Induction in transgenic mice of HLA-A2.1-restricted cytotoxic T cells specific for a peptide sequence from a mutated p21ras protein

Clin Exp Immunol. 1999 May;116(2):214-9. doi: 10.1046/j.1365-2249.1999.00873.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding, Competitive
  • Cell Line
  • HLA-A2 Antigen / physiology*
  • Humans
  • Immunophenotyping
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Peptide Fragments / immunology*
  • Proto-Oncogene Proteins p21(ras) / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*


  • HLA-A2 Antigen
  • Peptide Fragments
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)