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Review
. 2014 Oct;14(10):653-66.
doi: 10.1038/nri3737. Epub 2014 Sep 19.

Siglec-mediated Regulation of Immune Cell Function in Disease

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Free PMC article
Review

Siglec-mediated Regulation of Immune Cell Function in Disease

Matthew S Macauley et al. Nat Rev Immunol. .
Free PMC article

Abstract

All mammalian cells display a diverse array of glycan structures that differ from those that are found on microbial pathogens. Siglecs are a family of sialic acid-binding immunoglobulin-like receptors that participate in the discrimination between self and non-self, and that regulate the function of cells in the innate and adaptive immune systems through the recognition of their glycan ligands. In this Review, we describe the recent advances in our understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer.

Figures

Figure 1
Figure 1. Mechanisms by which sialoside ligands of the Siglecs mediate immunomodulatory effects
Illustrations are generic but are supported by one or more specific examples for individual Siglecs. Modulation of Siglec function by cis (a, b) and trans (c–f) ligands through promoting (a, c) or excluding (b, d) association with an activating receptor. Interactions with trans ligands can also promote apoptosis of the Siglec-expressing cells or drive apoptosis and/or alter migratory properties of the contacted cell (panel e).
Figure 2
Figure 2. Siglecs in host-pathogen interactions
(a) Siglec-10 (Siglec-G in mice) on DCs interacts with CD24 to inhibit DAMP-mediated TLR signaling, which is disrupted by bacterial sialidase to promote infection. (b) Double-stranded (DS) RNA from RNA viruses induces Siglec-G expression in macrophages, which in turn decreases type I interferons through RIG-I degradation and promotes infection. (c) Interactions between Siglec-E and sialoside ligands on Group B Streptococcus (GBS) on macrophages inhibit phagocytosis. (d, e, g) Recognition of various sialoside ligands on GBS, C. jejuni, or HIV by sialoadhesin on macrophages promotes uptake of these pathogens for a variety of outcomes. (f) Siglec-10 recognition of pseudaminic acid on the flagella of Campylobacter jejuni promotes IL-10 release by DCs.
Figure 3
Figure 3. Sialoside ligands on a cell that displays a cell surface antigen draws the B cell. Siglecs into the immunological synapse to inhibit B cell activation
Mouse B cells express CD22 and Siglec-G and are known to inhibit B cell activation when co-ligated with the BCR by a membrane that displays both antigen and Siglec ligand. Inhibition is initiated by phosphorylation of the Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on CD22 and Siglec-G, resulting in recruitment of the phosphatase Shp-1 that dampens signaling by dephosphorylation of the BCR signaling complex. This mechanism probably contributes to the role of CD22 and Siglec-G in maintaining peripheral B cell tolerance.
Figure 4
Figure 4. Therapeutic potential of targeting Siglecs in disease
(a) The endocytic property of the Siglecs expressed on lymphoma/leukemia cells (CD22/CD33) or macrophages (sialoadhesin) has been exploited to deliver cargo to the cell type of interest. Toxin or antigens can be delivered via conjugated anti-Siglec antibodies (left) or encapsulated in the lumen of liposomes displaying high affinity Siglec ligands (right). Once endocytosed, toxins are released to cause cell death, while antigens are loaded on MHC or CD1d for presentation to T cells and NKT cells, respectively. It is notable that in the case of targeting via glycan ligands, the modestly reduced endosomal pH is enough to cause dissociation ofSiglecs and their cargo, which allows for recycling of the Siglecs to the cell surface for additional rounds of cargo uptake. (b) Siglec-engaging tolerance-inducing antigenic liposomes (STALs) display both antigen and a high affinity ligand of the B cell Siglecs (CD22 and Siglec-G). STALs enforce association of the Siglecs with the BCR on B cells, inhibiting B cell activation that otherwise occurs when ligands are absent. Through downstream signaling events, a pro-apoptotic signal is delivered that results in apoptosis of the antigen-specific B cells, resulting in antigen-specific B cell tolerance.

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