FACTORS MODIFYING SURVIVAL PATHWAYS OF GERMINAL CENTER B-CELLS - GLUCOCORTICOIDS AND TRANSFORMING GROWTH-FACTOR-BETA, BUT NOT CYCLOSPORINE-A OR ANTI-CD19, BLOCK SURFACE IMMUNOGLOBULIN-MEDIATED RESCUE FROM APOPTOSIS

The tendency for germinal center (GC) B cells to enter apoptosis is suppressed on engaging antigen receptor with immobilized anti-immunoglobulin; cross-linking of surface CD40 by monoclonal antibodies provides an additional signal for rescuing GC cells from programmed death. These observations are believed to reflect events that, in vivo, would allow for the selection of centrocytes which have undergone somatic mutation on Ig V-region genes to generate antigen receptor of high affinity. The purpose of the present study was to identify factors capable of modifying the survival pathways of GC cells. Transforming growth factor-beta, at an optimal concentration of 1 ng/ml, was found to inhibit surface immunoglobulin (sIg)-mediated rescue of GC cells but had no influence on survival promoted through CD40. Both routes of rescue were blocked by the glucocorticoid prednisolone at pharmacological concentrations (ID50 = 10(-7) m). Cyclosporin A, an antagonist of sIg-mediated signaling in resting B cells, failed to block rescue of GC cells through either of the receptor-activated pathways. Antibody to CD19 - which also suppresses the activation of resting B cells - not only left GC cell rescue undiminished, but rather provided a modest survival signal of its own; interferon-alpha behaved similarly while interferon-gamma failed to influence GC cell survival in either direction.