How does polyunsaturated fatty acid biosynthesis regulate T lymphocyte function?

多不饱和脂肪酸（PUFA），也被称为Omega-3和Omega-6脂肪，对免疫细胞的正常功能很重要。当免疫细胞被病毒或细菌激活时，它们使用PUFA产生控制免疫反应的化学信号。然而，老年人抵抗感染或对疫苗的反应能力较差，而且比年轻人更容易患上炎症性疾病。导致免疫功能下降的过程尚不完全清楚。因此，了解免疫细胞如何获得PUFA来制造控制免疫反应的化学信号以及这是如何受到年龄增长的影响是很重要的。免疫细胞可以从血液中获取多聚脂肪酸。然而，少数研究表明，免疫细胞可能能够从植物中提取的必需脂肪酸（EFAs）中制造PUFA，而这些必需脂肪酸必须从饮食中摄入。我们最近发表了一个由BBSRC资助的项目的研究结果，该项目研究了人类免疫细胞从EFAs中制造PUFA的能力。我们发现，当在培养中模拟免疫细胞时，将EPAs转化为PUFA的生化过程被开启，这是一个模拟免疫反应的过程。我们的研究结果表明，这涉及到一组基因控制的变化，这些基因包含制造将EFAs转化为PUFA的酶的信息。这种基因活性的变化涉及一个主要基因控制过程的适应；DNA甲基化。我们还发现，阻断一种参与PUFA合成的酶可以阻止免疫细胞增殖，这是免疫反应的关键早期阶段。这些结果很重要，因为它们首次表明PUFA合成调节免疫反应。该项目的目的是研究免疫细胞中PUFA合成的激活与其繁殖能力之间的联系过程。我们将研究T细胞，一种具有广泛功能的免疫细胞，来自两组健康的人类志愿者。首先，我们将使用年龄在18至30岁之间的男性和女性的T细胞，通过依次降低每个相关基因的活性，来详细描述PUFA合成的特征。我们将把这与T细胞在免疫反应过程中被激活和增殖的能力联系起来。我们将研究来自T细胞环境的PUFA或它们将EPAs转化为PUFA的能力是否是产生调节免疫反应的化学信号的最重要的PUFA来源。将研究两种可能将PUFA合成与T细胞增殖联系起来的过程。激活的T细胞在其表面形成结构，促进驱动免疫反应的化学信号的作用。这些微结构域包含一种特定类型的PUFA；非常长的链PUFA (VLCPUFA)，控制它们的形成，这些PUFA来源于被激活的T细胞合成的PUFA类型。我们将测试EFAs是否在活化的T细胞中转化为VLCPUFA，如果是的话，是如何控制的。我们将研究从EFAs合成的PUFA是否用于合成驱动免疫反应的化学信号。我们还将确定DNA甲基化如何控制参与PUFA合成的基因的激活。最后，将研究来自第二组老年男性和女性（65至75岁）的T细胞，以确定将PUFA合成与T细胞激活联系起来的过程是否会随着年龄的增长而改变。这一研究领域是非常新的，但它有可能从本质上改变对免疫细胞被激活以产生免疫反应的方式的理解。这种知识的潜在好处是，它可能允许开发新的方法来支持最佳的免疫功能，例如通过营养，并了解免疫反应的有效性在个体之间和年龄的增长中是如何不同的。

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.