Role of TCR-dependent AICD in tumor immunity

TCR依赖性AICD在肿瘤免疫中的作用

• 批准号: 7006707
• 负责人: Adam G. Schrum
• 金额: $ 0.65万
• 依托单位: UNIVERSITY HOSPITAL BASEL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006707
• 关键词: T cell receptor; T lymphocyte; antitumor antibody; cell death; enzyme mechanism; gene mutation; genetically modified animals; immune tolerance /unresponsiveness; immunogenetics; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; postdoctoral investigator

DESCRIPTION (provided by applicant): Tumors are known for providing T cells with poor costimulatory environments for T cell activation, making T cell anergy, ignorance, and "exhaustion" to tumors well-documented phenomena. Previously, it has not been possible to accurately assess the specific role of TCR-dependent activation-induced T cell death (AICD) in determining whether T cell tolerance or immunity to tumors prevails. This is because a means of specifically blocking the death signal from the TCR has not been available. We have generated a mutation in the TCR beta-chain constant region (bTM-g) which imparts wild-type T cell proliferation but resistance to AICD to antigen-stimulated T cells in transgenic mice. The specific resistance of bTM-g T cells to TCR-dependent AICD will be very useful in determining the role this pathway normally plays in determining peripheral immune responses to tumors. Specific Aims: (1) Identify the death-signaling pathway(s) that is(are) directly inhibited by the bTM-g mutation. (2) Determine the role of TCR-dependent AICD in the development of tumor immunity. We believe the bTM-g model will be immediately useful in clarifying the role of TCR-dependent AICD in maximizing immunity and escape from tolerance to tumors. We hypothesize that the ability to specifically inhibit TCR-dependent AICD will reveal that this process normally plays a role in downregulating anti-tumor immune responses. We further propose that the bTM-g mutation may spotlight an important motif which could be targeted pharmacologically.

描述（由申请人提供）：众所周知，肿瘤为T细胞提供了较差的T细胞活化共刺激环境，使得T细胞对肿瘤无反应、无知和“疲惫”现象已有充分记录。此前，尚无法准确评估 TCR 依赖性激活诱导 T 细胞死亡 (AICD) 在确定 T 细胞对肿瘤的耐受性或免疫是否占主导地位方面的具体作用。这是因为目前还没有专门阻断 TCR 死亡信号的方法。我们在 TCR β 链恒定区 (bTM-g) 中产生了一个突变，该突变使转基因小鼠中的野生型 T 细胞增殖，但对抗原刺激的 T 细胞具有 AICD 抗性。 bTM-g T 细胞对 TCR 依赖性 AICD 的特异性抵抗力对于确定该途径通常在确定肿瘤外周免疫反应中所起的作用非常有用。具体目标： (1) 确定 bTM-g 突变直接抑制的死亡信号通路。 (2)确定TCR依赖性AICD在肿瘤免疫发展中的作用。我们相信 bTM-g 模型将立即有助于阐明 TCR 依赖性 AICD 在最大化免疫和逃避肿瘤耐受方面的作用。我们假设，特异性抑制 TCR 依赖性 AICD 的能力将揭示该过程通常在下调抗肿瘤免疫反应中发挥作用。我们进一步提出，bTM-g 突变可能会突出一个可以在药理学上靶向的重要基序。