Abstract
The majority of known human tumor-associated antigens, derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunnity must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class I binding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitope derived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecific IFN-γ-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire.
Original language | English (US) |
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Pages (from-to) | 2118-2130 |
Number of pages | 13 |
Journal | European Journal of Immunology |
Volume | 38 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2008 |
Externally published | Yes |
Keywords
- T cells
- Tolerance
- Transgenic mice models
- Tumor immunology
- Vaccination
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology