The ability of peptides to induce cytotoxic T cells in vitro does not strongly correlate with their affinity for the H-2Ld molecule: implications for vaccine design and immunotherapy.

The hypothesis that the ability of a peptide to bind to a class I molecule correlates with its immunogenicity is controversial. In this paper we have measured the affinity constants of nine synthetic peptides, which have been previously identified as binding to H-2L(d) molecules, and have determined their immunogenicity in an in vitro cytotoxic T lymphocyte (CTL) induction assay. We find that six peptides bind with high affinity (K(a) > 10(7)/M); of these, four are of viral origin but only two elicit potent CTLs, one is a self peptide which is not immunogenic, while the sixth is of bacterial origin and also does not generate effective CTLs. Two peptides bind with intermediate affinity (K(a) > 10(6)/M); one of these elicits a moderate CTL response, while the other, a tumor-derived epitope, is highly immunogenic. Intriguingly, the peptide with lowest affinity (p2Ca) is exceedingly effective at eliciting CTLs. The efficacy of peptides with modest affinity for their restriction elements appears to correlate well with the CTL precursor frequency. We have also examined intrinsic parameters of some of the peptides such as solubility and stability. Taken together, our results underscore the relevance of factors other than affinity which affect immunogenicity and which may be critical in the design of peptide-based vaccines as well as tumor immunotherapy approaches.