title: Membrane IgM-mediated signaling of human B cells. Effect of increased ligand binding site valency on the affinity and concentration requirements for inducing diverse stages of activation.
abstract: The potential for ligand-initiated signal transduction through B cell membrane IgM is assessed in terms of ligand concentration, binding site valency, and binding site affinity for membrane Ig. Estimates of the physicochemical requirements for achieving G0* enhancement of class II MHC expression, G1 entry, and S phase entry in human B cells were made by comparing the stimulatory effects of three affinity-diverse anti-Cmu2 mAb when in bivalent (unconjugated) form, or as mAb-dextran conjugates with low binding site valency (oligovalent ligands) or high binding site valency (multivalent ligands). An increase in binding site number (and concomitant molecular mass) caused a profound reduction in both the minimal concentration and affinity requisites for B cell activation. The enhancing effect of increased binding site valency was most evident for the signaling of those most distal stages in B cell activation, i.e., G1 and S phase, which were difficult to induce with bivalent ligands. The results suggest that highly multimeric TI-2 Ag may be good immunogens because they are able to elicit a full activation response not only from infrequent high affinity B cells, but also from a substantial proportion of the many lower affinity Ag-specific B cells in virgin B cell populations. Interestingly, the activation of B cells by ligands with binding sites of high intrinsic affinity (Ka = 5 x 10(8) M-1) was less influenced by increases in binding site valency than was B cell activation by ligands with intermediate binding site affinity (Ka = 2 x 10(7) M-1). This suggests that the minimal epitope valency requirement for T cell-independent B cell activation by mIg cross-linking Ag may be dependent on the intrinsic affinity with which membrane Ig molecules on a given B cell interact with the redundantly expressed epitopes.
authors.affiliation: Department of Rheumatic Diseases, Hospital for Joint Diseases, New York, NY 10003.
authors.forename: P K
authors.initials: PK
authors.lastname: Mongini
authors.forename: C A
authors.initials: CA
authors.lastname: Blessinger
authors.forename: P F
authors.initials: PF
authors.lastname: Highet
authors.forename: J K
authors.initials: JK
authors.lastname: Inman
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D002453:Cell Cycle; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006681:HLA-D Antigens / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000502:physiology*; D066298:In Vitro Techniques; D008024:Ligands; D008213:Lymphocyte Activation; D012313:RNA / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D006681:HLA-D Antigens; D007075:Immunoglobulin M; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D012313:RNA; D004247:DNA