can homo-oligomerize via the back sides of their CRDs, and the chimera-type galectins can pentamerize via their N-terminal domains. The tandem-repeat or bivalent galectins, with two related but distinct CRDs, can oligomerize in a fashion analogous to the homodimerization of monomeric galectins: association of the N-terminal CRD of one galectin with the N-terminal CRD of another galectin and association of the C-terminal CRD with another C-terminal CRD, so that bivalent galectins can form very large multimers containing numerous CRDs that can bind many ligands (imagine an extended scaffold structure of connected CRDs linking glycan ligands on multiple glycoproteins; 42–46).

WHERE ARE GALECTINS FOUND, AND HOW DO THEY GET OUT OF THE CELL? Galectins are synthesized in the cytosol on free ribosomes (47, 48). Once synthesized, galectins can stay in the cytosol and participate in protein-protein interactions to regulate intracellular events (19, 29). For example, galectin-12 associated with lipid droplets in adipocytes regulates lipolysis and insulin sensitivity (49, 50). Galectin-3 in the cytosol can prevent mitochondrial cytochrome C release and thus inhibit apoptosis (51), and galectin-3 can also bind cytosolic β-catenin to regulate Wnt signaling (52). Cytosolic galectin-8 is a danger receptor that targets damaged lysosomes and endosomes for autophagy (53). Both galectin-1 and galectin-3 can also traffic to the nucleus, where they may participate in pre-mRNA splicing or stabilize protein-DNA interactions to promote transcription (54, 55). With regard to immune cells, however, most studies have focused on the functions of galectins binding to cell surface glycoprotein or glycolipid receptors. But galectins are made in the cytosol and are not exported to the endoplasmic reticulum–Golgi secretory pathway (56, 57). It has been proposed that galectins do not enter the secretory pathway because the CRDs would bind so many 9.4

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glycoproteins that secretory pathway trafficking would be disrupted (30, 31), but this hypothesis has not been formally tested. So, how do galectins get secreted into the extracellular milieu? This pathway has been termed nonclassical secretion or leaderless secretion (30), and it is also used by some fibroblast growth factors and IL-1 (58, 59). This pathway may involve accumulation of galectins at the cytoplasmic side of the plasma membrane and release in vesicles or exosomes, or direct translocation across the plasma membrane by a poorly understood process (60, 61). Once outside the cell, galectins are largely retained in the vicinity of the cell, either by binding to glycan ligands on cell surface glycoproteins and glycolipids or by binding to glycan ligands on extracellular matrix glycoproteins surrounding the cell (27, 29, 30, 62, 63). Importantly, galectins can account for up to 1% of the total protein made by a cell (64), so secretion and retention around the cell can result in very high local concentrations of galectins: up to 40 mg/kg of wet tissue, or roughly micromolar concentrations (65). Although galectins typically remain tissue associated, increased production by cancer cells or release by damaged tissues can result in increased serum levels of galectins; this has been described for galectin-3 in thyroid and bladder cancer (66, 67) and galectin-3 in heart failure (68). Given that some galectins denature in the absence of glycan ligands (69), it is not clear that all circulating galectins have carbohydrate-binding activity—indeed, that might be potentially harmful, as galectins can agglutinate erythrocytes (25), which would be disastrous in the vasculature. However, the presence of inactive galectins in the serum or a change in their concentration in the serum can be a useful biomarker for inflammatory and neoplastic disease (70).

WHAT DO GALECTINS BIND? As mentioned above, the minimal glycan ligand for most mammalian galectins is the disaccharide lactosamine, Gal-β1,4GlcNAc (Figure 1b). However, this structure is really, only the minimal ligand—the Kd of galectin-1 for lactosamine is in the low micromolar range, which alone would not result in any biologically relevant interaction between a receptor and a ligand. In contrast, the Kd of biotin for avidin is 10−15 M (71) and the Kd of a high-affinity immunoglobulin for cognate antigen is about 10−12 M. But in a biological context, galectins do not bind soluble lactosamine disaccharides—they bind to lactosamine sequences on complex N-glycans and O-glycans on glycoproteins that can present numerous glycan branches. N-glycans can present lactosamine sequences on up to four parallel branches or, like O-glycans, on extended polylactosamine-containing branches (Figure 3a; 42, 44, 72, 73). This multivalent binding of the multivalent galectins leads to relatively high-avidity binding, as the individual affinities of each CRD for each glycan ligand are additive or even synergistic in a multimeric complex. Moreover, additional structural variation among glycans made by mammalian cells can significantly influence binding of various galectins. Some galectins tolerate a terminal sialic acid capping the lactosamine sequence, whereas others do not (74, 75), and some galectins, such as galectin3, have a more flexible CRD that can accommodate mannose-containing sequences in addition to lactosamine-containing sequences (76). The differing specificities of galectin CRDs are very evident from glycan array experiments performed by the Consortium for Functional Glycomics (Figure 4; http://www.functionalglycomics.org; 77). These glycan arrays are composed of approximately 600 glycans obtained from a variety of biological sources, each linked to the array via an amino linker. Even without knowing the structure of each of the hundreds of glycans displayed along the x-axis, it is clear from the relative binding data that different galectins have distinct patterns of recognition. Several methods to profile galectin-binding specificities for various glycans have been used. These include binding to immobilized glycans on the glycan arrays mentioned above (77) and to www.annualreviews.org • Galectins and Immune Responses


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a N-acetylgalactosamine N-acetylglucosamine Galactose -N-X-S/T

High mannose

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Asialo core 1

Sialylated core 1

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b tein

opro

lyc lar g

Surface glycoprotein A

Surface glycoprotein B

lu

acel

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Figure 3 Examples of N- and O-glycans found on glycoproteins. (a) N-glycans (left) are attached to asparagine (N) residues, whereas O-glycans (right) are attached to either serine (S) or threonine (T) residues. (b) Multivalent galectins (e.g., dimeric galectin-1, orange) bind lactosamine sequences on N- and O-glycans presented on cell surface glycoproteins. Galectins can bind glycans on the same glycoprotein counterreceptor; form intermolecular clusters of the same receptor (homotypic binding) or different receptors (heterotypic binding) on the cell surface; or bind glycans on cell surface proteins and extracellular proteins in solution, in the extracellular matrix or on adjacent cells.

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1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 191 201 211 221 231 241 251 261 271 281 291 301 311 321 331 341 351 361 371 381 391 401 411 421 431 441 451 461 471 481 491 501 511 521 531 541 551 561 571 581 591 601 611


1,000

Individual glycans (numbered 1- 611) Figure 4 Galectin family members preferentially bind different glycans. Analysis of human galectin-1 (top) and galectin-3 (bottom) binding to the Consortium for Functional Glycomics glycan array version 5.0. (For glycan structures, see http://www.functionalglycomics.org/static/consortium/resources/resourcecoreh16. shtml.) Note the differences in amplitude of the relative binding of galectin-1 or galectin-3 to each glycan on the array.

glycans linked to lipid linkers (78), as well as chromatographic approaches (79). These techniques are very useful for identifying candidate glycan ligands and for making educated guesses about how expression of various glycosyltransferases by a particular cell might create or mask specific glycan ligands. However, these approaches do not definitively identify which glycans on which glycoproteins can be bound by a galectin in a biological context. For example, galectin-1 has very poor affinity for asialo core 1 O-glycans, which are Galβ1,3-GalNAc disaccharides linked to hydroxyl residues on Ser or Thr residues (Figure 3a); in fact, there is no detectable binding of galectin-1 to this disaccharide on the Consortium for Functional Glycomics glycan array (80). However, these disaccharides are typically presented as clustered glycans on a glycoprotein backbone; many proteins, such as mucins, contain numerous Ser and Thr residues in extended peptide domains, and the addition of O-glycans to these clustered Ser and Thr residues contributes to the extended structure

www.annualreviews.org • Galectins and Immune Responses


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of these molecules. One abundant T cell mucin is CD43, which has approximately 80 Ser and Thr residues; CD43 can be decorated with only the short core 1 O-glycans or with core 2 O-glycans containing extended polylactosamine sequences (80, 81). From the glycan binding array data, one might expect that galectin-1 would bind only to CD43 decorated with core 2 O-glycans. However, to our surprise, galectin-1 also bound to CD43 decorated with core 1 O-glycans, which have only a slightly higher Kd (80). The presentation of up to 80 low-affinity core 1 O-glycan ligands on CD43 allows galectin-1 to bind with sufficient avidity to make CD43 decorated with core 1 O-glycans a biologically relevant glycoprotein counterreceptor for galectin-1 on T cells (80, 82). Conversely, CD45 also bears O-glycans, but on specific Ser and Thr residues at the folded N-terminal domain of the protein (81). If CD45 is decorated with core 2 O-glycans, galectin-1 can bind to CD45 via these glycans, but if CD45 is decorated only with core 1 O-glycans, there is insufficient avidity to detect galectin-1 binding (83). The creation of glycan ligands for galectins depends on the activities of various glycosyltransferases expressed by a particular cell (Figure 5; 84). As mentioned above, expression of some glycosyltransferases may promote creation of glycan ligands. For example, expression of core 2 N-acetylgalactosaminyltransferase (C2GnT), which initiates formation of polylactosamine chains on O-glycans, increases galectin-1 binding to cells (83, 85). Similarly, expression of Mgat5 N-acetylgalactosaminyltransferase (Mgat5), which initiates polylactosamine addition to tetraantennary N-glycans, promotes galectin binding (86). Conversely, addition of a single sugar to the lactosamine sequences recognized by galectins can mask the glycan ligand and prevent galectin binding. The clearest example of this effect is addition of a terminal sialic acid in an α2,6-linkage to the galactose residue on an N-glycan branch (87). Addition of sialic acid in this linkage causes the sialic residue to protrude up from where the galactose residue would interact with the CRD (Figure 1a), thus preventing glycan binding. In cultured T cells, overexpression of the enzyme that adds this sialic acid, β-galactosamide α-2,6-sialyltransferase 1 (ST6Gal1), prevents galectin-1 binding and thus death of the cells (88); similarly, expression of this enzyme by Th2 cells prevents galectin-1 binding and cell death (87). Masking with α2,6-linked sialic acid also prevents galectin-9 binding to glycan ligands and initiation of T cell death (89).


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WHY IS MULTIVALENCY IMPORTANT? As mentioned above, galectins typically exist as multimers, from the homodimers of galectin-1 to the pentamers of galectin-3 to the large multimers of tandem-repeat galectins, such as galectin-9 (Figure 2). As also mentioned above, cells do not display isolated glycan ligands for galectins on cell surface glycoproteins—the complex N-glycans and O-glycans attached to cell surface proteins can bear multiple lactosamine-terminated chains or polylactosamine chains that can bind multiple galectin CRDs (Figure 3). Importantly, the multivalency of the glycans on a glycoprotein can determine the outcome of galectin binding, driving either cell proliferation or cell cycle arrest depending on the number of glycans and the extent of glycan branching (90). Thus, with multivalent galectins and multivalent ligands, galectins can create cell surface scaffolds or lattices that cluster or bundle glycoprotein receptors into homotypic or heterotypic aggregates (Figure 3b; 5, 42, 44). The binding of multivalent galectins to glycan ligands on specific glycoproteins can also segregate these glycoproteins from binding partners on the cell surface. This is one of the effects of galectins on T cells: Galectin-3 segregates CD8 from CD3 to impair the ability of CD8 T cells to kill tumor target cells (91). Beyond clustering or segregating cell surface receptors, the scaffolding effect of galectins is critical for virtually all outcomes of galectin binding to cell surface glycoprotein receptors (19, 26, 27, 42, 44, 72, 73). On lymphocytes, epithelial cells, and neuronal cells, galectin binding to 9.8

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α2,3

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tetraantennary complex N-glycan

α2,6 sialylated complex N-glycan

Enzyme

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Mgat5

ST6Gal1

Galectin-1 binding

+

+

–

Figure 5 Glycosyltransferases that influence galectin-1 binding to glycan ligands. Galectin-1 binding can be promoted by the activity of the core 2 N-acetylgalactosaminyltransferase (C2GnT), which initiates formation of polylactosamine chains on O-glycans, and the activity of the Mgat 5 N-acetylgalactosaminyltransferase (Mgat5), which initiates the addition of polylactosamine to tetraantennary N-glycans. Conversely, addition of a terminal sialic acid in an α2,6-linkage by β-galactosamide α-2,6-sialyltransferase 1 (ST6Gal1) to the terminal galactose residue on an N-glycan branch inhibits galectin-1 binding to the underlying lactosamine sequence.

