CD40 signaling-mediated induction of Bcl-XL, Cdk4, and Cdk6. Implication of their cooperation in selective B cell growth.

Signals sent through CD40 play crucial roles in B cell differentiation, including blocking apoptosis of germinal center B cells. In this study, using a murine B cell WEHI-231 line that undergoes apoptosis by the cross-linking of surface Ag receptors (sIgM), we have demonstrated that CD40 signalings are linked to induction of the Bcl-xL, Cdk4, and Cdk6 proteins whose expression was significantly suppressed by the apoptotic signal through sIgM. Mutational analyses of CD40 revealed that the domain of human CD40 required for blocking apoptosis of WEHI-231 cells coincides with that required for Bcl-xL induction. Signals through sIgM arrest cells in the G1 phase of the cell cycle, which is followed by apoptosis. However, while constitutive expression of Bcl-XL leads to the inhibition of apoptosis. Nevertheless, Bcl-xL fails to induce S phase entry. By CD40 signalings, both Cdk4 and Cdk6 resume their normal expression levels, which are sufficient for passing the restriction point in G1 even in the presence of the apoptotic signals mediated by sIgM. These results suggest that cooperation of Bcl-xL, Cdk4, and Cdk6 induced by CD40 signaling plays a key role in CD40-mediated selective growth of B cells.