THE AFFINITY THRESHOLD FOR HUMAN B-CELL ACTIVATION VIA THE ANTIGEN RECEPTOR COMPLEX IS REDUCED UPON CO-LIGATION OF THE ANTIGEN RECEPTOR WITH CD21 (CR-2)

The present studies have examined whether the potential of an Ag to co -ligate the complement (C3d)-binding CD21 receptor complex with the me mbrane IgM (mIgM) receptor complex can reduce the mIgM:Ag affinity thr eshold for triggering human B cell S phase entry. A series of Ab:dextr an conjugates consisting of affinity-diverse anti-IgM mAb, with and wi thout anti-CD21 mAb, were synthesized as polyclonally reactive, modera tely multivalent ligands that mimic C3d-bearing and non-C3d-bearing Ag . Co-ligation of mIgM and CD21 significantly diminished both the ligan d concentration threshold and the IgM:ligand affinity threshold for el iciting S phase entry in the presence of IL-4. Furthermore, such co-en gagement ablated the triggering bonus associated with high mIgM:ligand affinity, suggesting that B cells with a high affinity for Ag are not preferentially activated over B cells of intermediate affinity upon e ncountering a multivalent Ag with bound C3d. The enhancing effects of mIgM:CD21 co-ligation were restricted to law concentrations of ligand; at high concentrations, a decrease in B cell DNA synthesis was often observed. The findings suggest that the ability of a moderately multiv alent Ag substrate to engage B cells through both mIgM and CD21 is cri tical for B cell activation at limiting Ag concentrations, and further more, that mIgM:CD21 co-engagement may be particularly important in el iciting an immune response to such Ags in unprimed individuals in whom the majority of specific B cells are of low affinity.