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 alloge neic bone marrow transplantation. Although the tissue damage and subse quent patient mortality are clearly dependent on T lymphocytes present in the grafted inoculum, the lethal effector molecules are unknown. H ere, we show that acute lethal GVHD, induced by the transfer of spleno cytes 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 tra nsferred to sublethally irradiated allogeneic recipients, mice survive d. 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-defi cient T cells failed to lyse most target cells in vitro. However, they still efficiently killed tumor necrosis factor alpha-sensitive fibrob lasts, demonstrating that cytotoxic T cells possess a third lytic path way.