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 lead to the generation of tumor cell-specific T cell immunity. The effect 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 investigated 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 CTLs undergo activation-induced cell death upon killing the target cell. Instead of proliferation and clonal expansion, the majority of the CTLs 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 cells, but not in MCF-7 or a panel of other breast cancer cell lines. This excludes an active role for MCF-7 during CTL death and indicates that the CTL apoptosis is due to an autocrine production of the Fas ligand by CTLs. Costimulation of CTLs by retrovirally B7.1-transfected MCF-7 drastically reduced the sensitivity of the CTLs to apoptosis during target contact. Thus, in tumor cell vaccination, B7.1 might play a major role in preventing T cell death by altering T cell susceptibility for apoptosis.
Daniel
P T
PT
Max Delbrück Center for Molecular Medicine, University Medical Center Rudolf Virchow, Berlin-Buch, Germany.
Kroidl
A
A
Cayeux
S
S
Bargou
R
R
Blankenstein
T
T
Dörken
B
B
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D018122:B7-1 Antigen / Q000502:physiology*; D001943:Breast Neoplasms; D018106:CD28 Antigens / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D018122:B7-1 Antigen; D018106:CD28 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor