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X-linked Inhibitor of Apoptosis Regulates T Cell Effector Function¹

Simone P. Zehntner^2,*, Lyne Bourbonnière^*, Craig S. Moore, Stephen J. Morris, Danielle Methot, Martine St. Jean, Eric Lacasse, Andrea L. O. Hebb, George S. Robertson^¶, Jon Durkin, John W. Gillard and Trevor Owens^*,

^* Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Canada; Aegera Therapeutics, Montreal, Quebec, Canada; Medical Biotechnology Center, University of Southern Denmark, Odense, Denmark; Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; and ^¶ Department of Psychiatry, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ S.P.Z. and T.O. acknowledge support from a Multiple Sclerosis Society of Canada Pilot Grant. T.O. was also the recipient of grant support from Canadian Institutes of Health Research (CIHR). G.S.R., C.S.M., and A.L.O.H. were supported in part by a grant from Genome Canada. C.S.M. and A.L.O.H. were also supported by salary awards from the MS Society of Canada. G.S.R. is a CIHR-Research and Development Chair.

² Address correspondence and reprint requests to Dr. Simone P. Zehntner, Neuroimmunology, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada. E-mail address: simone.zehntner{at}mcgill.ca

³ Abbreviations used in this paper: IAP, inhibitor of apoptosis; XIAP, X-linked inhibitor of apoptosis; BIR, baculovirus inhibitory repeats; MS, multiple sclerosis; ASO, antisense oligonucleotides; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; 7-AAD, 7-aminoactinomycin D; AICD, activation induced cell death; LN, lymph node.