The efficiency of antigen recognition by CD8+ CTL clones is determined by the frequency of serial TCR engagement.
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.
Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland.
D
D
Hudrisier
B
B
Kessler
S
S
Valitutti
C
C
Horvath
J C
JC
Cerottini
I F
IF
Luescher
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D019138:Antibodies, Blocking; D018984:Epitopes, T-Lymphocyte; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain