A partially agonistic peptide acts as a selective inducer of apoptosis in CD8+ CTLs

We have analyzed the effect of partially agonistic peptides on the activation and survival of CTL clones specific for a highly immunogenic HLA A11-restricted peptide epitope derived from the EBV nuclear Ag-4. Several analogues with substitutions of TCR contact residues were able to trigger cytotoxic activity without induction of IL-2 mRNA and protein or T cell proliferation. Triggering with these partial agonists in the absence of exogenous IL-2 resulted in down-regulation of the cytotoxic potential of the specific CTLs. One analogue selectively triggered apoptosis as efficiently as the original epitope, subdividing the partial agonists into apoptosis-inducing and noninducing ligands. Analysis of early T cell activation events, induction of Ca2+ influx, and acid release did not reveal significant differences between the two types of analogue peptides. These results demonstrate that some partial agonists can dissociate the induction of CTL death from CTL activation. Peptides with such properties may serve as useful tools to study signal transduction pathways in CD8+ lymphocytes and as therapeutic agents modulating natural immune responses.