SV40 is a small DNA containing tumor virus that encodes a 94 kD oncogene, tumor or T antigen, which converts normal cells to tumorigenic phenotype both in vitro and in vivo. T antigen-induced tumor progression is heavily influenced by the T cell-mediated immune response to T antigen. The T antigen induces CD8 ? T lymphocyte responses to four H2 b epitopes in B6 mice in a hierarchical manner (IV>I>II/III>V). In fact, CD8+ T cells specific for epitope V are not detected unless the immunodominant epitopes I, II/III and IV have been inactivated. Thus, the T antigen system provides an opportunity to study the role of CD8+ T cells specific for multiple epitopes in the control of spontaneous T antigen-induced tumors and to identify biological factors which contribute to immunodominance. In the previous grant period we characterized the T antigen-specific CD8+ T cell response in several T antigen transgenic mouse lines. Using a model of central T cell tolerance we found that adoptively transferred donor cells could be ensitized against the endogenous T antigehl leading to the induction of epitope IV-specific CD8 ? T cells that migrated to the tumor site and were associated with control of tumor progression. Additionally, we established a model of peripheral T cell tolerance in which T antigen epitope-specific CD8+ T cells were differentially tolerized before or in association with spontaneous tumor progression. Thus, the overall objectives of this project are to identify those aspects of the CD8 ? T cell immune response to T antigen which are critical for the control of spontaneous tumor progression in T antigen transgenic mice and to understand the basis for the immunorecessive nature of epitope V in the immune response to T antigen. The following four specific aims are _Dro0osed: 1. Requirements for effective CD8 ? T cell-mediated control of advanced choroid plexus tumors in T antigen transgenic mice with central CD8 ? T cell tolerance. 2. Counteracting peripheral tolerance for the control of tumor progression in T antigen transgenic mice. 3. CD8 ? T cell control of tumor metastasis in T antigen transgenic mice. 4. Immunodomination of epitope V CD8 ? T cell responses by dominant T antigen epitopes. We will utilize various models of T antigen transgenic mice and T antigen epitope-specific T cell receptor transgenic mice to determine the effect of various immunization approaches on the control of spontaneous tumor progression.
|Effective start/end date||6/1/07 → 5/31/09|
- National Cancer Institute: $631,071.00