Requirement for Caspase-8 in NF- B Activation by Antigen Receptor

Caspase-8, a proapoptotic protease, has an essential role in lymphocyte activation and protective immunity. We show that caspase-8 deficiency (CED) in humans and mice specifically abolishes activation of the transcription factor nuclear factor κB (NF-κB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells. Caspase-8 also causes the αβ complex of the inhibitor of NF-κB kinase (IKK) to associate with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex. Recruitment of the IKKα, β complex, its activation, and the nuclear translocation of NF-κB require enzyme activity of full-length caspase-8. These findings thus explain the paradoxical association of defective apoptosis and combined immunodeficiency in human CED. A missing link in the pathway by which antigens activate the immune response is the full-length form of a protease, a fragment of which was known to trigger cell death. A missing link in the pathway by which antigens activate the immune response is the full-length form of a protease, a fragment of which was known to trigger cell death.