glycoproteins reduces cell surface turnover and increases their abundance on the cell surface by reducing either internalization or shedding (5, 92–95). This effect can increase receptor signaling, change the cell surface redox potential, or alter nutrient uptake by cells (44, 92). There are critical implications of this type of multivalent binding. First, although binding of a single galectin to a single glycan ligand is a low-affinity interaction, the summation of multivalent galectin binding to multivalent ligands results in overall high-avidity binding. Because the individual interaction of a single CRD with a single glycan has low-micromolar affinity, a CRD is frequently binding and releasing a glycan ligand, either rebinding to the same glycan or binding another one in the vicinity. This is like Velcro on shoes or a backpack, where numerous hooks connect to numerous loops to keep your shoes on or your backpack closed. Low-affinity/high-avidity binding means that the interaction is tunable and can be readily reversed (like unhooking Velcro to remove your shoes or open your backpack). Either the presentation of higher-affinity ligands or the modification of ligands with other sugars would unhook the individual Velcro loops. So the binding of a galectin to a glycan ligand is not a lock-and-key event but rather the sum of a series of short-term associations allowing modification of ligands to alter galectin binding to the cell surface. This is illustrated by the finding that the presence or absence of a single sugar in a specific linkage can prevent or allow galectin-1 binding to T cells (88). Galectin-1 binding and induction of apoptosis of a T cell line can be blocked simply by overexpressing the ST6Gal1 sialyltransferase enzyme, which adds sialic acid in a terminal α2,6-linkage to lactosamine and blocks binding of galectin-1 to the underlying lactosamine ligand. Similarly, galectin-1 kills Th1 but not Th2 cells that have cell surface α2,6-linked sialic acids. However, removal of sialic acid from the Th2 cell surface by treatment with neuraminidase resulted in susceptibility to galectin-1-induced cell death (87). In both cases, nothing but a change in cell surface glycosylation is required to change the status of a cell from death susceptible to death resistant. So the first set of factors for understanding how galectin binding regulates cell function are (a) galectins have a common CRD structure, but variations in amino acids in the CRD allow individual galectins to bind to distinct sets of glycan ligands; (b) multivalent galectins are secreted www.annualreviews.org • Galectins and Immune Responses


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from cells via a nonclassical pathway to bind multivalent glycan ligands displayed on cell surface– or matrix-associated glycoproteins; (c) low-affinity but high-avidity binding means that multivalent galectin-glycoprotein interactions are reversible and tunable; and (d ) creation or masking of glycan ligands can result from regulated cell expression of specific glycosyltransferase enzymes.

WHAT CELL TYPES EXPRESS GALECTINS? Annu. Rev. Immunol. 2016.34. Downloaded from www.annualreviews.org Access provided by Orta Dogu Teknik Universitesi - Middle East Technical University on 02/24/16. For personal use only.

It appears that every cell type expresses at least one galectin. Even erythrocytes express their own galectin, galectin-5 (96). Little is known about the function of galectin-5, although it has been proposed to be important for sorting glycoprotein cargo into exocytic vesicles released by erythrocytes during maturation (97). Galectin-7 is largely expressed by stratified squamous epithelia (98), galectin-4 and -6 are primarily expressed in the gastrointestinal tract (99), and galectin-12 is expressed in adipocytes (49). Galectin-1, -3, and -9 are broadly expressed by many cell types, including cells of the immune system (3, 8, 19, 27, 29). In addition, there are a few galectins, e.g., galectin-10, that are expressed exclusively by cells of the immune system (19). Cells of the innate immune system are rich in galectins (3, 6, 8, 29, 31). Neutrophils express galectin-1, -3, -9, and -10, and basophils express galectin-3 and -10. Eosinophils express galectin9 as well as galectin-10, also known as Charcot-Leyden crystal protein. Although galectin-10 was initially thought to be granulocyte specific, a report described loss of galectin-10 expression in Treg cells that resulted in cell proliferation and loss of suppressive activity, suggesting that galectin-10 expression is important for the regulatory activity of Treg cells (100). A variety of functions have been described for granulocyte galectins, including cell activation, cell adhesion, and cell migration (29, 30, 101, 102). Galectin-1 and -3 can directly mediate granulocyte binding to extracellular matrix and to endothelial cells to regulate cell migration (3, 4), whereas galectin-9 has been reported to act as a chemotactic factor (40). Relatively little is known about the granulocyte receptors recognized by various galectins, although galectin-1 has been reported to bind to CD43 on neutrophils (103). Antigen-processing and antigen-presenting cells, i.e., macrophages and dendritic cells, also express multiple galectins, including galectin-1, -3, and -9 (3, 6, 8, 104–106). Galectin-3 was originally called Mac-2, as it was identified on macrophages (107). In macrophages, one function of galectin-3 is to promote phagocytosis of pathogens, including mycobacteria, fungi, and parasites (108). Macrophages, but not dendritic cells, express galectin-2, and galectin-2 binding induces a proinflammatory phenotype in monocytes and macrophages (109). Galectins regulate macrophage and dendritic cell activation, adhesion, and migration (3, 4, 8, 13, 30, 104–106, 110–112).

HOW CAN GALECTINS HAVE BOTH CIS AND TRANS EFFECTS ON CELLS? The work cited above describes expression of certain galectins by certain immune cell types. Clearly, there are instances when galectins stay in the cell of origin and have an intracellular function, such as galectin-12 regulating lipolysis in adipocytes (50, 113). But, as described above, many galectins, including galectin-1, -3, and -9, are secreted into the extracellular milieu, where the lectins bind glycan ligands on cell surface glycoproteins (on either the cell that made the galectin or another one nearby) and on extracellular matrix glycoproteins (7, 19, 27, 29, 30, 62). So it is entirely possible for a galectin to have an effect on a cell that does not make that particular galectin but is in the milieu of a neighboring cell that secretes the galectin. Indeed, given the very high local concentration of galectins secreted by adjacent cell types, such as endothelial cells, at sites of inflammation (3, 114–116), immune cells are often swimming in a sea of different galectins. 9.10

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Given the overlapping functions of some galectins and the ability of several galectins to recognize highly glycosylated and abundant cell surface glycoproteins, such as CD43 and CD45 (29, 32, 80, 81, 110, 117), it is very likely that there are gradients of different galectins in different tissue settings and that the final physiologic outcome will be the sum of the different galectins binding to cognate glycoproteins on various cell types.

