The Ligand-Binding Domain of Siglec-G Is Crucial for Its Selective Inhibitory Function on B1 Cells

Abstract

Siglec-G is an inhibitory receptor on B1 cells. Siglec-G–deficient mice show a large B1 cell expansion, owing to higher BCR-induced Ca2+ signaling and enhanced cellular survival. It was unknown why Siglec-G shows a B1 cell–restricted inhibitory function. With a new mAb we could show a comparable Siglec-G expression on B1 cells and conventional B2 cells. However, Siglec-G has a different ligand sialic acid–binding pattern on peritoneal B1 cells than on splenic B cells, and its sialic acid ligands are expressed differentially on these two B cell populations, suggesting that cis-ligand binding plays a crucial role on B1 cells. This observation was further studied by generation of Siglec-G knockin mice with a mutated ligand-binding domain. These mice show increased B1 cell numbers, increased B1 cell Ca2+ signaling, better B1 cell survival, and changes in the B1 cell Ig repertoire. These phenotypes are very similar to Siglec-G–deficient mice. The mutation of the ligand-binding domain of Siglec-G strongly reduces the Siglec-G–IgM association on the B cell surface. Thus, Siglec-G sialic acid–dependent binding to the BCR is crucial for the B1 cell–restricted inhibitory function of Siglec-G and is regulated in an opposite way to that of the related protein CD22 (Siglec-2) on B cells.

Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice

“…B cells normally diffentiate into plasmablasts and plasma cells after Ag encounter and T cell help in lymphatic organs in a tightly regulated manner. Recently, Siglec-G expression was confirmed on DCs, which are responsible for T cell priming during an immune response (19,21). Therefore, loss of Siglec-G on DCs could potentially result in a enhanced activation of T cells, which in turn leads to an uncontrolled activation of Siglec-G B6 -deficient B cells by T cells.…”

“…2A). Because Siglec-G is also expressed on dendritic cells (DCs) (19,21), we analyzed DC numbers in aging mice and also determined activation markers such as MHC class II and CD86 on DCs. We did not detect any significant changes in the three knockout mouse strains (not shown).…”

“…B1 cell surfaces show a higher expression of a2,3-linked sialic acids, which is the preferential ligand for Siglec-G. It is therefore likely that the differential abundance of Siglec-G ligands on B1 and B2 cells leads to this specific phenotype in Siglec-G-deficient mice (21).…”

“…These tyrosine phosphatases can dephosphorylate positive regulators of the BCR signaling cascade and cause a dampening of the BCR signal (19,20). Although Siglec-G is expressed on all B cell subsets (19,21), deficiency of Siglec-G in mice causes a strong enlargement of the B1 cell population, but not of B2 cells, indicating that Siglec-G has mainly a B1 cell-restricted inhibitory function. Additionally, Siglec-G-deficient B cells are hyperreactive and exhibit a highly elevated Ca 2+ flux as well as a prolonged live span only in B1 but not in B2 cells (9).…”

Chemical composition of circulating native and desialylated low density lipoprotein: what is the difference?

“…[ [79][80][81][82] In atherosclerosis, decreased sialic acid content in desialylated LDL might result in increased cholesterol intake and inflammation through macrophage and B-cell activation.…”