Siglec-G/10 in self-nonself discrimination of innate and adaptive immunity

Abstract

Siglec-G/10 is broadly expressed on B cells, dendritic cells and macrophage subsets. It binds strongly to CD24, a small glycosyl-phosphatidylinositol-anchored sialoprotein, in a sialylation-dependent manner. Targeted mutation of Siglecg dramatically elevates the level of natural IgM antibodies and its producer, B1 B cells. Incorporation of Siglec-G ligands to both T-dependent and T-independent immunogens reduces antibody production and induces B-cell tolerance to subsequent antigen challenges. By interacting with CD24, Siglec-G suppresses inflammatory responses to danger (damage)-associated molecular patterns, such as heat-shock proteins and high mobility group protein 1, but not to Toll-like receptor ligands. By a CD24-independent mechanism, Siglec-G has been shown to associate with Cbl to cause degradation of retinoic acid-inducible gene 1 and reduce production of type I interferon in response to RNA virus infection. The negative regulation by Siglec-G/10 may provide a mechanism for the host to discriminate between infectious nonself and noninfectious self, as envisioned by the late Dr. Charles A. Janeway.

Keywords: DAMP; PAMP; Siglec-G; self–nonself.

© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1.

Phylogenetic analysis of the Siglec family. The sialic acid binding Ig V-set domain was aligned to create the phylogenetic tree using ClustalW (Thompson et al. 1994) and TreeView (Page 1996).

Fig. 2.

Siglec-G in adaptive and innate immunity. (A) Regulation of B1a B-cell proliferation and BCR signaling by Siglec-G. Siglec-G dampens the calcium signal on B1 cells and inhibits the activity of the transcription factor NFATc1 and NFκB by recruiting the ITIM-binding protein SHP-1 or Grb2. (B) Regulation of B-cell activation and tolerance. Self-antigens are expressed on cells with abundance of Siglec-G ligands and thus likely engage both BCR and Siglec-G. In contrast, foreign antigens are presented to B cells in the absence of Siglec-G ligands. (C) Siglec-G represses host response to DAMPs unless its ligand CD24 is desialylated by bacterial sialidase. (D) Siglec-G suppresses type I IFN production by promoting c-Cbl-mediated ubiquitination and proteasomal degradation of RIG-I.