title: 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 mechanisms by which blood cells displaying a foreign Ag induce tolerance remain poorly understood. Based on recent findings showing that the B cell siglecs, CD22 and Siglec-G, can promote tolerance to Ags 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 Ags by initiating an inhibitory signal that culminates in elimination of the Ag-reactive B cell. CD22 and Siglec-G are recruited to the immunological synapse by sialic acid ligands on the Ag-bearing cells, producing a tolerogenic signal involving Lyn and the proapoptotic factor BIM that promotes deletion of the B cell and failure of mice to develop Abs to the Ag 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.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Macauley
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037 jpaulson@scripps.edu.
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D007108:Immune Tolerance; D056724:Immunity, Humoral; D054992:Immunological Synapses / Q000276:immunology / Q000378:metabolism; D037102:Lectins / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000502:physiology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics / Q000502:physiology*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000941:Antigens; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D037102:Lectins; D008024:Ligands; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases