FAS LIGAND-MEDIATED KILLING BY INTESTINAL INTRAEPITHELIAL LYMPHOCYTES- PARTICIPATION IN INTESTINAL GRAFT-VERSUS-HOST DISEASE

In vitro studies have demonstrated that intestinal intraepithelial lym phocytes (IEL) are constitutively cytotoxic; however, the mechanism an d target of their cytotoxicity are unknown. Apoptosis of intestinal ep ithelial cells (IEC) and an increase in IEL numbers are classical sign s of intestinal graft-versus-host disease (GVHD), although whether IEL can mediate IEC apoptosis directly in GVI-TD is unclear. Recent evide nce suggests that target epithelial organ injury observed in GVHD is p redominantly Fas-mediated; therefore, we investigated the possibility that IEL induce apoptosis of IEC through a Fas-mediated mechanism. Her e, we demonstrate that the TEL isolated from normal mice readily displ ay potent Pas ligand (FasL)-mediated killing activity after CD3 stimul ation, and that IEC express Fas, suggesting that IEC are potential tar gets for Fist-mediated killing by IEL, In vitro, IEL isolated from GVH D mice have markedly increased Fast-mediated killing potential and are spontaneously cytolytic toward host-derived tumor cells predominantly through a Fas-mediated pathway. In vivo transfer of IEL isolated from GVHD mice induced significantly more IEC apoptosis in F1 wild-type mi ce than in Fas-defective F1lpr mice. Thus, these results demonstrate t hat FasL-mediated death of IEC by IEL is a major mechanism of IEC apop tosis seen in GVHD.