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 activati on and survival of CTL clones specific for a highly immunogenic HLA A11-res tricted peptide epitope derived from the EBV nuclear Ag-4, Several analogue s with substitutions of TCR contact residues were able to trigger cytotoxic activity without induction of IL-2 mRNA and protein or T cell proliferatio n. 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 origin al epitope, subdividing the partial agonists into apoptosis-inducing and no ninducing ligands. Analysis of early T cell activation events, induction of Ca2+ influx, and acid release did not reveal significant differences betwe en the two types of analogue peptides, These results demonstrate that some partial agonists can dissociate the induction of CTL death from CTL, activa tion, Peptides with such properties may serve as useful tools to study sign al transduction pathways in CD8(+) lymphocytes and as therapeutic agents mo dulating natural immune responses.