COSTIMULATORY SIGNALS THROUGH B7.1 CD28 PREVENT T-CELL APOPTOSIS DURING TARGET-CELL LYSIS/

Expression of B7 on tumor cells can circumvent T cell tolerance and le ad to the generation of turner cell-specific T cell immunity. The effe ct of B7 expression on the generation of protective antitumor immunity has been attributed primarily to 1) more efficient T cell activation and 2) better generation of tumor-specific killer T cells. We have inv estigated the role of costimulation through B7.1 and its receptor, the CD28 molecule, in the generation of allogeneic human CTLs against MCF -7 breast cancer cells. In this setting, we describe how activated CTL s undergo activation-induced cell death upon killing the target cell. Instead of proliferation and clonal expansion, the majority of the CTL s underwent apoptotic cell death. CTL apoptosis could be blocked by 50 % when binding of the Fas ligand to its receptor, the CD95 (APO-1/Fas) molecule, was prevented. Fas ligand was detected in the activated T c ells, but not in MCF-7 or a panel of other breast cancer cell lines. T his excludes an active role for MCF-7 during CTL death and indicates t hat the CTL apoptosis is due to an autocrine production of the Fas lig and by CTLs. Costimulation of CTLs by retrovirally B7.1-transfected MC F-7 drastically reduced the sensitivity of the CTLs to apoptosis durin g target contact. Thus, in tumor cell vaccination, B7.1 might play a m ajor role in preventing a cell death by altering T cell susceptibility for apoptosis.