Biology of SV40-Specific Transplantation Antigen

SV 40是一种含有小DNA的肿瘤病毒，其编码94 kD癌基因、肿瘤或T抗原，其在体外和体内将正常细胞转化为致瘤表型。T抗原诱导的肿瘤进展受到T细胞介导的对T抗原的免疫应答的严重影响。T抗原诱导CD 8？B6小鼠T淋巴细胞对4个H2 B表位的应答呈分级方式（IV>I>II/III>V）。事实上，除非免疫显性表位I、II/III和IV已经失活，否则检测不到对表位V特异性的CD 8 + T细胞。因此，T抗原系统提供了一个机会，研究的作用，CD 8 + T细胞特异性的多个表位在控制自发性T抗原诱导的肿瘤，并确定生物因素，有助于免疫优势。在上一个资助期，我们的特点是T抗原特异性的CD 8 + T细胞反应在几个T抗原转基因小鼠品系。使用中央T细胞耐受模型，我们发现，过继转移的供体细胞可以敏感对内源性T抗原导致诱导表位IV特异性CD 8？T细胞迁移到肿瘤部位，并与肿瘤进展的控制有关。此外，我们建立了外周T细胞耐受模型，其中T抗原表位特异性CD 8 + T细胞在自发性肿瘤进展之前或与自发性肿瘤进展相关时差异耐受。因此，本项目的总体目标是确定这些方面的CD 8？T细胞对T抗原的免疫应答对于控制T抗原转基因小鼠中自发肿瘤进展至关重要，并了解T抗原免疫应答中表位V的免疫隐性性质的基础。以下四个具体目标是_Dro 0 osed：1。有效CD 8的要求？T细胞介导的控制晚期脉络丛肿瘤的T抗原转基因小鼠与中央CD 8？T细胞耐受性2.在T抗原转基因小鼠中抵消外周耐受以控制肿瘤进展。3. CD8？T抗原转基因小鼠肿瘤转移的T细胞控制。4.表位V CD 8的免疫优势？通过显性T抗原表位的T细胞应答。我们将利用T抗原转基因小鼠和T抗原表位特异性T细胞受体转基因小鼠的各种模型来确定各种免疫方法对控制自发性肿瘤进展的影响。

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.