WHAT MAKES A GLYCOPROTEIN A GALECTIN COUNTERRECEPTOR? As mentioned above, the minimal glycan ligand for galectins is the disaccharide lactosamine, which is found on every complex N-glycan, on several types of O-linked glycans (Figure 3a), and on some glycolipids (118, 119). Moreover, as we described for galectin-1 and CD43, if there are enough nonpreferred ligands, e.g., core 1 O-glycans (Galβ1,3GalNAc) on the extended mucin domain of CD43, these can act as physiologic receptors for a galectin (80). Thus, where is the selectivity and what are the rules? A critical concept to consider is that just because something can bind in one context does not mean it will bind in a physiologic context. Thus, when plasma membranes are solubilized in detergent and the plasma membrane glycoproteins are isolated by affinity chromatography on a galectin-conjugated matrix, many glycoproteins that are not significant binding partners may bind on the cell surface. On the cell surface, the presentation or accessibility of the glycan ligands may or may not be optimal to allow a galectin to bind. The glycoprotein may be of low abundance, so that other, more abundant glycoproteins compete for galectin binding on the cell surface. Or, on a given cell, there may be endogenous lectins, both galectins and other lectins such as siglecs, that preferentially bind a cell surface glycoprotein, so that other galectins are denied sufficient access. Even when a cell surface glycoprotein has abundant unoccupied glycans containing the appropriate saccharide ligands, why do some galectins bind some glycoproteins whereas others do not? An example mentioned above is the finding that galectin-1 and -3 both bind CD45 on T cells but galectin-9 apparently does not (32, 33). Likely, there are multiple features of the presentation of the abundant glycan ligands, including the proximity of the ligands along the protein backbone and the distance that the glycan extends from the protein backbone, that make some glycans fit only certain galectins. The monomeric galectins make relatively rigid homodimers, whereas the pentameric association of galectin-3 via the N-terminal peptide domains allows flexible binding of the C-terminal CRDs, and the extended lattices of tandem-repeat galectins, with their flexible peptide linkers, also allow flexible CRD binding (Figure 2; 26, 46). Construction of chimeric molecules with galectin-1 CRDs on a flexible galectin-9 peptide linker domain has demonstrated that, although glycan ligand preference is determined by the CRD, the valency of binding is determined by the galectin’s presentation as a rigid homodimer or a flexible bivalent molecule (43). Another relevant example of this type of spatial constraint regulating galectin binding is our finding that galectin-1 binding to trimeric fusion glycoproteins on an enveloped virus likely resulted in cross-linking of adjacent trimers rather than intratrimer binding (35). Can one predict if a glycoprotein will be a receptor for a galectin? Probably not, but several methods exist to identify glycoprotein counterreceptors for different galectins. Glycan microarrays, such as those offered by the Consortium for Functional Glycomics (http://www. functionalglycomics.org), are extremely useful for comparing binding patterns of different galectins and finding discrete modifications, such as addition of fucose or sialic acid in different linkages, that promote or prevent binding of different galectins. Knowledge of the fine specificity of certain galectins can help predict the binding of glycoproteins bearing these modifications. Isolation of galectin-binding glycoproteins on a solid support (e.g., affinity chromatography, as www.annualreviews.org • Galectins and Immune Responses


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described above), followed by mass spectrometric identification of the isolated glycoproteins, can provide a slate of candidate counterreceptors (33). Binding of labeled galectins to cells expressing or lacking candidate glycoproteins can be detected with methods such as flow cytometry, immunohistochemistry, and immunofluorescence to determine if those counterreceptors are available on the cell surface for binding (33, 120). After binding and then cross-linking of galectins to cells, immunoprecipitation of the galectins can pull down the repertoire of bound glycoproteins, and the identity of these glycoproteins can be confirmed by immunoblotting (32, 110, 121). What this really means is that determining the counterreceptors for a galectin on a particular cell type will probably always be empiric and very cell type specific; even when one knows that a certain glycoprotein on one cell type binds a galectin, that glycoprotein may be glycosylated in a different manner on another cell type and thus may or may not bind that same galectin. To complicate matters further, the counterreceptors identified may not all be involved in the particular galectin effect being investigated. T cell death induced by galectin-1 is an example. In 1999, our group identified several glycoproteins on human T cell lines that can bind galectin-1 (121). We initially used about 20 monoclonal antibodies to ask which antibodies would block galectin-1 binding to MOLT4 T cells, and we identified six T cell surface molecules for which different monoclonal antibodies could block galectin-1 binding by approximately 50% or more: CD3, CD4, CD7, CD8, CD43, and CD45. These molecules were simply the ones we looked for—if we had used more antibodies, we might have found more. These results did not mean that these cell surface glycoproteins directly bound galectin-1 or were involved in galectin-1-induced cell death; rather, they meant that antibody binding to these molecules on the T cell surface sterically blocked galectin-1 binding to either these glycoproteins or adjacent glycoproteins. To ask which glycoproteins could directly bind galectin-1, T cell membranes were solubilized and applied to a galectin-1 affinity column; after extensive washing, elution with lactose yielded a mix of glycoproteins that separated on SDS-PAGE as five major bands and three minor bands (121). Again, there may have been additional glycoproteins that bound to the column that we did not detect at this limit of resolution. Using a variety of methods, we identified these bands as CD45RA and CD45R0, CD43, CD7, CD4, and three glycoproteins in the CD3 complex. But, for example, we did not elute detectable amounts of CD8; this could be because MOLT4 cells express low levels of CD8 or, conversely, because although monoclonal antibodies to CD8 blocked binding of galectin-1 to the cells, CD8 did not bind galectin-1 on the column with sufficient affinity to be isolated. In that work and in later studies, we determined that CD7 is essential for galectin-1-induced death of human T cell lines. Cells that did not express CD7 were resistant to galectin-1-induced death, whereas transfection of cDNA encoding CD7 rendered these cells susceptible to galectin-1induced death (122). In additional reports, we showed that CD43, despite being a major galectin-1binding protein, is not required for cell death but appears to be involved in galectin-1 regulation of T cell migration (80, 123). We also showed that CD45 is not essential for galectin-1 cell death; however, if the cells expressed CD45, it had to be properly glycosylated to allow galectin-1 clustering of CD45 and inhibition of intracellular CD45 phosphatase activity (83, 88). This implies that unopposed CD45 phosphatase activity blocks galectin-1 death. So although we found that numerous T cell glycoprotein counterreceptors bind galectin-1, our data identified only CD7 as absolutely essential for galectin-1-induced human T cell death. We give this example to point out that although studies that identify putative galectin-1 counterreceptors using antibody blocking or even affinity isolation provide an important first step, identification of a counterreceptor does not automatically mean that that particular glycoprotein is involved in the particular galectin function being examined.


