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

Abstract

Fas ligand (FasL) is increased in several immune-mediated diseases, including acute graft versus host disease (aGVHD), a donor cell-mediated disorder post-hematopoietic stem cell transplantation (post-HSCT). In this disease, FasL 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 GVHD murine model, we found that precocious gut damage and mice mortality are increased with graft of donor T- and B-depleted bone marrow cells (TBD-BM) devoid of FasL as compared with their wild type counterparts. Interestingly, serum levels of both soluble FasL (s-FasL) and of IL-18 are drastically reduced in the recipients of FasL-deficient grafts indicating that s-FasL stems from donor BM-derived cells. In addition, the correlation between the concentrations of these two cytokines suggests that IL-18 production arises through a s-FasL-driven mechanism. These data highlight the importance of FasL-dependent production in IL-18 production and in mitigating aGVHD. Overall, our data reveal the functional duality of FasL according to its source.