Germinal center cells express bcl‐2 protein after activation by signals which prevent their entry into apoptosis

Abstract

B cells undergo selection within germinal centers on the basis of their capacity to be activated by antigen held on follicular dendritic cells. Isolated germinal center B cells in culture kill themselves by apoptosis but this is prevented if their receptors for antigen are cross‐linked. In this study it is confirmed that almost all germinal center B cells, unlike other B cells, do not express the 25‐kDa protein encoded by the bcl‐2 oncogene. Cross‐linking the surface Ig of isolated germinal center cells causes them to express bcl‐2 protein. Two other stimuli which inhibit the entry of germinal center cells to apoptosis result in the expression of bcl‐2 protein. These stimuli are: (a) CD40 antibody and (b) recombinant 25‐kDa fragment of the CD23 protein plus recombinant interleukin 1α. Respectively, these induce germinal center cells to differentiate to resting B cells or plasmablasts. Dual‐fluorescence studies on small lymphocytes confirm the presence of bcl‐2 protein in mitochondria but show that this is also present in other extra‐nuclear areas. Burkitt lymphoma cells have a phenotype which indicates that they are neoplastic cells of germinal center origin. The expression of bcl‐2 protein by Burkitt lymphoma lines was also studied. Burkitt lines which retain the phenotype of fresh Burkitt lymphoma cells can be induced to enter apoptosis on culture with the Ca²⁺ ionophore ionomycin. These cells were found not to express bcl‐2 protein. By contrast, Burkitt lines which have drifted towards a lymphoblastoid cell line phenotype and are resistant to the induction of apoptosis express high levels of the bcl‐2 protein. The findings support the concept that the susceptibility of germinal center cells to entering apoptosis is associated with their lack of expression of bcl‐2 protein. Aberrant expression of bcl‐2 protein by some neoplastic germinal center cells may allow survival in situations where their normal counterparts die.