Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type 1 T-cell process. However, a prototypical type 1 cytokine, interferon-gamma (IFN-gamma), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-gamma-receptor-deficient (IFN-gamma RKO) MHC-matched C57BL/6 recipients. In IFN-gamma RKO recipients, host cells were unresponsive to IFN-gamma whereas wt donor cells were exposed to exceptionally high levels of IFN-gamma. From an IFN-gamma perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-gamma R prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-gamma RKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-gamma: Ccnd1 and Myc. We conclude that IFN-gamma produced by alloreactive T cells may entail a severe g raft-versus-g raft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.