IFN-gamma dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses.
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.
Coley
Shana M
SM
Department of Surgery, Emory Transplant Center, Emory University, Atlanta, GA 30322, USA.
Ford
Mandy L
ML
Hanna
Samantha C
SC
Wagener
Maylene E
ME
Kirk
Allan D
AD
Larsen
Christian P
CP
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D018796:Immunoconjugates / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous; D000096743:Interferon gamma Receptor
D000069594:Abatacept; D000911:Antibodies, Monoclonal; D023201:CD40 Ligand; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor