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Siglecs in the immune system

Siglecs1 (sialic acid binding Ig-like lectins) are I-type (Ig-type) lectins2 characterized by an N-terminal V-set Ig domain that mediates sialic acid binding,3 followed by varying numbers of C2-set Ig domains (Fig. 1). The initial discovery of this lectin family came about through independent studies on sialoadhesin (Siglec-1/CD169), a macrophage lectin-like adhesion molecule,4 and CD22 (Siglec-2), a B-cell restricted member of the Ig superfamily (IgSF)5 that plays an important role in regulating B-cell activation. Both molecules were found to mediate cell–cell interactions in vitro via recognition of sialylated glycoconjugates.6–10 The cloning of sialoadhesin11 revealed striking sequence similarities to CD22 and led to the demonstration that two other related IgSF proteins, myelin-associated glycoprotein (MAG/Siglec-4) and CD33 (Siglec-3), which were not previously known to bind sialic acids, were also members of the Siglec family (Table 1).12,13 
 
 
 
Figure 1 
 
Structural features of Siglecs. (a) Siglecs are type I membrane proteins with an extracellular region containing a sialic acid binding V-set Ig-like domain at the N-terminus and 1–16 C2-set Ig-like domains. The cytoplasmic tails of all Siglecs ... 
 
 
 
 
 
Table 1 
 
Properties of Siglecs 
 
 
 
Six additional human Siglecs (Siglecs 5–10) have been identified and characterized over the last 3 years. These previously unknown molecules share a high degree of sequence similarity with CD33 in their extracellular and intracellular regions, and are hence collectively referred to as ‘CD33-related Siglecs’. A striking feature of the CD33-related Siglecs is their differential expression pattern amongst the cell lineages of the haemopoietic system (see Table 1). This, together with the presence of two conserved immunoreceptor tyrosine-based inhibition motif (ITIM)-like motifs in their cytoplasmic tails, suggests that, like CD22, CD33-related Siglecs are involved in regulating cellular activation within the immune system. Here we discuss how sialic acid recognition by Siglecs might contribute to the regulation of immune functions.