Siglecs Induce Tolerance to Cell Surface Antigens by BIM-Dependent Deletion of the Antigen-Reactive B Cells

Abstract

Infusion of blood cells from a donor can induce humoral tolerance in a recipient and increase the probability of successful organ transplant; a clinical method defined as donor-specific transfusion (DST). Despite the clinical success of DST, the immunological mechanism(s) by which blood cells displaying a foreign antigen induce tolerance remain poorly understood. Based on recent findings showing that the B cell siglecs, CD22 and Siglec-G, can promote tolerance to antigens presented on the same surface as their ligands, we speculated that the B cell siglecs are key players in tolerance induced by DST. Using a variety of chemical and genetic approaches, we show that the B cell siglecs mediate tolerance to cell surface antigens by initiating an inhibitory signal that culminates in elimination of the antigen-reactive B cell. CD22 and Siglec-G are recruited to the immunological synapse by sialic acid ligands on the antigen-bearing cells, producing a tolerogenic signal involving Lyn and the pro-apoptotic factor BIM that promotes deletion of the B cell and failure of mice to develop antibodies to the antigen upon subsequent challenge. We speculate that this tolerogenic mechanism is a contributing factor in DST and a mechanism of peripheral B cell tolerance to cell surface autoantigens.

Unmasking of CD22 Co-receptor on Germinal Center B-cells Occurs by Alternative Mechanisms in Mouse and Man

“…Decreased levels of cis ligands and subsequent unmasking of CD22 on GC B-cells has the potential to participate in the biology of the GC B-cells in numerous ways. Recently, we have shown that trans ligands on cells expressing a cell surface autoantigen recruit CD22 to the immunological synapse (7). Therefore, one intriguing possibility is that B-cells acquiring autoreactivity in GC to cell surface autoantigens may be clonally deleted through enhanced sensitivity of CD22 trans ligand interactions.…”

“…Studies ablating CD22-ligand interactions have concluded that cis ligands limit CD22 association with the BCR (3,4), and less dramatic alterations to cis ligands can provide a finer control over CD22-BCR association (5,6). In contrast, trans ligands on a contacting cell displaying an antigen recognized by the BCR draw CD22 into the immunological synapse to inhibit B-cell activation (7,8). In addition to regulating the association of CD22 with the BCR, trans CD22-ligand interactions are also involved in B-cell homing (9,10).…”

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

“…The physiological circumstances in which CD22 is in close proximity to the BCR has been the topic of numerous studies, with many lines of evidence suggesting that its sialic acid-containing glycan ligands on either the same cell ( cis ) or on another cell ( trans ) can modulate the function of CD22 as an inhibitor of B-cell activation by sequestering it away or enforcing ligation to the B-cell receptor (10–15). The ligands for CD22 are α2-6-linked sialic acids, which are abundantly found on the cell surface of lymphocytes.…”

Siglec-G represses DAMP-mediated effects on T cells

“…Those that focused on negative regulatory effects of Siglecs focused only on innate immunity or on B cell-intrinsic functions (3,6,24,25). However, the roles of DAMPs and Siglecs in T cell biology remain unexplored.…”