ANTIGEN RECEPTOR-INDUCED APOPTOSIS OF HUMAN GERMINAL CENTER B-CELLS IS TARGETED TO A CENTROCYTIC SUBSET

The outcome of the signals transduced through the B cell antigen recep tor (BCR) depends both on their maturational stage and on the extent o f receptor cross-linking. It is established that the BCR-mediated apop tosis of immature B cells represents an important mechanism for tolera nce induction in the preimmune B cell compartment. We show here that m ature germinal center (GC) B cells can re-acquire sensitivity to BCR-i nduced cell death following CD40 ligation. In contrast, neither virgin nor memory B cells become susceptible to antigen receptor-triggered a poptosis upon CD40 stimulation, suggesting that this phenomenon may pl ay a role in the shaping of the mature B cell repertoire in GC. Our da ta reveal that the death signal evoked through the BCR does not involv e the Fc gamma receptors, does not operate through the Fas/Fas ligand system, and can be blocked by interleukin-4. Finally, we found that th e acquisition of sensitivity to the death-promoting effect of anti-Ig antibodies in CD40-stimulated GC B cell cultures correlates with the i nduction of a centrocytic phenotype. We propose that negative regulato ry signals via the BCR may delete somatically mutated centrocytes with self-reactivity.