Defining post-transcriptional mechanisms that control CD8 T cell longevity, proliferation and differentiation

项目摘要 CD 8 T细胞在消除感染和癌性宿主细胞中起关键作用。圆满成功之 免疫应答依赖于细胞的适当维持（存活和增殖）和精确分化。 CD 8 T细胞。在抗原刺激后，活化的抗原特异性CD 8 T细胞经历克隆扩增， 分化为具有细胞溶解功能的效应淋巴细胞。尽管大多数效应细胞在 在抗原清除后，少数抗原特异性细胞存活并形成长寿命的保护性记忆CD 8 T细胞。 然而，在慢性感染和癌症期间，免疫应答经常受到损害：CD 8 T细胞表现出免疫应答。 存活和增殖的缺陷，不能形成记忆细胞，而是被转移到分化成 衰竭的细胞，其特征在于效应子功能的丧失。因此，至关重要的是， 了解调节CD 8 T细胞维持和分化的潜在机制。我们 已经证明let-7介导的转录后机制控制分化， 效应T细胞的功能。此外，我们的初步结果表明，let-7水平的调制具有 对T细胞的维持、记忆的形成和转向疲劳产生深远的影响。探讨 let-7在CD 8 T细胞中调节的分子机制，我们提出以下目标： 目的-1将确定let-7介导的对CD 8 T细胞维持作用的分子基础：bcl-2依赖性 存活和CDC 34驱动的增殖。目的-2将剖析let-7介导的机制，指导CD 8 T细胞 分化：Eomes依赖和Eomes独立的分子程序。为了实现这些目标，我们将 分析具有不同水平let-7 microRNA的CD 8 T细胞的维持和分化为效应细胞， 记忆和耗尽的T淋巴细胞使用感染和肿瘤模型。我们希望能找到新的 转录后机制调节CD 8 T细胞介导的免疫应答的结果。是 预期这些实验将确定let-7为新的治疗靶点。

PROJECT SUMMARY CD8 T cells play a critical role in the elimination of infected and cancerous host cells. The success of these immune responses depends on the proper maintenance (survival and proliferation) and precise differentiation of CD8 T cells. Upon antigen stimulation, activated antigen-specific CD8 T cells undergo clonal expansion and differentiate into effector lymphocytes with cytolytic function. Although the majority of effector cells die after antigen clearance, a few antigen-specific cells survive and form long-lived protective memory CD8 T cells. However, during chronic infection and cancer, the immune response is often compromised: CD8 T cells exhibit defects in survival and proliferation, fail to form memory cells and instead are diverted to differentiate into exhausted cells which are characterized by the loss of effector function. Thus, it is of utmost importance to understand the underlying mechanisms that regulate the maintenance and differentiation of CD8 T cells. We have already demonstrated that let-7-mediated posttranscriptional mechanism controls the differentiation and function of effector T cells. Furthermore, our preliminary results suggest that modulation of let-7 levels have a profound impact on the maintenance of T cells, memory formation and diversion into exhaustion. To investigate the molecular mechanisms of let-7 regulation in CD8 T cells we propose the following aims: Aim-1 will determine the molecular basis of let-7-mediated effects on CD8 T cell maintenance: bcl-2-dependent survival and cdc34-driven proliferation. Aim-2 will dissect let-7-mediated mechanisms that guide CD8 T cell differentiation: Eomes-dependent and Eomes-independent molecular programs. To address these aims we will analyze the maintenance and differentiation of CD8 T cells with different levels of let-7 microRNAs into effector, memory and exhausted T lymphocytes using infection and tumor models. We expect to identify novel posttranscriptional mechanisms that regulate the outcome of CD8 T cell-mediated immune responses. It is anticipated that these experiments will define let-7 as a new therapeutic target.