RESUMO
To better understand the stoichiometry of CD95L required to trigger apoptotic and nonapoptotic signals, we generated several CD95L concatemers from dimer to hexamer conjugated via a flexible link (GGGGS)2 . These ligands reveal that although the hexameric structure is the best stoichiometry to trigger cell death, a dimer is sufficient to induce the apoptotic response in CD95-sensitive Jurkat cells. Interestingly, only trimeric and hexameric forms can implement a potent Ca2+ response, suggesting that while CD95 aggregation controls the implementation of the apoptotic signal, both aggregation and conformation are required to implement the Ca2+ pathway.
Assuntos
Apoptose , Receptor fas , Humanos , Apoptose/fisiologia , Proteína Ligante Fas , Células JurkatRESUMO
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.
