Vital Nonapoptotic Functions for Caspase-8 in B Cells

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Clinical data have suggested both apoptotic and nonapoptotic roles for caspase-8 in human disease. Caspase-8 is a cysteine protease best known for mediating signals downstream of death receptors leading to apoptosis. Its mutation is associated with immunodeficiency in humans. Caspase-8 is known to be important in regulating T cells. To study B cell-specific roles for caspase-8, Lemmers et al . generated mice with B cell-specific inactivation of caspase-8 ( bcasp8 −/− ). Although caspase-8 was not necessary for B cell development, B cells from bcasp8 −/− mice were more resistant to apoptosis stimulated by the death receptor CD95 than were cells from wild-type mice. After infection with vesicular stomatitis virus (VSV), bcasp8 −/− mice exhibited lower production of VSV-neutralizing immunoglobulin G (IgG). This is similar to the situation observed in patients with a mutation in caspase-8, who have decreased concentrations of circulating antibodies after antigenic stimulation. Deletion of caspase-8 inhibited the increase in B cell numbers elicited by agonists for the Toll-like receptors (TLRs), TLR2, -3, and -4. Although bcasp8 −/− B cells were resistant to apoptosis induced by CD95, the lack of bcasp8 −/− B cell expansion in response to the TLR4 agonist lipopolysaccharide (LPS) was due to increased cell death mediated by caspase-3. Coimmunoprecipitation studies revealed that caspase-8 was recruited to the complex that activated nuclear factor κB (NF-κB), the IKKαβ complex, after LPS stimulation. Consistent with these findings, real-time polymerase chain reaction (PCR) analysis of the abundance of transcripts of NF-κB target genes showed that deletion of caspase-8 decreased the LPS-induced expression of these genes. Nuclear translocation of NF-κB in response to LPS was found to be substantially slower in B cells from bcasp8 −/− mice than in wild-type B cells. These data may provide a mechanism to explain the immunodeficiency in patients with a mutation in caspase-8. B. Lemmers, L. Salmena, N. Bidère, H. Su, E. Matysiak-Zablocki, K. Murakami, P. S. Ohashi, A. Jurisicova, M. Lenardo, R. Hakem, A. Hakem, Essential role for caspase-8 in Toll-like receptors and NFκB signaling. J. Biol. Chem. 282 , 7416-7423 (2007). [Abstract] [Full Text]