title: The affinity threshold for human B cell activation via the antigen receptor complex is reduced upon co-ligation of the antigen receptor with CD21 (CR2).
abstract: The present studies have examined whether the potential of an Ag to co-ligate the complement (C3d)-binding CD21 receptor complex with the membrane IgM (mIgM) receptor complex can reduce the mIgM:Ag affinity threshold for triggering human B cell S phase entry. A series of Ab:dextran conjugates consisting of affinity-diverse anti-IgM mAb, with and without anti-CD21 mAb, were synthesized as polyclonally reactive, moderately multivalent ligands that mimic C3d-bearing and non-C3d-bearing Ag. Co-ligation of mIgM and CD21 significantly diminished both the ligand concentration threshold and the IgM:ligand affinity threshold for eliciting S phase entry in the presence of IL-4. Furthermore, such co-engagement ablated the triggering bonus associated with high mlgM:ligand affinity, suggesting that B cells with a high affinity for Ag are not preferentially activated over B cells of intermediate affinity upon encountering a multivalent Ag with bound C3d. The enhancing effects of mIgM:CD21 co-ligation were restricted to low concentrations of ligand; at high concentrations, a decrease in B cell DNA synthesis was often observed. The findings suggest that the ability a moderately multivalent Ag substrate to engage B cells through both mIgM and CD21 is critical for B cell activation at limiting Ag concentrations, and furthermore, that mIgM:CD21 co-engagement may be particularly important in eliciting an immune response to such Ags in unprimed individuals in whom the majority of specific B cells are of low affinity.
authors.affiliation: Department of Rheumatology, Hospital for Joint Diseases, New York 10003, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Mongini
authors.forename: M A
authors.initials: MA
authors.lastname: Vilensky
authors.forename: P F
authors.initials: PF
authors.lastname: Highet
authors.forename: J K
authors.initials: JK
authors.lastname: Inman
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001666:Binding Sites, Antibody; D002648:Child; D002675:Child, Preschool; D004261:DNA Replication / Q000276:immunology; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism* / Q000502:physiology*; D017464:Receptors, Complement 3d / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D016196:S Phase / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D003911:Dextrans; D007075:Immunoglobulin M; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d