IFN- dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses

Coley, S. M., Ford, M. L., Hanna, S. C., Wagener, M. E., Kirk, A. D. and Larsen, C. P. (2009) IFN- dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses. Journal of Immunology, 182(1), pp. 225-233. (doi: 10.4049/​jimmunol.182.1.225) (PMID:19109153) (PMCID:PMC2683416)

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Abstract

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-γ promotes CD8 T cell-mediated immune responses, but IFN-γ-deficient mice show early graft loss despite costimulation blockade. In contrast, we found that IFN-γ receptor knockout mice show dramatically prolonged graft survival under costimulation blockade. To investigate this paradox, we addressed the effects of IFN-γ on T cell alloresponses in vivo independent of the effects of IFN-γ on graft survival. We identified a donor-specific CD8 T cell breakthrough response temporally correlated with costimulation blockade-resistant rejection. Neither IFN-γ receptor knockout recipients nor IFN-γ-deficient recipients showed a CD8 breakthrough response. Graft death on IFN-γ-deficient recipients despite costimulation blockade could be explained by the lack of IFN-γ available to act on the graft. Indeed, the presence of IFN-γ was necessary for graft survival on IFN-γ receptor knockout recipients, as either IFN-γ neutralization or the lack of the IFN-γ receptor on the graft precipitated early graft loss. Thus, IFN-γ 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.

Item Type:Articles
Additional Information:This work was supported by National Institutes of Health Grant R37 AI40519-11 (to C.P.L.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Coley, Dr Shana
Authors: Coley, S. M., Ford, M. L., Hanna, S. C., Wagener, M. E., Kirk, A. D., and Larsen, C. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Immunology
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606

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