HYPERCROSS-LINKING SURFACE IGM OR IGD RECEPTORS ON MATURE B-CELLS INDUCES APOPTOSIS THAT IS REVERSED BY COSTIMULATION WITH IL-4 AND ANTI-CD40

Cross-linking of sIgM or sIgD receptors on mature B cells with appropr iate anti-Ig Abs normally induces B cell activation and DNA synthesis. We show here that hypercross-linking of either class of sig receptor on these cells by biotinylated, normally mitogenic anti-mu or anti-del ta mAb by avidin rapidly induces unresponsiveness to heterologous anti -Ig, accompanied by DNA fragmentation characteristic of apoptosis. Apo ptotic nuclei can be detected within 4 h after stimulation, but cells that survive for 12 to 16 h are abortively activated, as evidenced by increased levels of MHC class II Ags. Because the induction of B cell tolerance is known to be modulated by T cell-derived influences, we in vestigated the effects of two stimuli-IL-4 and ligation of CD40-that a re known to affect B cell survival in this system. IL-4 partially reve rsed the induction of apoptosis, as did a mAb to CD40, and both reagen ts together caused almost complete reversal. We therefore conclude tha t in the absence of T cell help the extent of sIg receptor cross-linki ng on mature B cells determines whether the cells enter cycle or becom e deleted. We believe that this system represents a polyclonal model o f clonal deletion of mature B cells induced by highly cross-linking Ag s, such as type 2 T-independent polysaccharide Ags.