Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence.
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.
Wasem
Christoph
C
Division of Immunopathology, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland.
Arnold
Diana
D
Saurer
Leslie
L
Corazza
Nadia
N
Jakob
Sabine
S
Herren
Simon
S
Vallan
Claudio
C
Mueller
Christoph
C
Brunner
Thomas
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D007108:Immune Tolerance; D007167:Immunotherapy; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D014779:Virus Replication / Q000187:drug effects
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008301:Maleimides; C064755:Ro 31-7549