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ALL THE EFFECTS OF GALECTINS ON DIFFERENT COUNTERRECEPTORS AND DIFFERENT IMMUNE CELL TYPES—REALLY, WHAT ARE THE RULES? Early reports of galectin activities described cell adhesion as a primary function (30, 124–126). However, one report described that administration of a galectin from an electric eel into rabbits ameliorated experimental autoimmune myasthenia gravis; this was the first demonstration of an immune function for a galectin (127). Our finding that galectin-1 killed a subset of appropriately glycosylated thymocytes and activated T cells (128, 129) implies that the function of galectins is to kill immune cells, and there have been many reports of galectins inducing apoptosis of various cell types (9, 10, 27, 29, 31, 73, 130–132). One implication of this focus on apoptosis is that many of the immune suppressive functions of galectin-1 administered in various animal models of autoimmunity have been assumed to result from death of autoreactive T cells (29, 105, 133). But in other contexts, or with other cell types, galectins do not kill cells; galectin binding can prevent cell death, regulate adhesion and migration, alter cellular signaling, promote cytokine secretion, and regulate responses to pathogens (7, 19, 27, 29, 30, 133). A galectin can have different effects even when binding to the same receptor on the same cell type, e.g., galectin-1 binding to CD45 on T cells. As described above, when T cells lack α2,6 sialylation of CD45, galectin-1 binds to CD45 as well as to CD7 and CD43 and induces apoptosis (80, 83, 88, 122). However, when T cells have CD45 decorated with α2,6-linked sialic acid to prevent galectin-1 binding, galectin-1 still binds to and clusters CD43 on the T cells; the T cells do not, but they fail to migrate across endothelium or through extracellular matrix (123). Similarly, galectin-1 binds to and coclusters CD45 and CD43 on immature dendritic cells to regulate cell signaling and drive tolerogenic maturation of the dendritic cells (110, 111). However, galectin-1 binding to CD43 on mature, LPS-induced inflammatory dendritic cells clustered CD43 and prevented cell migration (134). These are very different functions! So with all these galectins with all these glycoprotein receptors that have to be empirically identified doing all these functions—really, are there rules? The answer is yes. There is only one important rule to determine the effect of a galectin on a cell: Identify the glycoprotein(s) bound by the galectin, determine the effect of galectin binding on the receptor (e.g., clustering, segregation, internalization, retention on the cell surface, promoting or inhibiting intracellular signaling), and determine the downstream consequence of that receptor effect on the cell. In general, to borrow James Carville’s U.S. presidential campaign slogan for Bill Clinton in 1992, “It’s the lattice, stupid.” Everything that galectins do, at least on the cell surface, results from their effect on glycoprotein counterreceptors. These are scaffolding molecules that bundle and arrange glycoproteins into different domains on the plasma membrane. If galectin-3 binding to the glycoprotein CD8 clusters CD8 away from CD3, then the cytotoxic T cell cannot kill (91). If galectin-9 binds protein disulfide isomerase, retaining it on the T cell surface, it will allow increased reductase activity and reduction of disulfide bonds on integrins, promoting cell migration (33). If the counterreceptor is a particular glycosphingolipid on fibroblasts, galectin-3 binding will promote clathrin-independent endocytosis of CD44 and other cell surface proteins (118). Conversely, galectin-3 can bundle specific glycoproteins and target them for delivery to the apical cell membrane of polarized epithelial cells (135). If the counterreceptors are glycolipids on gastric epithelial cells, galectin-4 can cross-link and retain these glycolipids to create a raft domain; release of galectin-4 from the cell surface results in dissolution of the raft domain (136), indicating that galectin-glycan interactions can be a critical feature determining plasma membrane domain organization. This same dizzying array of sometimes opposing functions characterizes the interactions of galectins with microbial pathogens. Galectins can promote or prevent pathogen binding to host

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target cells, and galectins can enhance pathogen production or have direct microbicidal activity on bacteria and fungi (7, 28, 137, 138). Again, the outcome is determined by which host and pathogen glycan-bearing counterreceptors are bound by a specific galectin. In fact, host-pathogen interactions mediated by galectins are fantastic examples of the Red Queen effect of coevolution (139, 140); the microbes quickly evolve to evade any inhibitory effect of galectins and exploit features that promote microbial survival and reproduction. So the second set of factors for understanding how galectin binding regulates cell function are (a) many different cell types express different repertoires of galectins that remain in the cell or can be secreted and stay in the vicinity of the cell; (b) galectins secreted by one cell type can bind to and affect a different cell type; (c) galectins bind glycan ligands that are presented on glycoproteins and glycolipid counterreceptors; (d ) both the fine structure of the glycans, including modifications by specific glycosyltransferases, and the spatial presentation of the glycans on the protein or lipid background contribute to specific recognition of a counterreceptor by a particular galectin; (e) specific counterreceptors control different cell effects that may be triggered by the same galectin, and specific counterreceptors on the same cell can bind different galectins with different effects; and ( f ) galectins do not have a unique function or even set of functions—the effect of a galectin is the effect that scaffolding or clustering or segregating or retaining has on that particular counterreceptor on that particular cell type. If it is CD3 on T cells, there will be effects on TCR signaling (91); if it is a glucose transporter on pancreatic cells, there will be effects on glucose-stimulated insulin secretion (141); if it is EGFR on tumor cells, there will be effects on EGFR signaling (90, 94). It’s the lattice.


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ARE GALECTINS “AGNOSTIC” WITH REGARD TO EFFECTS ON IMMUNE CELLS? As described above, there appear to be no a priori functions of galectins—the outcome of galectin binding is the outcome that engaging specific glycoprotein or glycolipid counterreceptors has on a particular cell in a particular context. In general, across many cell types, this means that, for a wide range of basic cell functions, galectins can have directly opposing effects. Galectins can promote or prevent apoptosis. Galectins can promote or block cell migration. Galectins can promote or attenuate cell signaling, depending on the counterreceptor engaged and where the counterreceptor localizes on the cell surface. A similar “agnostic” or stochastic outcome of galectin engagement appears to characterize the roles of galectins in microbial interactions with host cells. As mentioned above, and recently reviewed (7, 28, 137, 138), there are galectins that are directly microbicidal for some organisms but able to promote or block binding of other pathogens to host cells. It might seem logical to expect that galectins have a similarly wide range of effects on the adaptive immune system, both promoting and attenuating immune responsiveness. However, that does not appear to be the case. The 1983 experiment in which Teichberg and colleagues (127) administered galectin from electric eels to rabbits with myasthenia gravis led to what was described as a complete recovery in the treated animals, although there was no diminution in the level of circulating autoantibodies against the acetylcholine receptor. So in this case, a galectin ameliorated an autoimmune disease in an animal model. Administration of recombinant galectin-1 dramatically improved survival in a mouse model of graft-versus-host disease, with reduced inflammatory infiltrates in tissues, reduced alloreactivity of host cells, and reduced IL-2 and IFN-γ production (142). Administration of galectin-1 ameliorated disease in a rat model of collageninduced arthritis, skewing toward a type 2 cytokine profile in vivo and inhibiting IL-2 production by collagen-specific T cell clones in vitro (143). Administration of galectin-1 to mice with 9.14

