Selective upregulation of fibroblast fas ligand expression, and prolongation of Fas/Fas ligand-mediated skin allograft survival, by retinoic acid: The skin as a retinoide-inducible immune privilege site

Fas/Fas ligand-mediated lymphocyte apoptosis has been implicated in the sup pression of immune responses and may cause immune privilege. Human corneas exhibit immune privilege and can be transplanted across allogeneic barriers without immunosuppressive therapy, perhaps, because corneal keratinocytes express Fas ligand. To characterize Fas and Fas ligand expression in skin, we examined expression by murine keratinocytes, dermal fibroblasts, melanoc ytes, and human umbilical endothelial cells. We also studied the regulation of Fas and Fas ligand in skin cells by retinoic acid, vitamin D-3, and dex amethasone as well as various cytokines. Among the molecules and cells test ed, retinoic acid selectively upregulated the expression of Fas ligand mole cule by fibroblasts. Retinoic acid-induced Fas ligand(+) fibroblasts killed Fas(+) target cells, and this killing was blocked by anti-Fas ligand antib ody. The function of Fas ligand on dermal fibroblasts in vivo was tested in a cutaneous allograft system. Histoincompatible BALB/C mouse (H-2d) donor skin was grafted on to allogeneic C57BL/6 mice (H-2b). Daily local injectio n of retinoic acid blocked inflammation and extended graft survival for mor e than 10 d. Injection of retinoic acid into Fas ligand mutated gld/gld don or skin did not prevent leukocyte infiltration into the allograft or prolon g graft survival. These experiments indicate that, in skin, retinoic acid s electively increases Fas ligand expression by fibroblasts and that retinoic acid has potent Fas/Fas ligand-dependent immunosuppressive activity.