title: Inhibitors of apoptosis proteins (IAPs) are required for effective T-cell expansion/survival during antiviral immunity in mice.
abstract: Inhibitors of apoptosis proteins (IAPs) were originally described as regulating apoptosis by direct binding to caspases. More recently, IAPs have been identified as important modulators of canonical and noncanonical nuclear factor κB signaling via their ubiquitin-E3 ligase activity. IAPs are therefore, not only gatekeepers of cell death, but are probably also involved in the regulation of inflammation, as well as innate and adaptive immunity. In this study, we analyzed the role of IAPs in T-cell immunity during lymphocytic choriomeningitis virus (LCMV) infection by pharmacological targeting with an IAP antagonist/second mitochondria-derived activator of caspase-mimetic. Expansion of virus-specific CD8 T cells was drastically reduced in LCMV-infected mice exposed to IAP antagonists. Accordingly, virus control was substantially impaired, indicated by high virus titres in the spleen and the spread of LCMV to peripheral organs. The profound negative effect of IAP antagonists on T-cell immunity was partially linked to tumor necrosis factor-mediated cell death of activated T cells and required inhibition of X-linked inhibitor of apoptosis, as well as cellular IAP-1. Thus, IAPs play an important role in T-cell expansion and survival in the context of a highly inflammatory environment such as a virus infection, indicating that IAP antagonists may interfere with immune responses.
authors: Institute of Microbiology and Hygiene.
authors: Ian E
authors: IE
authors: Gentle
authors: Isabel
authors: I
authors: Moelter
authors: Nadja
authors: N
authors: Lechler
authors: Sarah
authors: S
authors: Bambach
authors: Smiljka
authors: S
authors: Vucikuja
authors: Georg
authors: G
authors: Häcker
authors: Peter
authors: P
authors: Aichele
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002470:Cell Survival; D007109:Immunity; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D048069:Tumor Necrosis Factors / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D048069:Tumor Necrosis Factors; D051636:X-Linked Inhibitor of Apoptosis Protein