Role of TCR-dependent AICD in tumor immunity

描述（由申请人提供）：已知肿瘤为T细胞提供了用于T细胞活化的不良共刺激环境，使得T细胞对肿瘤无反应性、无知和“衰竭”是有充分证据的现象。以前，不可能准确地评估TCR依赖性活化诱导的T细胞死亡（AICD）在确定T细胞耐受性或对肿瘤的免疫性是否占优势中的具体作用。这是因为特异性阻断来自TCR的死亡信号的手段还不可用。我们已经在TCR β链恒定区（bTM-g）中产生了突变，该突变赋予野生型T细胞增殖，但在转基因小鼠中对抗原刺激的T细胞具有AICD抗性。bTM-g T细胞对TCR依赖性AICD的特异性抗性将非常有助于确定该途径通常在确定对肿瘤的外周免疫应答中所起的作用。具体目的：（1）鉴定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模型将立即用于阐明TCR依赖性AICD在最大化免疫和逃避肿瘤耐受中的作用。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应答中起作用。我们进一步提出，bTM-g突变可能突出了一个重要的基序，可以靶向的突变。

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.