Siglecs and immune regulation

Abstract

Sialic acid-binding Ig-like lectins, or Siglecs, vary in their specificity for sialic acid-containing ligands and are mainly expressed by cells of the immune system. Many Siglecs are inhibitory receptors expressed in innate immune cells that regulate inflammation mediated by damage-associated and pathogen-associated molecular patterns (DAMPs and PAMPs). This family also includes molecules involved in adhesion and phagocytosis and receptors that can associate with the ITAM-containing DAP12 adaptor. Siglecs contribute to the inhibition of immune cells both by binding to cis ligands (expressed in the same cells) and by responding to pathogen-derived sialoglycoconjugates. They can help maintain tolerance in B lymphocytes, modulate the activation of conventional and plasmacytoid dendritic cells, and contribute to the regulation of T cell function both directly and indirectly. Siglecs modulate immune responses, influencing almost every cell in the immune system, and are of relevance both in health and disease.

Figure 1

A schematic view of the structure of sialic acid

Figure 2

Glycan binding specificities of selected human and murine Siglecs. *While human CD22 binds to both Neu5Ac and Neu5Gc, murine CD22 is specific for Neu5Gc.

Figure 3

Relative gene expression of (a) conserved and (b) CD33-related (non-conserved) Siglecs across key innate and adaptive immune cells. Values in each panel are normalized to the maximum expression of the respective Siglec across the represented cell types and presented in a linear scale. PMN, Polymorphonuclear leukocyte; RPM, Red pulp macrophage; CD4⁺ DC, CD4⁺ dendritic cell; CD8α⁺ DC, CD8α⁺ dendritic cell; PDC, Plasmacytoid dendritic cell; LC, Langerhans cell; NK, NK cell; B.Fo, Follicular B cell, B.GC, Germinal center B cell; B.MZ, Marginal Zone B cell; B-1a, B-1a peritoneal B cell; CD4⁺ T.naive, CD4⁺ naïve T cell; CD4⁺ T. memory, CD4⁺ memory T cell; CD8⁺ T. naive, CD8⁺ naive T cell; CD8⁺ T.memory, CD8⁺ memory T cell; Treg, Regulatory T cell; γδ T, gamma-delta T cell. This work benefited from data assembled by the ImmGen Consortium Heng, T et al. Immunological Genome Project Consortium. Nat Immunol. 10:1091–1094 (2008).

Figure 3

Relative gene expression of (a) conserved and (b) CD33-related (non-conserved) Siglecs across key innate and adaptive immune cells. Values in each panel are normalized to the maximum expression of the respective Siglec across the represented cell types and presented in a linear scale. PMN, Polymorphonuclear leukocyte; RPM, Red pulp macrophage; CD4⁺ DC, CD4⁺ dendritic cell; CD8α⁺ DC, CD8α⁺ dendritic cell; PDC, Plasmacytoid dendritic cell; LC, Langerhans cell; NK, NK cell; B.Fo, Follicular B cell, B.GC, Germinal center B cell; B.MZ, Marginal Zone B cell; B-1a, B-1a peritoneal B cell; CD4⁺ T.naive, CD4⁺ naïve T cell; CD4⁺ T. memory, CD4⁺ memory T cell; CD8⁺ T. naive, CD8⁺ naive T cell; CD8⁺ T.memory, CD8⁺ memory T cell; Treg, Regulatory T cell; γδ T, gamma-delta T cell. This work benefited from data assembled by the ImmGen Consortium Heng, T et al. Immunological Genome Project Consortium. Nat Immunol. 10:1091–1094 (2008).

Figure 4

Siglecs that lack defined cytoplasmic tail signaling motifs or a charged transmembrane residue. The cytoplasmic tail of Siglec-4 has a tyrosine residue (Y) that does not fit into any known consensus for signaling. It has been referred to in the literature as a Fyn phosphorylation site.

Figure 5

Siglecs that contain ITIM motifs in their cytoplasmic tails A) Human and B) Murine. Siglec 12 is refrred to as Siglec XII in human by convention since the in-frame human form lacks the crucial arginine for sialic acid recognition (but the arginine is present in other primates).

Figure 5

Siglecs that contain ITIM motifs in their cytoplasmic tails A) Human and B) Murine. Siglec 12 is refrred to as Siglec XII in human by convention since the in-frame human form lacks the crucial arginine for sialic acid recognition (but the arginine is present in other primates).

Figure 5

Siglecs that contain ITIM motifs in their cytoplasmic tails A) Human and B) Murine. Siglec 12 is refrred to as Siglec XII in human by convention since the in-frame human form lacks the crucial arginine for sialic acid recognition (but the arginine is present in other primates).

Figure 6

Siglecs that contain a transmembrane lysine (+). A) Human, and B) Murine. Siglec 15 is shown associated with DAP12; it can also associate with DAP10. Murine CD3 has not yet been shown to associate with DAP12 experimentally.

Figure 6

Siglecs that contain a transmembrane lysine (+). A) Human, and B) Murine. Siglec 15 is shown associated with DAP12; it can also associate with DAP10. Murine CD3 has not yet been shown to associate with DAP12 experimentally.

Figure 7

Induction of ligand or Siglec expression by pathogens can regulate inhibitory signaling A. Activation of a TLR by a PAMP results in the generation of a Siglec ligand by regulating an enzyme or enzymes that regulate ligand availability. The generation of a Siglec ligand results in inhibitory signaling being brought into play B. Activation of a TLR by a PAMP results in the induction of Siglec expression. This results in inhibitory signaling being brought into play.

Figure 7

Induction of ligand or Siglec expression by pathogens can regulate inhibitory signaling A. Activation of a TLR by a PAMP results in the generation of a Siglec ligand by regulating an enzyme or enzymes that regulate ligand availability. The generation of a Siglec ligand results in inhibitory signaling being brought into play B. Activation of a TLR by a PAMP results in the induction of Siglec expression. This results in inhibitory signaling being brought into play.

Figure 8

Siglecs may be activated in cis by self-sialoglycoconjugates or in trans by sialylated pathogens A. Tonic inhibition refers to inhibitory signaling based on ongoing ligation in cis of a Siglec by its ligand B. A sialylated pathogen may displace a cis-ligand and more potently engage an inhibitory Siglec.

Figure 9

Engagement of a DAP12 associated Siglec may result in the induction and/or activation of proteins that can compromise TLR signaling and reduce the secretion of type I interferons in plasmacytoid dendritic cells.

Figure 10

A 9-O acetyl sialic acid acetyltransferase and a 9-O acetyl sialic acid acetylesterase (SIAE) regulate the availability of siglec ligands in B cells.

Figure 11

SIAE may maintain clonal ignorance in B cells preventing the activation of weakly self-reactive B cells. Activation of weakly self-reactive B cells would permit T-B collaboration and consequent somatic mutation of the B cell, potentially making it strongly self-reactive.

Figure 12

SIAE may permit promiscuous activation of B cells that might in turn facilitate the induction of CD4+ memory T cells that might be linked to disease.