Understanding the regulation of cytotoxic T lymphocyte signalling and activity through single-cell genomics

细胞毒性T淋巴细胞(CTL)是一种特殊类型的白细胞，在对抗病毒感染和癌症方面发挥着重要作用。事实上，几种新的癌症治疗方法专注于提高这些细胞对抗肿瘤的反应。像体内的许多细胞一样，CTL对周围的环境非常敏感，根据其他细胞和周围的信号分子改变它们的反应。因此，开发改变这些细胞功能的药物可能很困难。这种药物开发过程的第一步是了解这些细胞在不同环境中的行为。对免疫反应有利，但令研究人员困惑的是，CTL反应的内部信号事件极其迅速，大约在几分钟内。因此，在一组CTL中，每个细胞的反应阶段可能略有不同，并表现出不同的特征。直到最近，用于检查这些细胞变化的技术还需要将数千个细胞汇集在一起。因此，该测量是整个细胞池的平均值，并不能反映每个细胞的准确反应阶段。新技术现在可以在单个细胞中进行测量，从而可以收集关于单个细胞如何行为以及它们的反应的微调步骤的大量信息。在这个项目中，我们建议在与其对癌症的反应相关的各种环境中检查单个CTL，包括初始激活和在免疫增强药物存在的情况下。我们对突出潜在的毒品目标和改进分析这类新数据的方法特别感兴趣。

Cytotoxic T lymphocytes (CTLs) are a specialized type of white blood cell that play an important role in combating viral infections and cancer. In fact, several new cancer treatments focus on improving the response of these cells to fight tumours. Like many cells in the body, CTLs are very sensitive to their surroundings, altering their responses based on the other cells and signalling molecules around them. Thus, development of drugs that alter the function of these cells can be difficult. The first step in such a drug development process is understanding how these cells behave in different contexts. Beneficially for immune responses, but confusingly for researchers, the internal signalling events of CTL responses are extremely rapid, on the order of minutes. Thus, within a group of CTLs, each cell may be at a slightly different stage in its response and exhibit different characteristics. Until recently, technologies used to examine changes in these cells required that thousands be pooled together. The measurement was therefore an average across the whole pool of cells and didn't reflect the precise response stage of each individual cell. New technologies now enable measurements to be made in single cells, allowing a huge amount of information to be gathered about how individual cells behave and about the fine-tuned steps of their responses. In this project, we propose to examine single CTLs in various contexts relevant to their responses to cancer, including initial activation and in the presence of immune-enhancing drugs. We are particularly interested in highlighting potential drug targets and in improving methods to analyse this new type of data.