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Using H-2Kd-restricted CTL clones, which are specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS(252-260) (SYIPSAEKI) and permit assessment of TCR-ligand interactions by TCR photoaffinity labeling, we have previously identified several peptide derivative variants for which TCR-ligand binding and the efficiency of Ag recognition deviated by fivefold or more. Here we report that the functional CTL response (cytotoxicity and IFN-gamma production) correlated with the rate of TCR-ligand complex dissociation, but not the avidity of TCR-ligand binding. While peptide antagonists exhibited very rapid TCR-ligand complex dissociation, slightly slower dissociation was observed for strong agonists. Conversely and surprisingly, weak agonists typically displayed slower dissociation than the wild-type agonists. Acceleration of TCR-ligand complex dissociation by blocking CD8 participation in TCR-ligand binding increased the efficiency of Ag recognition in cases where dissociation was slow. In addition, permanent TCR engagement by TCR-ligand photocross-linking completely abolished sustained intracellular calcium mobilization, which is required for T cell activation. These results indicate that the functional CTL response depends on the frequency of serial TCR engagement, which, in turn, is determined by the rate of TCR-ligand complex dissociation.

Type

Journal article

Journal

J Immunol

Publication Date

15/07/1998

Volume

161

Pages

553 - 562

Keywords

Animals, Antibodies, Blocking, CD8-Positive T-Lymphocytes, Clone Cells, Cytotoxicity Tests, Immunologic, Cytotoxicity, Immunologic, Epitopes, T-Lymphocyte, Immunoglobulin Fab Fragments, Ligands, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Peptides, Phosphorylation, Receptors, Antigen, T-Cell, Signal Transduction