Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease.
Graft-versus-host disease (GVHD) is the main complication after allogeneic bone marrow transplantation. Although the tissue damage and subsequent patient mortality are clearly dependent on T lymphocytes present in the grafted inoculum, the lethal effector molecules are unknown. Here, we show that acute lethal GVHD, induced by the transfer of splenocytes from C57BL/6 mice into sensitive BALB/c recipients, is dependent on both perforin and Fas ligand (FasL)-mediated lytic pathways. When spleen cells from mutant mice lacking both effector molecules were transferred to sublethally irradiated allogeneic recipients, mice survived. Delayed mortality was observed with grafted cells deficient in only one lytic mediator. In contrast, protection from lethal acute GVHD in resistant mice was exclusively perforin dependent. Perforin-FasL-deficient T cells failed to lyse most target cells in vitro. However, they still efficiently killed tumor necrosis factor alpha-sensitive fibroblasts, demonstrating that cytotoxic T cells possess a third lytic pathway.
Braun
M Y
MY
Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
Lowin
B
B
French
L
L
Acha-Orbea
H
H
Tschopp
J
J
D000818:Animals; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin