Death receptor-mediated activation-induced apoptosis of
antigen-specific T cells is a major mechanism of peripheral tolerance induction and immune homeostasis. Failure to undergo activation-induced cell death (AICD) is an important underlying cause of many
autoimmune diseases. Thus, enhancing the T cell's own suicide mechanism may provide an efficient
therapy for the treatment of
autoimmune diseases.
Bisindolylmaleimide VIII (
Bis VIII), a PKC inhibitor, can sensitize T cells for
death receptor-induced apoptosis and thus can inhibit the development of T cell-mediated
autoimmune disease in vivo. In this study, we have analyzed the functional consequences of accelerated suicide for a protective CD8+ T cell-mediated immune response. Our data indicate that CD8+ T cells are sensitized by
Bis VIII to AICD, both in vitro and in vivo. The sensitizing effect of
Bis VIII appears to be mediated by specific downmodulation of the antiapoptotic molecule cellular FLICE-like inhibitory
protein (cFLIP(L)). Importantly,
Bis VIII administration during an acute lymphocytic choriomeningitis virus (LCMV)
infection causes the depletion of virus-specific CD8+ T cells and subsequently impaired cytotoxicity and virus clearance. We conclude that resistance to
death receptor-induced apoptosis is crucial for the efficient induction of a protective immune response, and that
Bis VIII-based
immunotherapies have to be applied under well-controlled conditions to avoid the induction of immune incompetence and the inability to respond to pathogen
infection.