Inhibition of NF-κB induces a switch from CD95L-dependent to CD95L-independent and JNK-mediated apoptosis in T cells.

NF-κB is a crucial transcription factor regulating apoptosis sensitivity and resistance. It has been shown that inhibition of NF-κB in T lymphocytes leads to sensitization towards apoptosis. The underlying molecular mechanism is not entirely understood. Therefore, we investigated T cell receptor (TCR) stimulated apoptosis in T cells in which NF-κB activity is blocked by an inhibitor or IκBα overexpression. We show that enhanced apoptosis upon TCR stimulation is caspase- and JNK-dependent, but independent of the CD95/CD95L system. Generation of reactive oxygen species (ROS) induced sustained JNK phosphorylation by inactivation of MAP kinase phosphatase 7 (MKP7). Sustained JNK activation causes upregulation of the pro-apototic protein BIM. Thus, inhibition of NF-κB causes a switch from classical activation-induced cell death (AICD) to CD95L-independent apoptosis.