X-linked inhibitor of apoptosis regulates T cell effector function.
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.
Zehntner
Simone P
SP
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Canada. simone.zehntner@mcgill.ca
Bourbonnière
Lyne
L
Moore
Craig S
CS
Morris
Stephen J
SJ
Methot
Danielle
D
St Jean
Martine
M
Lacasse
Eric
E
Hebb
Andrea L O
AL
Robertson
George S
GS
Durkin
Jon
J
Gillard
John W
JW
Owens
Trevor
T
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*
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