Published online before print October 15, 2008
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*Department of Immunology, Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut Health Center, Farmington, Connecticut, USA; and Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
@ To whom correspondence should be addressed. E-mail: vella{at}uchc.edu.
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 
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
B
(p-IB) and high basal levels of NF-B activity in the effector CD8 T cells. Bay11 trumped both events by reducing the presence of p-IB and ensuing NF-B activity. Not all pathways were impacted to this degree, however, as mitogen-mediated ERK phosphorylation was evident during NF-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.
Key Words: apoptosis • T cell survival • costimulatory molecules • cytokines
