Ambivalent role of FasL in murine acute graft-versus-host-disease

Abstract

Abstract Fas ligand is increased in several immune-mediated diseases, including acute graft-versus-host disease, a donor cell–mediated disorder post–hematopoietic stem cell transplantation. In this disease, Fas ligand is involved in T-cell–mediated damage to host tissues. However, the role of its expression on donor non–T cells has, so far, never been addressed. Using a well-established CD4- and CD8-mediated graft-versus-host disease murine model, we found that precocious gut damage and mice mortality are increased with a graft of donor T- and B-depleted bone marrow cells devoid of Fas ligand as compared with their wild-type counterparts. Interestingly, serum levels of both soluble Fas ligand and IL-18 are drastically reduced in the recipients of Fas ligand–deficient grafts, indicating that soluble Fas ligand stems from donor bone marrow–derived cells. In addition, the correlation between the concentrations of these 2 cytokines suggests that IL-18 production arises through a soluble Fas ligand–driven mechanism. These data highlight the importance of Fas ligand–dependent production in IL-18 production and in mitigating acute graft-versus-host disease. Overall, our data reveal the functional duality of Fas ligand according to its source.