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The Journal of Immunology, 2009, 182, 225 -233
Copyright © 2009 by The American Association of Immunologists, Inc.
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IFN-{gamma} Dictates Allograft Fate via Opposing Effects on the Graft and on Recipient CD8 T Cell Responses1

Shana M. Coley, Mandy L. Ford, Samantha C. Hanna, Maylene E. Wagener, Allan D. Kirk and Christian P. Larsen2

Department of Surgery, Emory Transplant Center, Emory University, Atlanta, GA 30322

CD8 T cells are necessary for costimulation blockade-resistant rejection. However, the mechanism by which CD8 T cells mediate rejection in the absence of major costimulatory signals is poorly understood. IFN-{gamma} promotes CD8 T cell-mediated immune responses, but IFN-{gamma}-deficient mice show early graft loss despite costimulation blockade. In contrast, we found that IFN-{gamma} receptor knockout mice show dramatically prolonged graft survival under costimulation blockade. To investigate this paradox, we addressed the effects of IFN-{gamma} on T cell alloresponses in vivo independent of the effects of IFN-{gamma} on graft survival. We identified a donor-specific CD8 T cell breakthrough response temporally correlated with costimulation blockade-resistant rejection. Neither IFN-{gamma} receptor knockout recipients nor IFN-{gamma}-deficient recipients showed a CD8 breakthrough response. Graft death on IFN-{gamma}-deficient recipients despite costimulation blockade could be explained by the lack of IFN-{gamma} available to act on the graft. Indeed, the presence of IFN-{gamma} was necessary for graft survival on IFN-{gamma} receptor knockout recipients, as either IFN-{gamma} neutralization or the lack of the IFN-{gamma} receptor on the graft precipitated early graft loss. Thus, IFN-{gamma} is required both for the recipient to mount a donor-specific CD8 T cell response under costimulation blockade as well as for the graft to survive after allotransplantation.

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 This work was supported by National Institutes of Health Grant R37 AI40519-11 (to C.P.L.).

2 Address correspondence and reprint requests to Dr. Christian P. Larsen, Emory Transplant Center, Department of Surgery, Emory University, 101 Woodruff Circle, WMRB Suite 5203, Atlanta, GA 30322. E-mail address: clarsen{at}emory.edu

3 Abbreviations used in this paper: CoB, costimulation blockade; GKO, IFN-{gamma} knockout; GRKO, IFN-{gamma}R knockout; MST, median graft survival time; PKC{theta}, protein kinase C-{theta}; POD, postoperative day; WT, wild type.






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