Mechanobiological control of immune cell activation (360G-Wellcome-212343_Z_18_Z)

Biomedical sciences increasingly recognise the importance of mechanobiology in health and disease. While most mechanisms of the immune response are adequately explained by cell-biology, biochemistry, and genetics, many of its features profoundly depend on biomechanical aspects. One such scenario involves the ability of immune cells to differently respond to antigens with similar binding affinities, highlighting additional parameters needed to fully explain antigen discrimination. Emerging evidence indicates that immune cells dynamically adjust their biomechanics to facilitate this process. The principle goal of this project is to uncover how biomechanical feedback modifies the mechanobiology of activating T-lymphocytes by altering the dynamic assembly and organisation of actin structures, hence adjusting the sensitivity of antigen recognition. With the advent of immune checkpoint blockade and T-cell re-direction there has never been more interest in controlling lymphocyte responses, and biomechanical signal integration has received relatively little attention despite the consistent failure of biochemical parameters to account for T-cell discrimination of different antigens. To address this research project, I will lead a team to apply new state-of-the-art force probing technology coupled with high-speed super-resolution microscopies, overcoming the limitations of previous approaches to generate a breakthrough understanding of mechanobiology in immune cell activation.