Induction of antigen-specific B cell tolerance through the development of a versatile platform to target siglecs (45.4)

Abstract CD22 and SiglecG are proposed to be negative regulators of B cell receptor signaling through their ability to recognize sialic acid-containing glycans. Recent studies have shown that multivalent presentation of high affinity CD22 and SiglecG ligands in cis with a T-independent antigen can tolerize B cells (Duong et al., J. Exp. Med., 2010). Here we describe studies aimed at showing the generality of this phenomenon. To realize this aim, a novel liposomal nanoparticle platform was developed for presentation of both high affinity Siglec ligands and antigen. Chemical conjugation of the Siglec ligand and antigen to this platform is facile and, importantly, this platform is highly compatible with in vivo studies. Using this new platform, robust B cell tolerance is achieved toward both T-independent and T-dependent antigens in mice. Mechanistic studies provide clear evidence that: i) CD22 and SiglecG are the targets; ii) apoptosis of B cells is the mode of tolerance; iii) tolerization is highly selective to B cells containing a BCR that is specific for the targeted antigen. These studies reinforce the hypothesis that CD22 and SiglecG are critical components of a B cell that allows it to distinguish self from non-self. This method has clear potential for treatment of autoimmune diseases and allergies by antigen specific tolerization of B cells.