The IKK-neutralizing compound Bay11 kills supereffector CD8 T cells by altering caspase-dependent activation-induced cell death

Antigen with dual costimulation through CD137 and CD134 induces powerful CD8 T cell responses. These effector T cells are endowed with an intrinsic survival program resulting in their accumulation in vivo, but the signaling components required for survival are unknown. We tested a cadre of pathway inhibitors and found one preclinical compound, Bay11-7082 (Bay11), which prevented survival. Even the gamma(c) cytokine family members IL-2, -4, -7, and -15 could not block death, nor could pretreatment with IL-7. We found that dual costimulation caused loading of phosphorylated I kappa B alpha (p-I kappa B alpha) and high basal levels of NF-kappa B activity in the effector CD8 T cells. Bay11 trumped both events by reducing the presence of p-I kappa B alpha and ensuing NF-kappa B activity. Not all pathways were impacted to this degree, however, as mitogen-mediated ERK phosphorylation was evident during NF-kappa B inhibition. Nonetheless, Bay11 blocked TCR-stimulated cytokine synthesis by rapidly accentuating activation-induced cell death through elicitation of a caspase-independent pathway. Thus, in effector CD8 T cells, Bay11 forces a dominant caspase-independent death signal that cannot be overcome by an intrinsic survival program nor by survival-inducing cytokines. Therefore, Bay11 may be a useful tool to deliberately kill death-resistant effector T cells for therapeutic benefit. J. Leukoc. Biol. 85: 175-185; 2009.