title: Induction in transgenic mice of HLA-A2.1-restricted cytotoxic T cells specific for a peptide sequence from a mutated p21ras protein.
abstract: Cytotoxic T cells (CTL) recognize short peptides that are derived from the proteolysis of endogenous cellular proteins and presented on the cell surface as a complex with MHC class I molecules. CTL can recognize single amino acid substitutions in proteins, including those involved in malignant transformation. The mutated sequence of an oncogene may be presented on the cell surface as a peptide, and thus represents a potential target antigen for tumour therapy. The p21ras gene is mutated in a wide variety of tumours and since the transforming mutations result in amino acid substitutions at positions 12, 13 and 61 of the protein, a limited number of ras peptides could potentially be used in the treatment of a wide variety of malignancies. A common substitution is Val for Gly at position 12 of p21ras. In this study, we show that the peptide sequence from position 5 to position 14 with Val at position 12-ras p5-14 (Val-12)-has a motif which allows it to bind to HLA-A2.1. HLA-A2.1-restricted ras p5-14 (Val-12)-specific CTL were induced in mice transgenic for both HLA-A2.1 and human beta2-microglobulin after in vivo priming with the peptide. The murine CTL could recognize the ras p5-14 (Val-12) peptide when they were presented on both murine and human target cells bearing HLA-A2.1. No cross-reactivity was observed with the native peptide ras p5-14 (Gly-12), and this peptide was not immunogenic in HLA-A2.1 transgenic mice. This represents an interesting model for the study of an HLA-restricted CD8 cytotoxic T cell response to a defined tumour antigen in vivo.
authors.affiliation: Institute of Biochemistry and Swiss Institute for Experimental Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Escobar
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: A
authors.initials: A
authors.lastname: Terskikh
authors.forename: N
authors.initials: N
authors.lastname: Holmes
authors.forename: G
authors.initials: G
authors.lastname: Corradin
authors.forename: J P
authors.initials: JP
authors.lastname: Mach
authors.forename: F
authors.initials: F
authors.lastname: Healy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D015789:HLA-A2 Antigen / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015789:HLA-A2 Antigen; D010446:Peptide Fragments; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)