GAMMA/DELTA T CELLS IN TOLERANCE AND TUMOR IMMUNITY

描述（改编自研究者摘要）：本更新申请的长期目标是确定γ/δ T细胞和非细胞溶解性α/β T细胞如何调节对作为外源性抗原、内源性抗原和肿瘤抗原的OVA的耐受性。将使用在CD 8 + T细胞（TCR-1）或CD 4 + T细胞（OT-11）上表达OVA特异性TCR的转基因小鼠和各种敲除小鼠来探索控制耐受性发展的生理信号。第一个目的是表征来自表达转基因TCR-1 T细胞和从上皮内淋巴细胞克隆的γ/δ T细胞的B6小鼠的非细胞溶解性CD 8 + T细胞。将通过过继转移到γ/δ TCR缺陷小鼠中来研究γ/δ T细胞与非细胞溶解性CD 8 + T细胞之间的相互作用。表达转基因OT-11 T细胞的受体将用于确定非细胞溶解性CD 8 + T细胞如何抑制抗体应答。在第二个目的中，将使用TCR-1小鼠评价OVA转基因小鼠中γ/δ T细胞和非细胞溶解性CD 8 + T细胞的功能。将在第三个目标中检验E.G7-OVA诱导肿瘤特异性耐受的假设。如果发现耐受性，研究者将确定CD 8 + T细胞是否缺失、无反应性或显示功能改变。将测试用共刺激分子转染的E.G7-OVA肿瘤逆转耐受性的能力。将确定诺斯卡品对肿瘤特异性耐受和免疫的细胞和分子作用。这些研究的结果应该为开发那可汀的人体临床试验提供基础。

DESCRIPTION (Adapted from Investigator's Abstract): The long-term goal of this renewal application is to determine how gamma/delta T cells and non-cytolytic alpha/beta T cells regulate tolerance to OVA as an exogenous antigen, an endogenous antigen and as a tumor antigen. Transgenic mice expressing OVA-specific TCR on CD8+ T cells (TCR-1) or CD4+ T cells (OT-11) and a variety of knockout mice will be used to explore the physiological signals that control development of tolerance. The first aim is to characterize non- cytolytic, CD8+ T cells from B6 mice expressing transgenic TCR-1 T cells and gamma/delta T cells cloned from intra-epithelial lymphocytes. Interactions between gamma/delta T cells and non- cytolytic, CD8+ T cells will be studied by adoptive transfer into gamma/delta TCR deficient mice. Recipients expressing transgenic, OT-11 T cells will be used to determine how non-cytolytic CD8+ T cells inhibit antibody responses. In the second aim, the function of gamma/delta T cells and non-cytolytic CD8+ T cells in OVA transgenic mice will be evaluated using TCR-1 mice. The hypothesis that E.G7-OVA induces tumor-specific tolerance will be tested in the third aim. If tolerance is found, the investigator will determine whether CD8+ T cells are deleted, anergic or display altered functions. The ability of E.G7-OVA tumors transfected with a co-stimulatory molecule to reverse tolerance will be tested. The cellular and molecular effects of noscapine on tumor-specific- tolerance and immunity will be identified. Results from these studies should provide the basis for developing clinical trials of noscapine in humans.