Regulation of tissue-resident helper type 2 T cells by fatty acid transport protein 4 (FATP4)

项目总结 蠕虫感染影响着全球10亿人，特别是在贫困国家，导致 诱导2型免疫反应，促进病原体清除。有趣的是，这种类型的免疫 过敏原也会引起过敏反应，并与过敏的发生密切相关 疾病，如哮喘。因此，2型免疫可以起到保护或致病的作用。形成了一种 CD4+辅助型2(Th2)细胞是适应性2型反应的中心特征，因此理解 控制这些细胞的形成和功能的转录和代谢机制有可能 促进开发新的治疗干预措施，以促进其保护功能和/或抑制 与之相关的致病反应。越来越多的证据表明，脂类代谢对 在Th2细胞中起着至关重要的作用，但确切的机制仍不清楚。为了填补这一知识空白，我们 建议评估具有酰基辅酶A合成酶(ACS)的脂肪酸运输蛋白4(FATP4)的作用 促进游离脂肪酸的活性，用于脂肪酸氧化和复杂的脂肪合成。我们的 初步数据表明，FATP4是一种新的Th2细胞调节蛋白，因为该蛋白在T细胞中的缺失导致 肠系膜脂肪组织和结肠组织中Th2细胞基底数增加。最引人注目的是， T细胞或IL-5分泌细胞中FATP4的缺失导致对蠕虫感染的抵抗力增强，因此 建立FATP4作为Th2细胞的新调节因子。我们假设，未能促进脂肪酸 FATP4缺陷的Th2细胞的激活导致游离脂肪酸的增加，这可以促进 配体激活的转录因子，如PPAR-g，以抑制Th2反应。来检验我们的假设并 充分了解FATP4在组织驻留Th2细胞中的作用，在目标1中，我们将检测其表型和 在蠕虫感染和食物过敏模型中删除该酶的功能后果。 这种方法将使我们能够检查这种酶在保护性和致病性环境中的作用。在……里面 目的2，我们将利用脂质组学和全基因组测序分析来评估细胞内的变化 脂肪含量、转录和染色质可及性。对收集的数据进行交互分析将允许 US以确定FATP4调节Th2细胞的分子机制。总的来说，这项工作的结果是 将使我们深入了解脂肪酸代谢在Th2细胞中的作用，并有可能有助于 对2型免疫介导的疾病的新治疗方法的开发。

PROJECT SUMMARY Helminth infections, which affect a billion people worldwide, especially in underprivileged counties, lead to the induction of type 2 immune response to promote clearance of the pathogens. Interestingly, this type of immune response is also induced in response to allergens and has been strongly linked to the development of allergic disorders, such as asthma. Thus, type 2 immunity can play a protective or pathogenic role. The formation of CD4+ helper type 2 (Th2) cells is a central feature of adaptive type 2 response, therefore understanding the transcriptional and metabolic mechanisms that govern the formation and function of these cells has the potential to facilitate the development of new therapeutic interventions to promote their protective functions and/or inhibit pathogenic responses with which they are associated. There is growing evidence that lipid metabolism plays a crucial role in Th2 cells, but the exact mechanisms are still poorly understood. To fill this gap in knowledge, we propose to assess the role of fatty acid transport protein 4 (FATP4), which possesses acyl-CoA synthetase (ACS) activity that promotes the activation of free fatty acids for fatty acid oxidation and complex lipid synthesis. Our preliminary data indicate that FATP4 is a novel regulator of Th2 cells as deletion of this protein in T cells resulted in an increase in the basal number of Th2 cells in the mesenteric adipose tissue and colon. Most strikingly, deletion of FATP4 in T cells or IL-5-secreting cells led to increased resistance to a helminth infection, thus establishing FATP4 as a novel regulator of Th2 cells. We hypothesize that the failure to promote fatty acid activation in FATP4-deficient Th2 cells leads to an increase of free fatty acids that can promote the activity of ligand-activated transcription factors, such as PPAR-g to restrain Th2 responses. To test our hypothesis and to fully understand the role of FATP4 in tissue-resident Th2 cells, in Aim 1, we will examine the phenotypic and functional consequences of deleting this enzyme in response to helminth infection and in a food allergy model. This approach will allow us to examine the role of this enzyme in a both protective and pathogenic setting. In Aim 2, we will utilize lipidomics and genome-wide sequencing assays to assess the changes in the intracellular lipid content, transcription, and chromatin accessibility. The interactive analysis of the collected data will allow us to define the molecular mechanism by which FATP4 regulates Th2 cells. Collectively, the result of this work will provide us with an insight into the role of fatty acid metabolism in Th2 cells and has the potential to contribute to the development of novel treatments for illnesses mediated by type 2 immunity.