Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-gamma receptor-deficient hosts.
The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I 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-gammaRKO) MHC-matched C57BL/6 recipients. In IFN-gammaRKO 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-gammaR prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-gammaRKO 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 graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.
Institute for Research in Immunology and Cancer, Montréal, QC, Canada.
Jean-Sébastien
JS
Delisle
Louis
L
Gaboury
Marie-Pier
MP
Bélanger
Eliane
E
Tassé
Hideo
H
Yagita
Claude
C
Perreault
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000502:physiology; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006410:Hematopoiesis / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology; D008213:Lymphocyte Activation; D038041:Lymphopoiesis / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D053222:Fas Ligand Protein; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C505658:Fasl protein, mouse