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. The development of tumors by the T antigen is heavily influenced by the T cell mediated immune response to this intranuclear transforming protein. Our efforts during the tenure of this grant have focused on understanding the nature of the cellular immune response to T antigen at the molecular level and developing immunological approaches to inhibit developing tumors. Using a mouse (C57BL/6) model, we have demonstrated that this intranuclear oncogene when expressed in transformed cells or in purified form induces the development of MHC class I restricted cytotoxic T lymphocytes (CTL) which recognize discrete residues (8-10 amino acids) processed from T antigen and presented by the MHC class I molecules. The T antigen is unique in that it contains four CTL epitopes; epitope I (206-215), epitope II/III (223-231), epitope IV (404-411) and epitope V (489-497) recognized by their respective CTL clones [Y-1, and K-11], [Y-2, Y-3 and K-19], Y-4, and Y-5. Epitope V is immunorecessive and, therefore, represents a model for identifying factors that influence immunodominance and immunorecessiveness. The CTL mediated immunosurveillance against T antigen can be modulated by the generation of CTL escape variants that carry genetic changes in an epitope region. The overall goal of this renewal application is to dissect the role of individual T antigen CTL epitopes in inducing a tumor rejection response using the T antigen transgenic mouse models and to study the mechanisms governing the basis for immunorecessive nature of epitope V and other potential epitopes in T antigen.
The specific aims are as follows. 1). To determine the hierarchy among T antigen MHC class I restricted CTL epitopes and the role of immunorecessive CTL epitopes in inducing a CTL response in vivo. 2). To determine the contribution of individual SV40 T antigen Cit epitopes I, II/III, V and IV in inducing a rejection response In T antigen transgenic mice. 3). To determine the role of CTL escape variants in the CTL response to T antigen. 4). To determine if the CTL escape variants act as antagonists and 5). To determine the cytotoxic T cell response to SV40 T antigen HLA-A2.1 restricted epitopes in A2/Kb transgenic mice. This last specific aim will address the question whether T cells specific for T antigen epitopes restricted by human HLA-A 2. l class I antigen can be demonstrated using a HLA-A 2.1 transgenic mouse system. Our proposed studies have direct relevance to dissecting development of cellular immune response to mutated cellular oncogenes.
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