LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1-DEPENDENT LYSIS OF FAS(+) (CD95(+) APO-1(+)) INNOCENT BYSTANDERS BY ANTIGEN-SPECIFIC CD8(+) CTL/

Exquisite specificity toward Ag-bearing cells (cognate targets) is one of the most important properties of CD8(+) CTL-mediated cytotoxicity. Using highly Ag-specific CD8(+) CTL lines and clones, which spare non cognate, Ag-free targets, we found that in the presence of Ag-bearing targets the CTL acquire the ability to lyse noncognate target cells (b ystanders), It is shown that the unexpectedly rapid and efficient lysi s of bystanders by Ag-activated CTL is mediated by a Fas ligand (FasL) /Fas-based mechanism and does not depend on perforin, The CTL lysed Fa s-expressing bystanders, but spared the Fas-negative or anti-fas mAb-r esistant bystander cells. Accordingly, the FasL-deficient gld/gld CTL did not kill bystanders, while perforin-deficient CTL did, Unlike anti -fas mAb-induced cell death, the lysis of bystanders was not only FasL /Fas dependent but also required adhesion molecule LFA-1 on the surfac e of the activated CTL. Lysis of bystanders is viewed as acceptable '' collateral'' damage, but the persistent presence of activated CTL coul d result in immunopathologies involving functional Fas-expressing tiss ues.