Fas/Fas Ligand Interactions Play an Essential Role in the Initiation of Murine Autoimmune Diabetes

Abstract

Apoptosis via Fas/Fas ligand (FasL) interactions has been proposed to be a major T-cell-mediated effector mechanism in autoimmune diabetes. To elucidate the role of Fas/FasL interactions in NOD diabetes, the effects of neutralizing anti-FasL antibody on autoimmune responses were evaluated. Islet-specific CD8⁺ and CD4⁺ T-cells expressed FasL upon activation and mediated FasL-dependent cytotoxicity against Fas-expressing target cells in vitro, although their cytotoxicity against islet cells was not blocked by anti-FasL antibody. Moreover, administration of anti-FasL antibody failed to inhibit diabetes in vivo in the CD8⁺ T-cell adoptive transfer model. On the other hand, blockade of Fas/FasL interactions significantly inhibited CD4⁺ T-cell-dependent diabetes in adoptive transfer models. These results suggest a substantial contribution of Fas/FasL interactions to CD4⁺, but not CD8⁺, T-cell-mediated destruction of pancreatic β-cells. When anti-FasL antibody was administered to NOD mice between 5 and 15 weeks of age, the onset of diabetes was slightly delayed but the incidence was not decreased. However, administration of anti-FasL antibody at 2–4 weeks of age completely prevented insulitis and diabetes. These results suggest that Fas/FasL interactions contribute to CD4⁺ T-cell-mediated β-cell destruction and play an essential role in the initiation of autoimmune NOD diabetes.