Siglecs as sensors of self in innate and adaptive immune responses

Abstract

Siglecs are expressed on most white blood cells of the immune system and are known to modulate the activity of cell signaling receptors via regulatory motifs in their cytoplasmic domains. This immunoglobulin subfamily of coreceptors recognize sialic acid containing glycans as ligands, which are found on glycoproteins and glycolipids of all mammalian cells. By virtue of their ability to recognize this common structural element, siglecs are increasingly recognized for their ability to help immune cells distinguish between self and nonself, and dampen autoimmune responses.

Figure 1. Interactions of siglecs with sialoside ligands in cis (A) and trans (B)

Figure 2. CD22 is negative regulator of B cell activation

(A) Negative regulation of B cell signaling requires that the CD22-SHP-1 complex be in close proximity to the BCR. (B) On resting B cells, CD22 and the B cell receptor (BCR) are in different sub-membrane compartments: while CD22 is located in clathrin rich domains, the BCR resides in GM1 rich domains. CD22 interacts with cis ligands on other CD22 molecules, which help maintain it in clathrin rich domains and away from the BCR, allowing for full B cell activation. (C) When the BCR encounters a cell surface autoantigen, CD22 becomes juxtaposed to the BCR through interactions with trans ligands. Recruitment of CD22 to the site of cell contact will result in phosphorylation of the ITIM motifs on the cytoplasmic tail of CD22, recruitment of the phosphate SHP-1, and, in turn, dampening of B cell activation. In such a manner, CD22 may inhibit B cell activation toward self and play a key role in preventing autoimmunity.

Figure 3. Regulation of TLR signaling by siglecs

(A) Siglec-G does not affect LPS-induced TLR signaling on DCs. (B) Endogenous TLR ligands such as HSPs and HMGB1 activate TLR4, resulting in an inflammatory response to the tissue damage. CD24-Siglec-G/10 complex suppresses the HMGB1-induced TLR activation upon binding of HMGB1 via CD24. (C) CD22 is an endocytic receptor that is localized in endosomes where endosomal TLRs reside. (D) Sequestration of CD22 may alter endosomal TLR signaling by reducing the local concentration of the siglecs in endosomes.