How does polyunsaturated fatty acid biosynthesis regulate T lymphocyte function?

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Polyunsaturated fatty acids (PUFA) play a critical role in immune function by modulating membrane fluidity and as substrates for lipid mediator synthesis. We have shown recently that activation of human peripheral blood mononuclear cells induces PUFA synthesis from essential fatty acids (EFA) via a novel pathway that regulates lymphocyte proliferation. Activation of PUFA synthesis also induced increased transcription of genes involved this pathway which involves altered DNA methylation. This project will investigate how PUFA synthesis regulates T cell proliferation and the effect of age on this process.
The project is comprised of integrated experiments using T cells from healthy men and women aged 18 to 30 years and 65 to 75 years (n = 15/age/sex).
1. We will use siRNA knockdown and stable isotope-labelled EFA to detail the role of specific metabolic reactions in T cell proliferation and their relationship to the time course of T cell activation. We will determine the roles of sex, and exogenous and newly synthesised PUFA in T cell activation and how the novel initial reactions affect regulation of PUFA synthesis by EFA.
2. These methods will also be used to determine whether newly synthesised PUFA are used preferentially for very long chain PUFA (>C24) synthesis and microdomain assembly, and for lipid mediator synthesis.
3. We will use pyrosequencing, transcription factor binding assays and cloning techniques to determine how altered DNA methylation regulates transcription of genes involved in PUFA synthesis during T cell activation.
4. Comparison of findings from these experiments between T cells from young and older subjects will be used to understand the role of PUFA synthesis in ageing-related immune decline.
This project will provide important information about a novel mechanism in the immune response that will have important implications for the dietary supplement and pharmaceutical industries, clinicians, immunologists, nutritionists and biochemists

The primary objective of the proposed project is to generate data that can be translated to develop novel strategies which facilitate improved immunological health across the life course. This project will benefit stakeholders in the commercial and public sectors.
1. UK Government and the Healthcare Sector: The UK Government and the BBSRC recognise that immunological dysfunction related to ageing is a major barrier to maintaining the health and wellbeing of a population characterised by an increased number of older individuals. This represents a growing economic burden in the face of a limited financial resource. Consequently, identification of novel mechanisms that regulate immune cell function that are potential targets for strategies to support immune health, particularly through the diet, are likely to be of considerable benefit both in terms of sustained immune health and lower economic burden. Thus, the findings of this project are likely to be of marked interest to government organisations such as Public Health England and the NHS.
2. The Pharmaceutical Industry: Non-steroidal anti-inflammatory drugs are currently the primary treatment of chronic inflammatory disease. These medicines can produce significant side effects, particularly in older individuals, and hence there is an unmet need for novel anti-inflammatory therapeutics. Conversely, there is a lack of medicines that ameliorate ageing-related immune decline. This project will identify specific processes that mediate the role of PUFA synthesis in T cell activation which are potential targets for the development of novel anti-inflammatory therapeutic agents and of medicines to ameliorate ageing-related immune decline. Furthermore, drugs that inhibit PUFA synthesis may represent a novel means to reduce risk of tissue graft rejection.
3. The Nutraceutical, Dietary Supplement and Food Industries: These commercial organisations will benefit from findings that demonstrate targets for nutritional interventions, and for the formulation of novel functional foods and ingredients to enhance or ameliorate the immune response, and in particular in the area of age-related immune decline.
4. Biotechnology/Biomarkers Industry: This project will develop our published findings which show the activation of PUFA synthesis involves changes in the epigenetic regulation of at least one key gene. Epigenetic biomarkers that predict treatment outcomes are being introduced into clinical practice, and new and established companies, such as Pfizer, have established precision medicine discovery programmes around epigenetic treatments outside cancer. Therefore, the findings of this project will generate commercial opportunities around the role of DNA methylation in regulating the immune response via PUFA synthesis.
5. Veterinary Medicines and Animal Nutrition Industries: Ageing domestic animals and larger species such as horses exhibit similar immune decline and inflammatory diseases to humans. Thus, the findings of this project will generate similar opportunities for companies producing veterinary therapeutics as those that produce medicines for humans. Functional foods for domestic animals are becoming increasingly popular and so the findings of this project are likely to be of marked interest to the animal food industry.
The UK economy. The findings of this project are likely to generate opportunities for several sectors of UK industry through identification and protection intellectual property arising from development of the findings of the project and the development of new products with associated benefits to the UK economy. Translation of the findings in terms of promoting health is also likely to reduce the burden of immunological disease on the UK economy.