MASSIVE UP-REGULATION OF THE FAS LIGAND IN LPR AND GLD MICE - IMPLICATIONS FOR FAS REGULATION AND THE GRAFT-VERSUS-HOST DISEASE-LIKE WASTING SYNDROME

Fas-deficient lpr and gld mice develop lymphadenopathy due to the accu mulation of T cells with an unusual double negative (DN) (CD4(-)CD8(-) ) phenotype. Previous studies have shown that these abnormal cells are capable of inducing redirected lysis of certain Fc receptor-positive target cells. Since the Fas ligand (FasL) has recently been shown to b e partly responsible for T cell-mediated cytotoxicity, lymph node cell s from lpr and gld mice were examined for the expression of FasL mRNA. Northern blot analysis revealed that lymph node cells obtained from l pr and gld mice had a striking increase in the level of expression of FasL mRNA predominantly due to expression in the DN T cells. Furthermo re, lpr, but not gld lymph node cells killed the B cell line, A20, in a Fas-dependent manner. These findings indicate that pas mutations res ult in a massive up-regulation of FasL which, most likely, results fro m repetitive exposure to (self) antigen. This phenomenon could explain the lpr-induced wasting syndrome observed when lpr bone marrow-derive d cells are adoptively transferred to wild-type recipients.