Analogues of CTL epitopes with improved MHC class-I binding capacity elicit anti-melanoma CTL recognizing the wild-type epitope.
The MHC class-I binding affinity of an epitope is an important parameter determining the immunogenicity of the peptide-MHC complex. In order to improve the immunogenicity of an epitope derived from melanocyte lineage-specific antigen gp100, we performed amino-acid substitutions within the epitope and assayed both HLA-A*0201 binding and CTL recognition. Anchor replacements towards the HLA-A*0201 peptide-binding motif gave rise to peptides with higher HLA-A*0201 binding capacity compared to the wild-type epitope. In addition, several of the gp100 154-162 epitope-analogues were more efficient at target-cell sensitization for lysis by anti-gp100 154-162 CTL compared to the wild-type epitope. These altered gp100 154-162 epitopes were subsequently tested for their capacity to induce CTL responses in vivo using HLA-A*0201/Kb transgenic mice, and in vitro using HLA-A*0201 + donor-derived lymphocytes. Interestingly, the peptide-specific CTL obtained, which were raised against the different gp100 154-162 epitope-analogues, displayed cross-reactivity with target cells endogenously processing and presenting the native epitope. These data demonstrate that altered epitopes can be exploited to elicit native epitope-reactive CTL. The use of epitope-analogues with improved immunogenicity may contribute to the development of CTL-epitope based vaccines in viral disease and cancer.
Bakker
A B
AB
Department of Tumor Immunology, University Hospital Nijmegen St. Radboud, The Netherlands.
van der Burg
S H
SH
Huijbens
R J
RJ
Drijfhout
J W
JW
Melief
C J
CJ
Adema
G J
GJ
Figdor
C G
CG
D000818:Animals; D003429:Cross Reactions / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D059848:HLA-DQ alpha-Chains; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D058951:gp100 Melanoma Antigen
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen