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

J Immunol. 1992 Jun 15;148(12):3892-901.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • B-Lymphocytes / immunology*
  • Cell Cycle
  • Cells, Cultured
  • DNA / biosynthesis
  • HLA-D Antigens / metabolism
  • Humans
  • Immunoglobulin M / physiology*
  • In Vitro Techniques
  • Ligands
  • Lymphocyte Activation*
  • RNA / biosynthesis
  • Receptors, Antigen, B-Cell / physiology*
  • Signal Transduction
  • Structure-Activity Relationship

Substances

  • HLA-D Antigens
  • Immunoglobulin M
  • Ligands
  • Receptors, Antigen, B-Cell
  • RNA
  • DNA