CONSTITUTIVE ACTIVATION OF THE FAS LIGAND GENE IN MOUSE LYMPHOPROLIFERATIVE DISORDERS

Mice homozygous for lpr (lymphoproliferation) or gld (generalized lymp hoproliferative disease) develop lymphadenopathy and splenomegaly and suffer from autoimmune disease. The lpr mice have a defect in a cell-s urface receptor, Fas, that mediates apoptosis, while gld mice have a m utation in the Fas ligand (FasL). Northern hybridization with the FasL cDNA as probe indicated that the cells accumulating in lpr and gld mi ce abundantly express the FasL mRNA without stimulation. By means of i n situ hybridization and immunohistochemistry, we identified the cells expressing the FasL mRNA as CD4(-)CD8(-) double negative T cells. The T cells from lpr mice were specifically cytotoxic against Fas-express ing cells. Since FasL is normally expressed in activated mature T cell s these results indicate that the double negative T cells accumulating in lpr and gld mice are activated once, and support the notion that t he Fas/FasL system is involved in activation-induced suicide of T cell s. Furthermore, the graft-versus host disease caused by transfer of lp r bone marrow to wild-type mice can be explained by the constitutive e xpression of the FasL in lpr-derived T cells.