Identification of epitope mimics recognized by CTL reactive to the melanoma/melanocyte-derived peptide MART-1((27-35))

Abstract

CTL reactivity to the epitope MART-1((27-35)) of the melanoma (self) antigen MART-1/melan A is frequently observed in tumor-infiltrating lymphocytes and may be readily elicited from the peripheral blood of melanoma patients that express HLA-A*0201. Available data suggest that these observations contrast with those made for other HLA-A*0201-presented melanoma self antigens regrading the regularity of observed CTL responses. Based of preliminary findings, we hypothesized that the CTL response to MART- 1 might be augmented in part by T cell encounters with peptides derived from sources other than MART-1, which show sequence similarity to MART-1((27- 35)). To test this idea, a protein database search for potential MART-1 epitope mimics was done using criteria developed from analyses of effector recognition of singly-substituted peptide analogues of MART-1((27-35)). Synthetic peptides were made for a portion of the sequences retrieve; 12/40 peptides tested were able to sensitive target cells for lysis by one or more ant-MART-1 effectors. The peptides recognized corresponds to sequences occurring in a variety of proteins of viral, bacterial, and human (self) origin. One peptide derives from glycoprotein C of the common pathogen HSV- 1; cells infected with recombinant vaccinia virus encoding native glycoprotein C were lysed by anti-MART-1 effectors. Our results overall indicate that sequences conforming to the A2.1 binding motif and possessing features essential to recognition by anti-MART-1 CTL, occur frequently in proteins. These findings further suggest that T cells might encounter a variety of such sequences in vivo, and that epitope mimicry may play a role in modulating the CTL response to MART-1((27-35)).