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The IKK‐neutralizing compound Bay11 kills supereffector CD8 T cells by altering caspase‐dependent activation‐induced cell death
Author(s) -
Lee SeungJoo,
Long Meixiao,
Adler Adam J.,
Mittler Robert S.,
Vella Anthony T.
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0408248
Subject(s) - biology , cd137 , programmed cell death , microbiology and biotechnology , effector , apoptosis , cytotoxic t cell , cd8 , caspase , iκb kinase , mapk/erk pathway , signal transduction , cancer research , nf κb , immunology , antigen , in vitro , biochemistry
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 γ 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 IκBα (p‐IκBα) and high basal levels of NF‐κB activity in the effector CD8 T cells. Bay11 trumped both events by reducing the presence of p‐IκBα and ensuing NF‐κB activity. Not all pathways were impacted to this degree, however, as mitogen‐mediated ERK phosphorylation was evident during NF‐κB 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.