The sialic acid (Sia)-binding Ig-like lectins (Siglecs)1 were discovered through independent studies on a macrophage lectin-like adhesion molecule named sialoadhesin2 and a B-cell restricted member of the Ig

Ajit Varki Glycobiology Research and Training Center, Dept of Medicine and Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. The sialic acid (Sia)-binding Ig-like lectins (Siglecs)1 were discovered through independent studies on a macrophage lectin-like adhesion molecule named sialoadhesin2 and a B-cell restricted member of the Ig superfamily (IgSF), CD22 (Ref. 3). Both proteins were found to mediate cell–cell interactions in vitro through the recognition of sialylated glycoconjugates4–8. The cloning of sialoadhesin9 revealed striking structural similarities to CD22 and led to the demonstration that two other related IgSF proteins – myelin-associated glycoprotein (MAG) and CD33 – which were not previously known to bind to Sia, were also members of the Siglec family10,11. Siglecs are I-type (Ig-type) lectins12 and are characterized by an N-terminal V-set Ig-like domain, which mediates Sia binding13, followed by varying numbers of C2-set Ig-like domains (Fig. 1). To date, no Siglec has been shown to recognize any cell-surface ligand other than Sia, suggesting that interactions with glycans containing this carbohydrate are important in mediating the biological functions of Siglecs. Very recently, another Ig superfamily member, CD83, expressed on mature dendritic cells (DCs), has been shown to mediate sialidase-sensitive interactions with one particular cell type14. CD83 does not contain the typical V-set and C2-set Ig-like domains characteristic of the known Siglecs. Further analyses will be required to determine whether CD83 should be classified as a Siglec or as an I-type lectin with some Sia binding properties. One striking feature of CD33 and the six recently described CD33-related human Siglecs (Fig. 1) is their differential expression pattern within the hematopoietic system (Fig. 2). This fact, taken together with the presence of two conserved motifs similar to immunoreceptor tyrosine-based inhibition motifs (ITIMs) in their cytoplasmic tails, raises the possibility that CD33-related Siglecs are involved in regulating cellular activation within the immune system. This article reviews the ways in which Sia recognition by CD33-related Siglecs might contribute to immune functions. New CD33-related Siglecs in the innate immune system Human (h) Siglecs-5, -7, -8 and -10 were identified in expressed sequence tag (EST) databases as being homologous to CD33 and were found to possess the key features required for Sia recognition (Fig. 1)15–20. Siglec-6 was isolated in a screen for leptin-binding proteins21, and Siglec-7 was also identified as a natural killer (NK)-cell inhibitory receptor in a redirected killing assay and was designated p75/AIRM-1 (Ref. 22). Siglec-9, a close homolog of Siglec-7, was identified as a Siglec-like cDNA23,24 and also as a Siglec-like gene25. Most recently, a novel mouse (m) Siglec with three Ig-like domains and two ITIM-like motifs, similar to hSiglecs-7, -8 and -9, was identified by one group as a CD33-like EST sequence (named MIS)26 and by another group as a binding partner for the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) in a yeast two-hybrid screen (named mSiglec-E)27. The hCD33-related Siglecs contain between two and five Ig-like domains and share a high degree of sequence similarity (Fig. 1). The genes encoding them are clustered on human chromosome 19q13.3–13.4 and appear to have evolved by repeated duplications. Until recently, the only published data on a mCD33related Siglec concerned a CD33-like protein with two Ig domains but lacking ITIM-like motifs28. In phylogenetic analyses, this molecule did not form an exclusive clade with hCD33, instead being loosely associated with several hCD33-related Siglecs23. The eventual classification of CD33-related Siglec orthologs in mice will depend on the detailed characterization of their expression patterns, binding specificities and functions. Monoclonal antibodies (mAbs) recognizing each of the recently discovered human Siglecs have allowed a detailed analysis of their expression patterns on blood leukocytes (Fig. 2). Some are expressed broadly; for example, Siglec-9 is found on neutrophils, monocytes, a substantial fraction of NK cells and B cells, and a minor subset of CD8+ T cells24. Others have a much more restricted distribution – notably Siglec-8 – which is expressed on circulating eosinophils17,18 and at very low levels on basophils18. Several Siglecs can be present on the same cell type [e.g. monocytes express CD33 and Siglecs-5, -7, -9 and -10 (Refs 15,16,20,23,24,29)], suggesting some degree of functional redundancy at the cellular level. However, each CD33-related Siglec exhibits a very specific expression pattern among hematopoietic cells, which Siglecs are members of the Ig superfamily that bind to sialic acid (Sia) and are mainly expressed by cells of the hematopoietic system. Until three years ago, only four Siglecs were known, namely sialoadhesin, CD22, myelin-associated glycoprotein and CD33. Since then, a further six human CD33-related Siglecs with features of inhibitory receptors have been identified and shown to be expressed by discrete subsets of leukocytes. Recognition of Sia by these Siglecs could play a role in the regulation of the innate immune system. Siglecs, sialic acids and innate immunity