Dissecting the effects of inhibitory signalling on T cell activation using optogenetics

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Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.Project overview:T cells are an essential part of our immune system that eliminate infections to keep us healthy despite constant exposure to pathogens. T cells contain an intricate signalling network that decides whether the cells of our body have become infected, but sometimes this decision-making process is ineffective and leads to disease. Many current drugs are designed to manipulate these signalling pathways to improve the immune response to infection or cancer. Whilst great progress has been made in identifying the parts of these networks, we must also understand the dynamic connections between them to know how these therapies work and hopefully improve them. However, for most signalling networks this knowledge remains very limited. To address this, we develop new molecular tools to investigate the dynamics of the T cell signalling network by engineering inputs that are light-responsive, giving us precise control over signalling in space and time.In this project, we will explore the effect inhibitory receptors expressed by T cells have on the downstream output response. It has been suggested that these inhibitory receptors only control one part of the signalling network, but this result has been hard to verify. We will develop and implement new tools to investigate this hypothesis at the mechanistic level. The result has important consequences, as many of the 'checkpoint' inhibitors currently used for cancer immunotherapy target inhibitory receptors such as PD 1, so elucidating how they work is required to improve their clinical function.The PhD student undertaking this project will master an array of biochemical and cell-biological techniques required to investigate questions relevant to medical research using quantitative approaches. The student will also get an excellent grounding in the principles and application of dataset modelling using computational and mathematical approaches from the second supervisor, which will provide strong interdisciplinary skills-training.