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This study describes a form of partial agonism for a CD8+ CTL clone, S15, in which perforin-dependent killing and IFN-gamma production were lost but Fas (APO1 or CD95)-dependent cytotoxicity preserved. Cloned S15 CTL are H-2Kd restricted and specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS 252-260 (SYIPSAEKI). The presence of a photoactivatable group in the epitope permitted assessment of TCR-ligand binding by TCR photoaffinity labeling. Selective activation of Fas-dependent killing was observed for a peptide-derivative variant containing a modified photoreactive group. A similar functional response was obtained after binding of the wild-type peptide derivative upon blocking of CD8 participation in TCR-ligand binding. The epitope modification or blocking of CD8 resulted in an > or = 8-fold decrease in TCR-ligand binding. In both cases, phosphorylation of zeta-chain and ZAP-70, as well as calcium mobilization were reduced close to background levels, indicating that activation of Fas-dependent cytotoxicity required weaker TCR signaling than activation of perforin-dependent killing or IFN-gamma production. Consistent with this, we observed that depletion of the protein tyrosine kinase p56(lck) by preincubation of S15 CTL with herbimycin A severely impaired perforin- but not Fas-dependent cytotoxicity. Together with the observation that S15 CTL constitutively express Fas ligand, these results indicate that TCR signaling too weak to elicit perforin-dependent cytotoxicity or cytokine production can induce Fas-dependent cytotoxicity, possibly by translocation of preformed Fas ligand to the cell surface.

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

12/1998

Volume

161

Pages

6939 - 6946

Addresses

Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland.

Keywords

T-Lymphocytes, Cytotoxic, Clone Cells, Animals, Mice, Plasmodium berghei, Mast-Cell Sarcoma, Azides, Lactams, Macrocyclic, Salicylic Acids, Quinones, Benzoquinones, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Peptide Fragments, Membrane Glycoproteins, Membrane Proteins, Receptors, Antigen, T-Cell, Antigens, CD95, Protozoan Proteins, Antigens, CD8, Antibodies, Monoclonal, H-2 Antigens, Epitopes, Enzyme Inhibitors, Photoaffinity Labels, Lymphocyte Activation, Calcium Signaling, Cytotoxicity, Immunologic, Protein Processing, Post-Translational, Phosphorylation, Immunoglobulin Fab Fragments, ZAP-70 Protein-Tyrosine Kinase, Pore Forming Cytotoxic Proteins, Protein-Tyrosine Kinases, Fas Ligand Protein, Perforin, Interferon-gamma