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experimental autoimmune encephalitis (EAE), a model for multiple sclerosis, also reduced clinical and histologic signs of disease (93), and galectin-1 reduced liver damage in a T cell–dependent model of hepatitis (144). Consistent with these observations, deleting galectin-1 expression has the anticipated effect of promoting autoimmunity, as galectin-1 null mice have a lower antigen threshold for developing EAE (93) and have altered negative selection of autoreactive thymocytes (2). As mentioned above, the anti-inflammatory effects of galectin-1 go beyond inducing T cell death; although galectin-1 can kill Th1 and Th17 cells (87), it also promotes Treg production and IL-10 secretion (145), promotes maturation of tolerogenic dendritic cells (111, 112, 145), and controls T cell and dendritic cell trafficking (3, 4). Galectin-9 also seems to have predominantly suppressive effects in autoimmune disease models. Intranasal administration of galectin-9 reduced airway hyperresponsiveness in a model of dust mite–induced asthma (146). Galectin-9 is essential for the immunosuppressive function of antibodies to 4-1BB, a tumor necrosis factor receptor family member (147). Administration of galectin-9 ameliorates disease in a murine model of glomerulonephritis (148), and galectin-9, through interaction with Tim-3, also promoted production of Tregs in a murine hepatitis model (149). The immune effects of galectin-3 are complex. In the innate immune system, it can have both pro- and anti-inflammatory activities (106). It is a chemoattractant for monocytes and macrophages (107, 150); promotes neutrophil adhesion to endothelial cells and induces respiratory burst (151); and participates in recognition and endocytosis of bacteria, mycobacteria, and fungi (76, 138, 152). In a peritonitis model, galectin-3 null mice had reduced numbers of neutrophils in the peritoneal cavity, compared to wild-type mice (153), demonstrating the proinflammatory influence of galectin-3. However, in adaptive immunity, galectin-3, like galectin-1 and -9, consistently demonstrates immunosuppressive effects. Galectin-3 negatively regulates TCR signaling by restricting TCR recruitment into immune synapses (154). Galectin-3 segregation of TCR from CD8 on the T cell surface has been shown to restrict killing of target tumor cells (91). Galectin-3 prevents T cell proliferation, inhibits Th1 differentiation, and directly induces T cell apoptosis, apparently via an apoptotic mechanism distinct from that triggered by galectin-1 (63). Galectin-3 also promotes phagocytosis of apoptotic cells (108) and promotes wound healing (155). Thus, it appears that galectin-1, -3, and -9, the three most abundant galectins expressed by cells of the immune system, consistently have immunosuppressive effects on adaptive immunity. This seems contradictory to the idea presented above, that galectins are neutral scaffolding molecules and thus galectin activities are stochastic or “agnostic,” and galectin effects simply depend on the outcome of receptor engagement. However, as abundant work from the past two decades has demonstrated, the adaptive immune system is a two-edged sword, or, as described by Steve Hedrick, “a moment of evolutionary ecstasy [that] brought us 400 million years of misery” (140). Although mammals have clearly evolved to require adaptive immunity, the adaptive immune system is responsible for the increasing prevalence of hypersensitivity and autoimmune disease in the developed world. Perhaps, despite the varied and often opposing nature of galectin effects in other cell and tissue systems, the default function that will be selected for among all the potential effects of galectins on T and B cells will be control of adaptive immune responses.

CONCLUSIONS It seems complicated—glycan ligands can be positively and negatively modified by hundreds of glycosyltransferase enzymes, can decorate every protein and lipid on the cell surface, and can be multivalently bound into a variety of complexes on the cell surface by over a dozen galectins secreted by a wide range of cell types, triggering every type of cellular effect that has been described. www.annualreviews.org • Galectins and Immune Responses


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But that is probably still too simplistic. Virtually all of the relevant studies have examined the effects of a single galectin, in vitro or in vivo, but we know that cells in tissues are surrounded by many galectins, likely at different concentration gradients. As an example, our group has shown that the thymic stroma contains abundant galectin-1, -3, and -9 (32, 43), but we have never examined the combined effects of the three galectins in varying concentrations on thymocyte maturation or apoptosis. Moreover, cells are exposed not simply to multiple galectins, but to multiple types of lectins in different settings: Endothelial cells express both selectins and galectins, which can regulate leukocyte rolling, adhesion, and transmigration, and dendritic cells display a repertoire of C-type lectins as well as galectins. The inhibitory, additive, or synergistic effects of the different lectins that a cell is exposed to in such settings have rarely been examined. Do the lectins compete for receptors? Do different lectins bind to different glycans on the same molecule to create multimolecular complexes? How are the signals sent by different lectins integrated inside the cell? Critical challenges for the future will be to manipulate cellular glycosylation and to control interactions of various galectins and other immune system lectins with an array of glycoconjugate counterreceptors on different immune cell types, with the goal of precisely promoting or attenuating immune responses in infection, autoimmunity, and cancer.


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DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS The authors thank past and present members of the Baum lab for insight, discussion, and review of the manuscript, and the members of the “galectin-ology” community for remarkable collegiality and productive collaboration. The authors also thank Drs. Zhijie Li and James Rini for providing the ribbon diagram in Figure 1.

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87. Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, et al. 2007. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat. Immunol. 8:825–34 88. Amano M, Galvan M, He J, Baum LG. 2003. The ST6Gal I sialyltransferase selectively modifies Nglycans on CD45 to negatively regulate galectin-1–induced CD45 clustering, phosphatase modulation, and T cell death. J. Biol. Chem. 278:7469–75 89. Bi S, Baum LG. 2009. Sialic acids in T cell development and function. Biochim. Biophys. Acta 1790:1599– 610 90. Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, et al. 2007. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129:123–34 91. Demotte N, Stroobant V, Courtoy PJ, Van Der Smissen P, Colau D, et al. 2008. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 28:414–24 92. Ohtsubo K, Takamatsu S, Gao C, Korekane H, Kurosawa TM, Taniguchi N. 2013. N-glycosylation modulates the membrane sub-domain distribution and activity of glucose transporter 2 in pancreatic β cells. Biochem. Biophys. Res. Commun. 434:346–51 93. Starossom SC, Mascanfroni ID, Imitola J, Cao L, Raddassi K, et al. 2012. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity 37:249–63 94. Lajoie P, Partridge EA, Guay G, Goetz JG, Pawling J, et al. 2007. Plasma membrane domain organization regulates EGFR signaling in tumor cells. J. Cell Biol. 179:341–56 95. Honig E, Schneider K, Jacob R. 2015. Recycling of galectin-3 in epithelial cells. Eur. J. Cell Biol. 94:309– 15 96. Gitt MA, Wiser MF, Leffler H, Herrmann J, Xia YR, et al. 1995. Sequence and mapping of galectin-5, a β-galactoside–binding lectin, found in rat erythrocytes. J. Biol. Chem. 270:5032–38 97. Barres C, Blanc L, Bette-Bobillo P, Andre S, Mamoun R, et al. 2010. Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 115:696–705 98. Madsen P, Rasmussen HH, Flint T, Gromov P, Kruse TA, et al. 1995. Cloning, expression, and chromosome mapping of human galectin-7. J. Biol. Chem. 270:5823–29 99. Gitt MA, Colnot C, Poirier F, Nani KJ, Barondes SH, Leffler H. 1998. Galectin-4 and galectin-6 are two closely related lectins expressed in mouse gastrointestinal tract. J. Biol. Chem. 273:2954–60 100. Kubach J, Lutter P, Bopp T, Stoll S, Becker C, et al. 2007. Human CD4+ CD25+ regulatory T cells: Proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood 110:1550–58 101. Sato S, St-Pierre C, Bhaumik P, Nieminen J. 2009. Galectins in innate immunity: dual functions of host soluble β-galactoside–binding lectins as damage-associated molecular patterns (DAMPs) and as receptors for pathogen-associated molecular patterns (PAMPs). Immunol. Rev. 230:172–87 102. Kuwabara I, Sano H, Liu FT. 2003. Functions of galectins in cell adhesion and chemotaxis. Methods Enzymol. 363:532–52 103. Auvynet C, Moreno S, Melchy E, Coronado-Martinez I, Montiel JL, et al. 2013. Galectin-1 promotes human neutrophil migration. Glycobiology 23:32–42 104. Bax M, Garcia-Vallejo JJ, Jang-Lee J, North SJ, Gilmartin TJ, et al. 2007. Dendritic cell maturation results in pronounced changes in glycan expression affecting recognition by siglecs and galectins. J. Immunol. 179:8216–24 105. Rabinovich GA, Liu FT, Hirashima M, Anderson A. 2007. An emerging role for galectins in tuning the immune response: lessons from experimental models of inflammatory disease, autoimmunity and cancer. Scand. J. Immunol. 66:143–58 106. Cerliani JP, Stowell SR, Mascanfroni ID, Arthur CM, Cummings RD, Rabinovich GA. 2011. Expanding the universe of cytokines and pattern recognition receptors: galectins and glycans in innate immunity. J. Clin. Immunol. 31:10–21 107. Liu FT, Hsu DK, Zuberi RI, Kuwabara I, Chi EY, Henderson WR Jr. 1995. Expression and function of galectin-3, a β-galactoside–binding lectin, in human monocytes and macrophages. Am. J. Pathol. 147:1016–28


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108. Sano H, Hsu DK, Apgar JR, Yu L, Sharma BB, et al. 2003. Critical role of galectin-3 in phagocytosis by macrophages. J. Clin. Investig. 112:389–97 109. Yildirim C, Vogel DY, Hollander MR, Baggen JM, Fontijn RD, et al. 2015. Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages. PLOS ONE 10:e0124347 110. Fulcher JA, Chang MH, Wang S, Almazan T, Hashimi ST, et al. 2009. Galectin-1 co-clusters CD43/CD45 on dendritic cells and induces cell activation and migration through Syk and protein kinase C signaling. J. Biol. Chem. 284:26860–70 111. Fulcher JA, Hashimi ST, Levroney EL, Pang M, Gurney KB, et al. 2006. Galectin-1–matured human monocyte–derived dendritic cells have enhanced migration through extracellular matrix. J. Immunol. 177:216–26 112. Kuo PL, Hung JY, Huang SK, Chou SH, Cheng DE, et al. 2011. Lung cancer-derived galectin-1 mediates dendritic cell anergy through inhibitor of DNA binding 3/IL-10 signaling pathway. J. Immunol. 186:1521–30 113. Baum LG. 2011. Burn control, an adipocyte-specific function for galectin-12. PNAS 108:18575–76 114. Garner OB, Aguilar HC, Fulcher JA, Levroney EL, Harrison R, et al. 2010. Endothelial galectin-1 binds to specific glycans on Nipah virus fusion protein and inhibits maturation, mobility, and function to block syncytia formation. PLOS Pathog. 6:e1000993 115. Baum LG, Seilhamer JJ, Pang M, Levine WB, Beynon D, Berliner JA. 1995. Synthesis of an endogeneous lectin, galectin-1, by human endothelial cells is up-regulated by endothelial cell activation. Glycoconj. J. 12:63–68 116. Thijssen VL, Hulsmans S, Griffioen AW. 2008. The galectin profile of the endothelium: altered expression and localization in activated and tumor endothelial cells. Am. J. Pathol. 172:545–53 117. Earl LA, Bi S, Baum LG. 2010. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. J. Biol. Chem. 285:2232–44 118. Lakshminarayan R, Wunder C, Becken U, Howes MT, Benzing C, et al. 2014. Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat. Cell Biol. 16:595–606 119. Mishra R, Grzybek M, Niki T, Hirashima M, Simons K. 2010. Galectin-9 trafficking regulates apicalbasal polarity in Madin-Darby canine kidney epithelial cells. PNAS 107:17633–38 120. Clark MC, Pang M, Hsu DK, Liu FT, de Vos S, et al. 2012. Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death. Blood 120:4635–44 121. Pace KE, Lee C, Stewart PL, Baum LG. 1999. Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1. J. Immunol. 163:3801–11 122. Pace KE, Hahn HP, Pang M, Nguyen JT, Baum LG. 2000. CD7 delivers a pro-apoptotic signal during galectin-1-induced T cell death. J. Immunol. 165:2331–34 123. He J, Baum LG. 2006. Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab. Investig. 86:578–90 124. Inohara H, Akahani S, Koths K, Raz A. 1996. Interactions between galectin-3 and Mac-2–binding protein mediate cell-cell adhesion. Cancer Res. 56:4530–34 125. Zhou Q, Cummings RD. 1993. L-14 lectin recognition of laminin and its promotion of in vitro cell adhesion. Arch. Biochem. Biophys. 300:6–17 126. Ahmed H, Sharma A, DiCioccio RA, Allen HJ. 1992. Lymphoblastoid cell adhesion mediated by a dimeric and polymeric endogenous β-galactoside–binding lectin (galaptin). J. Mol. Recognit. 5:1–8 127. Levi G, Tarrab-Hazdai R, Teichberg VI. 1983. Prevention and therapy with electrolectin of experimental autoimmune myasthenia gravis in rabbits. Eur. J. Immunol. 13:500–7 128. Perillo NL, Uittenbogaart CH, Nguyen JT, Baum LG. 1997. Galectin-1, an endogenous lectin produced by thymic epithelial cells, induces apoptosis of human thymocytes. J. Exp. Med. 185:1851–58 129. Perillo NL, Pace KE, Seilhamer JJ, Baum LG. 1995. Apoptosis of T cells mediated by galectin-1. Nature 378:736–39 130. Hsu DK, Liu FT. 2004. Regulation of cellular homeostasis by galectins. Glycoconj. J. 19:507–15 131. Perillo NL, Marcus ME, Baum LG. 1998. Galectins: versatile modulators of cell adhesion, cell proliferation, and cell death. J. Mol. Med. 76:402–12 132. Thijssen VL, Poirier F, Baum LG, Griffioen AW. 2007. Galectins in the tumor endothelium: opportunities for combined cancer therapy. Blood 110:2819–27 www.annualreviews.org • Galectins and Immune Responses


