What is the function of CTLA-4 endocytosis?

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The immune response is a powerful weapons system usually targeted against foreign invaders such as bacteria and viruses. However, control of this weaponary is crucial to avoid collateral damage to our own bodies. As with all systems, faults sometimes occur and it is thought that some diseases such as rheumatoid arthritis or insulin-dependent diabetes, arise when the immune system is not controlled properly. These are known as autoimmune diseases and occur when immune cells, called 'T cells', are triggered inappropriately. We are studying a major 'off switch' on these cells known as CTLA-4, which is extremely important in preventing collateral damage by T cells. However, CTLA-4 is similar to a powerful 'on switch' called CD28 so pressing the right button is critical. Surprisingly CTLA-4 is found inside cells, not on the cell surface like CD28, this makes it difficult to understand how it can work. One idea is that CTLA-4 gets delivered to the cell surface when it's needed, however our experiments show that it doesn't stay at the cell surface but continues to go back inside. We are therefore wondering whether it needs to be inside the cell to work properly. The experiments in this proposal will study the mechanisms used by CTLA-4 to get inside the cell and the bits of CTLA-4 that are needed for this process. Understanding these features will, in the future, allow us to directly test how important internalisation of CTLA-4 is to its function.