THE Fas-FasL PATHWAY OF ACTIVATION-INDUCED T CELL DEATH IS NOT CRITICAL FOR THE INDUCTION OF LONG-TERM ALLOGRAFT SURVIVAL

Abstract

457 Fas belongs to a family of membrane receptors that mediate T cell apoptosis. Activation of T lymphocytes upregulates the number of Fas molecules and induces de novo Fas ligand (FasL) expression. Fas-FasL interactions then lead to the apoptosis of activated T cells. Studies in Fas-deficient or FasL-mutant (gld) mice provide strong evidence that the Fas-FasL pathway of activation-induced cell death (AICD) is critical for the clonal deletion of autoreactive T lymphocytes. In this study, we tested whether the Fas-FasL pathway is necessary for the induction of long-term allograft survival or for the activation-induced apoptosis of alloreactive T cells. We therefore analyzed the survival of C57BL/6 (H-2b) vascularized cardiac allografts transplanted to C3H/He (H-2k) wild-type (w.t.) or FasL-mutant (gld) mice. Recipients were either left untreated or received 200μg CTLA4Ig i.p. two days post-transplantation. Rejection was defined as cessation of heart beat and was confirmed histologically. To study alloantigen-mediated AICD, we measured the apoptosis (by flow analysis, TUNEL) of w.t. and gld lymph node T cells following repeated in vivo stimulation with fully allogeneic spleen cells. Results: Allograft survival was significantly longer in untreated gld recipients than untreated w.t. recipients. In contrast, CTLA4Ig induced long-term allograft acceptance in both w.t. and gld mice: (Table)TableAlloantigen-induced CD4+ and CD8+ T cell apoptosis (AICD) was greater in w.t. than in gld mice; however, AICD in the gld group was still significantly greater than background T cell apoptosis (syngeneic stimulation): (Table)TableConclusions: Fas-FasL interactions promote acute allograft rejection but are not critical for the induction of long-term allograft survival. Mechanisms other than the Fas-FasL pathway contribute to the activation-induced apoptosis of alloreactive T lymphocytes.