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133. Rabinovich GA, Croci DO. 2012. Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. Immunity 36:322–35 134. Thiemann S, Man JH, Chang MH, Lee B, Baum LG. 2015. Galectin-1 regulates tissue exit of specific dendritic cell populations. J. Biol. Chem. 290:22662–77 135. Delacour D, Cramm-Behrens CI, Drobecq H, Le Bivic A, Naim HY, Jacob R. 2006. Requirement for galectin-3 in apical protein sorting. Curr. Biol. 16:408–14 136. Braccia A, Villani M, Immerdal L, Niels-Christiansen LL, Nystrom BT, et al. 2003. Microvillar membrane microdomains exist at physiological temperature. Role of galectin-4 as lipid raft stabilizer revealed by “superrafts”. J. Biol. Chem. 278:15679–84 137. Rabinovich GA, van Kooyk Y, Cobb BA. 2012. Glycobiology of immune responses. Ann. N. Y. Acad. Sci. 1253:1–15 138. Vasta GR. 2009. Roles of galectins in infection. Nat. Rev. Microbiol. 7:424–38 139. Brockhurst MA. 2011. Evolution. Sex, death, and the Red Queen. Science 333:166–67 140. Hedrick SM. 2004. The acquired immune system: a vantage from beneath. Immunity 21:607–15 141. Ohtsubo K, Takamatsu S, Minowa MT, Yoshida A, Takeuchi M, Marth JD. 2005. Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123:1307–21 142. Baum LG, Blackall DP, Arias-Magallano S, Nanigian D, Uh SY, et al. 2003. Amelioration of graft versus host disease by galectin-1. Clin. Immunol. 109:295–307 143. Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, et al. 1999. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J. Exp. Med. 190:385–98 144. Santucci L, Fiorucci S, Cammilleri F, Servillo G, Federici B, Morelli A. 2000. Galectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice. Hepatology 31:399– 406 145. Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, et al. 2009. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1–driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat. Immunol. 10:981–91 146. Katoh S, Shimizu H, Obase Y, Oomizu S, Niki T, et al. 2013. Preventive effect of galectin-9 on doublestranded RNA-induced airway hyperresponsiveness in an exacerbation model of mite antigen-induced asthma in mice. Exp. Lung. Res. 39:453–62 147. Madireddi S, Eun SY, Lee SW, Nemcovicova I, Mehta AK, et al. 2014. Galectin-9 controls the therapeutic activity of 4-1BB–targeting antibodies. J. Exp. Med. 211:1433–48 148. Zhang Q, Luan H, Wang L, He F, Zhou H, et al. 2014. Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice. Am. J. Physiol. Ren. Physiol. 306:F822– 32 149. Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, et al. 2010. A crucial role for Kupffer cell–derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLOS ONE 5:e9504 150. Sano H, Hsu DK, Yu L, Apgar JR, Kuwabara I, et al. 2000. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J. Immunol. 165:2156–64 151. Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG. 2002. Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J. Immunol. 168:1813– 22 152. Sato S, Nieminen J. 2004. Seeing strangers or announcing “danger”: galectin-3 in two models of innate immunity. Glycoconj. J. 19:583–91 153. Colnot C, Ripoche MA, Milon G, Montagutelli X, Crocker PR, Poirier F. 1998. Maintenance of granulocyte numbers during acute peritonitis is defective in galectin-3–null mutant mice. Immunology 94:290–96 154. Chen HY, Fermin A, Vardhana S, Weng IC, Lo KF, et al. 2009. Galectin-3 negatively regulates TCRmediated CD4+ T-cell activation at the immunological synapse. PNAS 106:14496–501 155. Cao Z, Said N, Amin S, Wu HK, Bruce A, et al. 2002. Galectins-3 and -7, but not galectin-1, play a role in re-epithelialization of wounds. J. Biol. Chem. 277:42299–305


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Invited review articles: do they inform or do they advertise?

Medical clinic referral letters. Do they say what they mean? Do they mean what they say?

Arterial stiffness parameters: how do they differ?

Immunosuppressive drugs: how do they act?

What do they want?

Where do they go and how do they get there? Older adults' travel behaviour in a highly walkable environment.

Social media and tomorrow's medical students--how do they fit?

Interstitial cells in the urinary tract, where are they and what do they do?

Nonsteroidal anti-inflammatory drugs and antihypertensives: how do they relate?

Patient Portals: Who uses them? What features do they use? And do they reduce hospital readmissions?

Micellar drug nanocarriers and biomembranes: how do they interact?

Connexin hemichannel and pannexin channel electrophysiology: how do they differ?

Beryllium Bonds, Do They Exist?

Salt bladders: do they matter?

Emerging properties of adhesion complexes: what are they and what do they do?

Who should do endovascular repair of complex aortic aneurysms and how should they do them?

Readthrough transcription: How are DoGs made and what do they do?

Weight conversations in romantic relationships: What do they sound like and how do partners respond?

Drinking Buddies: Who Are They and When Do They Matter?

Protons in ischemia: where do they come from; where do they go to?

Do observers like curvature or do they dislike angularity?

Flaviviruses are neurotropic, but how do they invade the CNS?

Premixed insulins. How do they compare with other insulin preparations?

Nutrition epidemiology: how do we know what they ate?