PEPTIDES DERIVED FROM SELF-PROTEINS AS PARTIAL AGONISTS AND ANTAGONISTS OF HUMAN CD8(-CELL CLONES REACTIVE TO MELANOMA() T)MELANOCYTE EPITOPE MART1(27-35)/

The self-peptide MART1(27-35) derives from the melanocyte/melanoma pro tein Melan A/MART1 and is a target epitope of CD8(+) T cells, commonly recovered from tumor-infiltrating lymphocytes of HLA-A2.1(+) melanoma patients. Despite their prevalence in such patients, these CTLs gener ally appear to be ineffective in mediating tumor regression in vivo. W e have noted previously that numerous peptides from both endogenous an d foreign proteins are similar to MART1(27-35) and, potentially, are c apable of productively engaging the T-cell receptors of patient-derive d CTLs. This observation raised the question of whether CTLs in vivo m ight encounter self-peptide analogues of MART1(27-35) that lack full a gonist activity, perhaps to the detriment of the antitumor CTL respons e. This possibility was evaluated using cloned, patient-derived CTLs w ith a panel of self-derived natural analogues of MART1(27-35) in assay s for cytolysis, cytokine release, and phosphorylation of T-cell recep tor signaling constituents. Several peptides were identified as partia l agonists, capable of eliciting cytolysis and/or release of cytokines tumor necrosis factor-a and IFN-gamma but not interleukin 2, Several other peptides showed antagonist behavior, effectively inhibiting cyto lysis of MART1(27-35)-pulsed targets, but did not inhibit killing of c ells prepulsed with a synthetic, heteroclitic variant of MART1(27-35). Some of these antagonists also had lasting effects on interleukin 2 s ecretion by CTLs under experimental conditions involving sequential ex posure to ligands. Together, these observations suggest that encounter s with self-peptide analogues of MART1(27-35) may contribute to the pe ripheral maintenance of these CTLs, while ultimately impairing the eff icacy of this antitumor T-cell response.