Graham Burdge: BBSRC: How does polyunsaturated fatty acid biosynthesis regulate T lymphocyte function?

Polyunsaturated fatty acids (PUFA), also known as Omega-3 and Omega-6 fats, are important for the normal function of immune cells. When immune cells are activated by viruses or bacteria, they use PUFA to make chemical signals that control the immune response. However, older individuals are less able to fight infection or respond to vaccines, and are more likely develop inflammatory disease than their younger counterparts. The processes responsible for this decline in immune function are not understood fully. Therefore, it is important to understand how immune cells obtain PUFA to make the chemical signals that control the immune response and how this is affected by increasing age. Immune cells can obtain PUFA from blood. However, a small number of studies have suggested immune cells may be able to make PUFA from essential fatty acids (EFAs) that are derived from plants and have to be consumed in the diet. We have recently published the findings of a project funded by the BBSRC that investigated the ability of human immune cells to make PUFA from EFAs. We found that the biochemical processes that convert EPAs to PUFA are switched on when immune cells are simulated in culture, a process that mimics the immune response. Our results showed that this involves changes in the control of a group of genes that contain the information to make the enzymes that convert EFAs to PUFA. This change in gene activity involved adaptation of a major gene control process; DNA methylation. We also found that blocking an enzyme involved in PUFA synthesis stopped immune cells proliferating, a critical early stage in the immune response. These results are important because they show for the first time that PUFA synthesis regulates the immune response. The aim of this project is to investigate the processes that link the activation of PUFA synthesis in immune cells to their ability to multiply. We will study T cells, a type of immune cell with a wide range of functions, from two groups of healthy human volunteers. First, we will use T cells from men and women aged 18 to 30 years to carry out detailed characterisation of PUFA synthesis by decreasing, in turn, the activity of each of the genes involved. We will relate this to the ability of T cells to become activated and to proliferate over the time course of the immune response. We will investigate whether PUFA from the environment of the T cells or their ability to convert EPAs to PUFA is the most important source of PUFA for making for chemical signals that regulate the immune response. Two possible processes that could link PUFA synthesis to T cell proliferation will be investigated. Activated T cells form structures on their surface that facilitate the action of chemical signs that drive the immune response. These microdomains contain a specific type of PUFA; very long chain PUFA (VLCPUFA) that control their formation which are derived from PUFA of the type synthesised by activated T cells. We will test whether EFAs are converted to VLCPUFA in activated T cells and, if so, how this is controlled. We will investigate whether PUFA synthesised from EFAs are used to synthesise chemical signals that drive the immune response. We will also determine how DNA methylation controls the activation of genes involved in PUFA synthesis. Finally, T cells from a second group of older men and women (aged 65 to 75 years) will be studied to determine whether the processes that link PUFA synthesis to T cell activation change with increasing age. This area of research is very new, but it has potential to substantially change understanding of the way in which immune cells become activated to mount an immune response. Potential benefits of this knowledge are that it may allow the development of new ways to support optimal immune function, for example through nutrition, and to understand how the effectiveness of the immune response differs between individuals and with increasing age.