The efficiency of antigen recognition by CTL is determined by the frequency of serial TCR engagement
Hudrisier D., Kessler B., Cerottini JC., Luescher IF.
To investigate the relation between the efficiency of antigen recognition and TCR-ligand binding, we utilized H-2-Kd-restricted CD8+CTL clones that permit assessment of TCR-ligand interactions by TCR photoaffinity labeling. The clones were specific for a derivative of the Plasmodium berghei cirumsporozoite peptide PbCS 252-260 (SYIPSAEKI) containing photoreactive iodo-4-azidosalicylic acid (IASA) in place of PbCS S-252 and 4- azidobenzoic acid (ABA) on PbCS K-259. Selective photoactivation of IASA permitted crosslinking to Kd and photoactivation of ABA to TCR. By assessing antigen recognition (cytotoxicity and IFNγ production) and TCR-ligand binding (TCR photoaffinity labeling) for 12 peptide derivative variants on seven CTL clones, several cases were found, for which the functional response was either ≥ 5-fold lower (antagonists and weak agonists) or higher (strong agonists) than TCR-ligand binding. The efficiency of antigen recognition correlated with the rates of TCR-ligand complex dissociation, but not the avidity of TCR-ligand binding. Strong agonist exhibited faster TCR-ligand complex dissociation than weak agonists, suggesting that CTL activation depends on the frequency of serial TCR engagement. Consistent with this, we observed that acceleration of TCR-ligand complex dissociation, brought about by blocking of CD8, can increase the efficiency of antigen recognition. On the other hand intercellular TCR-ligand photocrosslinking abrogated CTL function by an active, probably phosphatase mediated, inhibition of T cell activation. Our results indicate that CTL activation is driven by the frequency of serial TCR engagement.