Grant: Project Grant

In our globally interconnected world, many of us travel to and from work, fly between cities, or even set up residence somewhere entirely different. Establishing residence in a new place involves adapting to new circumstances, and impediments either to our travels or our adaptation to new environments can have a dramatic impact on our lives. T lymphocytes have a similarly cosmopolitan lifestyle within our bodies. The job of T cells in the immune system - to find and stop the replication of a pathogen or cancer cell as quickly as possible - requires them to commute continuously between the blood and secondary lymphoid organs. During infection T cells become able to enter other tissues and even set up residence there, establishing long-term tissue resident memory which protects the body from reinfection. We are only beginning to understand the processes that allow T cells to adapt to their new environmental circumstances and to retain their mobile behaviour even within tissues that are far more dense than the lymphoid organs they came from. From other work on heart cells and connective tissue cells, we know that cells have to protect their genomic material from external forces. The denser the tissue environment a cell finds itself in, the greater the external forces on the cell. Cells adapt by increasing the rigidity of their nucleus in which the DNA of a cell is kept. However, we also know that a very rigid nucleus can prevent the motion of cells through dense tissue. Here, we are investigating how T cells balance the need to protect their DNA from damage, and survive long-term in dense tissues, with their need to move around and search for possible pathogen invasion. If we figure this out, we may be able to selectively target the survival of T cells in tissue where they are doing damage (as is the case in autoimmune disease) or improve their ability to move into dense tissue to fight tumour cells.