IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure.
Interferon gamma (IFN-γ) has been reported to have both negative and positive activity on hematopoietic cells, adding complexity to the interpretation of its pleiotropic functions. We examined the effects of IFN-γ on murine hematopoietic stem cells (HSCs) and progenitors in vitro and in vivo by using mouse models. IFN-γ treatment expanded bone marrow (BM) c-Kit(+)Sca1(+)Lin(-) (KSL) cell number but reduced BM KLCD150(+) and KLCD150(+)CD48(-) cells. IFN-γ-expanded KSL cells engrafted poorly when tested by competitive repopulation in vivo. KSL, KLCD150(+), and KLCD150(+)CD48(-) cells from IFN-γ-treated animals all showed significant upregulation in Fas expression. When cocultured with activated T cells in vitro, KSL and KLCD150(+) cells from IFN-γ-treated donors showed increased apoptosis relative to those from untreated animals, and infusion of activated CD8 T cells into IFN-γ-injected animals in vivo led to partial elimination of KSL cells. Exposure of BM cells or KSL cells to IFN-γ increased expression of Fas, caspases, and related proapoptotic genes and decreased expression of Ets-1 and other hematopoietic genes. In mouse models of BM failure, mice genetically deficient in IFN-γ receptor expression showed attenuation of immune-mediated marrow destruction, whereas effector lymphocytes from IFN-γ-deficient donors were much less potent in initiating BM damage. We conclude that the activity of IFN-γ on murine hematopoiesis is context dependent. IFN-γ-augmented apoptotic gene expression facilitates destruction of HSCs and progenitors in the presence of activated cytotoxic T cells, as occurs in human BM failure.
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Jichun
J
Chen
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Xingmin
X
Feng
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Marie J
MJ
Desierto
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Keyvan
K
Keyvanfar
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Neal S
NS
Young
D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006457:Hemoglobinuria, Paroxysmal / Q000276:immunology* / Q000503:physiopathology; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D017471:Receptors, Interferon / Q000172:deficiency / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics; D000096743:Interferon gamma Receptor
D053222:Fas Ligand Protein; D007371:Interferon-gamma; D017471:Receptors, Interferon; D019014:fas Receptor; D000096743:Interferon gamma Receptor; C491899:Fas protein, mouse; C505658:Fasl protein, mouse