Article: article from journal or magazin.
Peptide modification or blocking of CD8, resulting in weak TCR signaling, can activate CTL for Fas- but not perforin-dependent cytotoxicity or cytokine production.
Journal of immunology
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
Animals, Antibodies, Monoclonal/pharmacology, Antigens, CD8/drug effects, Antigens, CD8/physiology, Antigens, CD95/immunology, Azides, Benzoquinones, Calcium Signaling, Clone Cells, Cytotoxicity, Immunologic, Enzyme Inhibitors/pharmacology, Epitopes/chemistry, Epitopes/drug effects, Fas Ligand Protein, H-2 Antigens/immunology, Immunoglobulin Fab Fragments/pharmacology, Interferon-gamma/biosynthesis, Interferon-gamma/genetics, Lactams, Macrocyclic, Lymphocyte Activation, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists &, inhibitors, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/physiology, Mast-Cell Sarcoma/pathology, Membrane Glycoproteins/biosynthesis, Membrane Glycoproteins/genetics, Membrane Proteins/metabolism, Mice, Peptide Fragments/chemistry, Peptide Fragments/immunology, Perforin, Phosphorylation/drug effects, Photoaffinity Labels, Plasmodium berghei/immunology, Pore Forming Cytotoxic Proteins, Protein Processing, Post-Translational/drug effects, Protein-Tyrosine Kinases/metabolism, Protozoan Proteins/chemistry, Protozoan Proteins/immunology, Quinones/pharmacology, Receptors, Antigen, T-Cell/immunology, Receptors, Antigen, T-Cell/metabolism, Salicylic Acids, T-Lymphocytes, Cytotoxic/drug effects, T-Lymphocytes, Cytotoxic/immunology, ZAP-70 Protein-Tyrosine Kinase
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