Modulation of T cell function through manipulation of fatty acids

我的NSERC计划的总体目标是建立饮食多不饱和脂肪酸(PUFA)调节免疫的机制。T淋巴细胞是免疫系统的关键组成部分，其功能在生命周期中发生变化。当这些细胞受到外部环境(即病原体、饮食抗原、微生物区系)或内部环境(即生理衰老)的挑战时，这些细胞对个体/动物变得重要。为了确定饮食脂肪对T细胞功能的重要性，有必要使用刺激(如有丝分裂原、细菌抗原、激素、细胞因子)代表正常的生理挑战。我们的研究已经证明，饮食中脂肪水平和n-6PUFA和n-3PUFA之间的平衡对T细胞功能起调节作用(有利或消极)。通过使用啮齿动物模型，我们建议确定在整个生命周期中优化T细胞功能所需的PUFA平衡。许多被提出的解释脂肪酸对T细胞功能影响的机制都是从细胞膜脂肪组成或含量的变化开始的。我们还没有确切地知道质膜脂类的变化是如何改变T细胞功能的已经建立，是我的NSERC计划的第二部分。最近发现了质膜中一种独特的微域，称为脂筏。这些微域参与信号过程，指导T细胞的生理功能。在T细胞中，许多重要的受体和信号蛋白要么位于脂筏中，要么在激活后进入脂筏。我们的数据和其他人的数据表明，脂筏中脂肪酸的变化可以改变这些脂筏中重要分子的数量和功能。迄今为止，这方面的研究仅限于细胞系或从患有癌症的动物身上分离出来的细胞。饮食脂肪对健康动物T细胞筏组成的影响尚不清楚。这些研究将提供对脂肪酸在T细胞终身功能中所起作用的基本了解。

The overall goal of my NSERC program is to establish the mechanisms by which dietary polyunsaturated fatty acids (PUFA) modulate immunity.  The T lymphocyte is a key component of the immune system and its function changes over the lifecycle.  These cells become important to the individual/animal when challenged by their external (i.e. pathogens, dietary antigens, microflora) or internal (i.e. physiological aging) environments.  To determine the importance of diet fat on T cell function it becomes necessary to challenge T cells using stimuli (e.g. mitogens, bacterial antigens, hormones, cytokines) representative of 'normal' physiological challenges.  Our research has demonstrated that both the level of fat and the balance between n-6 PUFA and n-3 PUFA in the diet modulate (beneficially or negatively) T cell function.  Using rodent models we propose to determine the balance of PUFA necessary to optimize T cell function across the lifespan.  Many of the mechanisms proposed to explain the effect of fatty acids on T cell function begin with changes in the composition or content of fats in the membrane.  Exactly how a change in plasma membrane lipids alters T cell function has not been established and is the second part of my NSERC program.  Distinct microdomains in the plasma membrane called 'lipid rafts' have recently been identified.  These are involved in signaling processes that direct the physiological function of T cells.  In T cells, many important receptors and signaling proteins are either constitutively located in the lipid rafts or upon activation move into rafts.  Our data and that of others suggest that changes in fatty acids in the raft can change the amount and function of important molecules in these rafts.  To date, studies in this area have been limited to cell lines or to cells isolated from animals with cancer.  The effect of diet fat on T cell raft composition from healthy animals is not known.  These studies will provide a fundamental understanding of the role of fatty acids on the function of T cells across the lifespan.