T cells are vital for our response to infection, directly killing infected cells and stimulating other cells of the immune system. Major health problems world-wide involve deregulated T cells, including lymphomas, leukaemias, auto-immune disorders and organ transplant rejection. Damaging deficiencies of T cells are found in old-age. T cells also form a major defence against the accumulation of cancer cells. Current research efforts aim to enhance the T cell response to cancer and furthermore to engineer T cells which target particular tumour cells. To develop therapeutic approaches which target or utilise T cells, it is important that we understand how they function. The aim of the TCAPS project is to understand how T cells respond to activation during an infection or in response to tumours by increasing their size and contents.
It is important for our society to understand how T cells function because of the burden of T cell pathologies. Diseases in which T cell pathologies are the driver occur in the very young, e.g. lymphomas, leukaemias, throughout life, e.g. auto-immune disorders and organ transplant rejection, and in old age, e.g. T cell deficiencies. In addition, the current efforts to engineer T cells which target cancer cells are showing great promise. If we can contribute to efforts to determine how T cells function, we may provide therapeutic opportunities to prevent some pathologies and to treat others.
The objective of this TCAPS project is to determine the contribution of a structure called the mRNA cap to T cell function. Our preliminary data had indicated that regulation of the mRNA cap is critical for the physiology of T cells.
1. We will determine how the mRNA cap is regulated in T cells following activation.
2. We will determine the role of the mRNA cap in naïve T cells which circulate in the blood, surveying for signs of infection.
3. We will determine the role of the mRNA cap in activated T cells, following interaction with infected cells.
At the conclusion of the funding we have published several papers describing the role of the RNA capping enzymes in T cell function. We have determined how the RNA capping enzymes are regulated and used knock-out technology to report the function of the capping enzymes in T cell gene expression and function. Our work indicates that the RNA capping enzymes have very different roles in gene expression and cell function. This leads to the RNA capping enzymes having different functions in immunity, which is interesting from a clinical and drug discovery perspective.
