FAS ANTIGEN IS THE MAJOR TARGET MOLECULE FOR CD4-CELL-MEDIATED CYTOTOXICITY( T)

Activation of the Fas cell surface molecule, either by specific antibo dy or by its as yet unidentified ligand, has been shown to induce apop tosis. Because apoptosis is also evoked in target cells by cytolytic T cells, we investigated whether the Fas pathway is involved in CD4+ T cell-mediated cytotoxicity. Analysis of Fas expression in APC, such as the B lymphoma A20.2J and MHC class II-transfected fibroblasts RT2.3, revealed a correlation between the degree of expression and sensitivi ty to cytotoxic attack, high level of Fas expression in A20.2J being a ssociated with efficient lysis. To examine whether increased Fas expre ssion in RT2.3 would render these cells more susceptible to CD4+ CTL l ysis, they were transfected with a Fas gene expression vector. indeed, Fas- but not mock-transfected RT2.3 proved to be more sensitive to ly sis by either Ag specifically or nonspecifically activated CD4+ CTL. S imilarly, MHC class II-negative, Fas-transfected Ll 210 leukemia cells were lysed with nonspecifically activated CD4+ CTL. The importance of the Fas engagement in CD4+ CTL-mediated cytotoxicity is further subst antiated by the failure of both cloned and normal CD4+ CTL to lyse B c ell blasts from lpr mice. These mice are known to have a defect in fun ctional Fas expression. Although the bulk of CD4+ T cell-mediated lysi s appears to be Fas induced, the fact that the effector phase of A20.2 J lysis is only partially Ca2+ independent indicates that other pathwa ys also contribute to target cell death.