Modulation of anti-IgM-induced B cell apoptosis by Bcl-x(L) and CD40 in WEHI-231 cells: Dissociation from cell cycle arrest and dependence on the avidity of the antibody-IgM receptor interaction

The demise of B cell progenitors expressing functional IgM receptors for self appears to be the main mechanism by which B cell tolerance is accomplished. The genetic mechanisms that regulate the death process during this critical step of B cell development are still poorly understood. We have studied the regulation of apoptosis in WEHI-231 lymphoma cells after treatment with a panel of anti-IgM mAbs as an in vitro model of clonal B cell deletion. We showed that a product of bcl-x, Bcl-x(L), can inhibit anti-IgM- induced apoptosis but not cell cycle arrest in a dose-dependent manner. Bcl- x(L0 was efficient in protecting B cells from low but not high avidity anti- IgM mAbs. In contrast to that observed with Bcl-x(L), CD40 stimulation was efficient in inhibiting both cell cycle arrest and apoptosis after IgM cross- linking regardless of the binding avidity of the anti-IgM Ab. Moreover, activation through IgM receptors but not CD40 induced up-regulation followed by rapid down-modulation of Bd-x(L). Thus, the capacity of Bcl-x(L) to modulate anti-IgM-induced apoptosis in WEHI-231 cells is highly dependent on the avidity of the Ab-IgM receptor interaction.