Opposing Roles of Interferon-γ on CD4⁺ T Cell-Mediated Graft-Versus-Host Disease: Effects of Conditioning

Although alloreactive T cells are required for the induction of graft-versus-host disease (GVHD), other factors can influence outcome in murine models of the disease. Lethal total body irradiation (TBI) conditioning regimens followed by reconstitution with allogeneic lymphohematopoietic cells results in the generation of donor anti-host cytotoxic T lymphocyte (CTL)-mediated solid organ (gut, liver, skin) destruction. In contrast, donor anti-host CTL-mediated hematopoietic failure is the primary cause of morbidity following sublethal TBI. To determine the role of interferon (IFN)-γ in graft-versus-host reactions against hematopoietic and solid organ targets, we used IFN-γ knockout mice as donors in both lethal TBI and bone marrow transplantation (BMT) rescue and sublethal TBI models. In this report, we show that CD4⁺ T cells from IFN-γ knockout (KO) mice resulted in accelerated GVHD after lethal TBI/BMT using a single major histocompatibility class II mismatch model. In marked contrast, the use of these same IFN-γ KO CD4⁺ donor cells in combination with sublethal TBI significantly ameliorated GVHD-associated mortality. In these recipients, severe anemia, bone marrow aplasia, and intestinal lesions were observed in the presence but not the absence of donor-derived IFN-γ. Administration of anti-IFN-γ antibodies to sublethally irradiated recipients of wild-type donor cells confirmed the role of IFN-γ depletion in CD4⁺ T cell-mediated GVHD. In conclusion, the extent of conditioning markedly affects the role of IFN-γ in GVHD lesions mediated by CD4⁺ T cells. In models using sublethal TBI, the absence of IFN-γ is protective from GVHD, whereas in lethal TBI situations, the loss is deleterious.