In murine colon cancer, the investigator has identified an immunodominant T-cell epitope recognized by CD8+ CTL. This peptide epitope, AH1, is derived from a normally silent endogenous retroviral gp70 gene that has been transcriptionally activated in the tumor cells. He now plans to study in detail the kinetics of interactions between this peptide and its MHC class I restricting element, Ld, as well as the T-cell receptor specific for the peptide MHC complex. By comparing these values with other Ld-restricted murine tumor antigens and display distinct biological properties, he hopes to define specific parameters of immunogenicity and immunodominance of tumor antigens. Specifically, he proposes to: 1) measure association and dissociation kinetics of tumor specific peptide antigens with their MHC class I restricting elements, and with T-cell receptors specific for the peptide MHC complex; 2) analyze the effects of specific amino acid modifications of the tumor antigens to further correlate MHC and TCR binding kinetics with in vivo immunogenicity; 3) develop and utilize multivalent soluble Ig-Ld molecules to directly visualize the cellular dynamics of peptide + MHC specific T cells in vivo; and 4) analyze the mechanisms responsible for lack of presentation of AH1 in certain BALB/c tumors that are gp70+.
| Lu, Z; Yuan, L; Zhou, X et al. (2000) CD40-independent pathways of T cell help for priming of CD8(+) cytotoxic T lymphocytes. J Exp Med 191:541-50 |
| Slansky, J E; Rattis, F M; Boyd, L F et al. (2000) Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex. Immunity 13:529-38 |
| Levitsky, H I; Lazenby, A; Hayashi, R J et al. (1994) In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression. J Exp Med 179:1215-24 |
