title: X-linked inhibitor of apoptosis regulates T cell effector function.
abstract: To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice with experimental autoimmune encephalomyelitis, correlating with disease severity. Daily administration (10 mg/kg/day i.p.) of a 19-mer antisense oligonucleotide specific for XIAP (ASO-XIAP) abolished disease-associated XIAP mRNA and protein expression, and given from day of onset, alleviated experimental autoimmune encephalomyelitis and prevented relapses. Prophylactic treatment also reduced XIAP expression and prevented disease. Random or 5-base mismatched ASO was not inhibitory, and ASO-XIAP did not affect T cell priming. In ASO-XIAP-treated animals, infiltrating cells and inflammatory foci were dramatically reduced within the CNS. Flow cytometry showed an 88-93% reduction in T cells. The proportion of TUNEL(+) apoptotic CD4(+) T cells in the CNS was increased from <1.6 to 26% in ASO-XIAP-treated mice, and the proportion of Annexin V-positive CD4(+) T cells in the CNS increased. Neurons and oligodendrocytes were not affected; neither did apoptosis increase in liver, where XIAP knockdown also occurred. ASO-XIAP increased susceptibility of T cells to activation-induced apoptosis in vitro. Our results identify XIAP as a critical controller of apoptotic susceptibility of effector T cell function.
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Canada. simone.zehntner@mcgill.ca
authors.forename: Simone P
authors.initials: SP
authors.lastname: Zehntner
authors.forename: Lyne
authors.initials: L
authors.lastname: Bourbonnière
authors.forename: Craig S
authors.initials: CS
authors.lastname: Moore
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Morris
authors.forename: Danielle
authors.initials: D
authors.lastname: Methot
authors.forename: Martine
authors.initials: M
authors.lastname: St Jean
authors.forename: Eric
authors.initials: E
authors.lastname: Lacasse
authors.forename: Andrea L O
authors.initials: AL
authors.lastname: Hebb
authors.forename: George S
authors.initials: GS
authors.lastname: Robertson
authors.forename: Jon
authors.initials: J
authors.lastname: Durkin
authors.forename: John W
authors.initials: JW
authors.lastname: Gillard
authors.forename: Trevor
authors.initials: T
authors.lastname: Owens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D005260:Female; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein