Role of TCR-dependent AICD in tumor immunity

描述(由申请人提供)：众所周知，肿瘤为T细胞激活提供了不良的共刺激环境，使T细胞无能、无知和对肿瘤的“耗尽”现象得到了很好的证明。以前，还不可能准确地评估TCR依赖的激活诱导的T细胞死亡(AICD)在确定T细胞耐受或肿瘤免疫是否占优势方面的具体作用。这是因为还没有一种专门阻止来自TCR的死亡信号的手段。我们已经在TCRβ链恒定区(BTM-g)产生了突变，该突变使转基因小鼠的野生型T细胞增殖，但对抗原刺激的T细胞产生了对AICD的抵抗。BTM-g T细胞对TCR依赖的AICD的特异性抵抗力将非常有助于确定该途径在确定肿瘤的外周免疫反应中所起的作用。具体目的：(1)鉴定被BTm-g突变直接抑制的死亡信号通路(S)。(2)确定TCR依赖的AICD在肿瘤免疫中的作用。我们相信，BTM-g模型将立即用于阐明依赖TCR的AICD在最大化免疫和逃避对肿瘤的耐受性方面的作用。我们假设，特异性抑制TCR依赖的AICD的能力将揭示这一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突变可能突出了一个重要的基序，该基序可能是药理学上的靶向。

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.