DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire

Jason Rice, Michelle L. Dossett, Claes Öhlén, Sarah L. Buchan, Timothy J. Kendall, Stuart N. Dunn, Freda K. Stevenson, Philip D. Greenberg

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 languageEnglish (US)
Pages (from-to)2118-2130
Number of pages13
JournalEuropean Journal of Immunology
Volume38
Issue number8
DOIs
StatePublished - Aug 2008
Externally publishedYes

Keywords

  • T cells
  • Tolerance
  • Transgenic mice models
  • Tumor immunology
  • Vaccination

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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