About This Project

Our immune T-cells are a type of white blood cell that are crucial to recognise and attack infections and cancerous cells. For this reason, T-cells are important drug targets in vaccines and cancer immunotherapies. A drug currently in pre-clinical development is showing promising results in boosting a key regulator in T-cell functions 500-fold, but how this happens remains a mystery. We hypothesise that the drug increases the active state of the T-cell regulator by inducing a structural change.

Ask the Scientists

What is the context of this research?

We are particularly interested in how the T-cells – an important part of our adaptive immune system – are spurred into action. T-cells receive and relay signals from their environment using a complex signaling network. Core players in this network includes the T-cell receptor, which can switch the T-cell into active mode when it binds a pathogen. Whether or not the protein can activate the T-cell depends on the 3D form it takes: either be ‘open and active’ or ‘closed and inactive’. Our lab has previously demonstrated that the structure of this phosphorylating protein affects how it clusters on the membrane. The working hypothesis is that the drug enhances T-cell activation by increasing the ‘open and active state’ of the protein, which in turn affects its clustering.

What is the significance of this project?

T-cells are incredibly important in immunity, protecting us against infections and diseases. In our study we aim to work out the mechanism of action of a promising, yet unpublished, peptide-based immunotherapeutic drug that boosts T-cell responses. Once we know the mode of action of this drug, it will help us understand and further refining therapeutic approaches to boosting immune responses.

What are the goals of the project?

The working hypothesis is that the drug of interest enhances T-cell activation by increasing the ‘open and active state’ of the protein, leading to more of the protein clustering around the T-cell receptor. We will first examine clustering of a T-cell activating protein with and without the drug. Subsequently we will investigate the mechanism of the drug, by using mutants of the protein that will keep the protein in a locked structure. We will make use of super resolution microscopy techniques developed in our lab to detect and measure clustering of the protein in response to the drug.