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

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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish
Pages (from-to)225-233
Number of pages9
JournalJournal of Immunology
Issue number1
StatePublished - 1 Jan 2009
Externally publishedYes


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