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

脂肪酸转运蛋白 4 (FATP4) 对组织驻留辅助型 2 T 细胞的调节

• 批准号: 10677098
• 负责人: Anna K. Kania
• 金额: $ 6.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677098
• 关键词: Acyl Coenzyme A; Adipose tissue; Affect; Allergens; Allergic; Animals; Asthma; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Cell secretion; Cells; Cellular Assay; Chromatin; Coenzyme A Ligases; Colon; Complex; County; Data; Development; Disease; Disease Progression; Enzymes; Epidermis; Failure; Fatty Acids; Fibroblasts; Flow Cytometry; Food Hypersensitivity; Frequencies; GATA3 gene; Gene Expression; Genes; Genetic Transcription; Greater sac of peritoneum; Hypersensitivity; Immune; Immune response; Immunity; Immunophenotyping; Impairment; Infection; Interleukin-4; Interleukin-5; Intestines; Knock-out; Knowledge; Lead; Ligands; Link; Lipids; Mediating; Mesentery; Metabolic; Modeling; Molecular; Mouse Strains; Mus; Nematoda; Nematospiroides dubius; Nonesterified Fatty Acids; PPAR gamma; Parasites; Pathogenicity; Persons; Phenotype; Play; Population; Proteins; Public Health; Publishing; Regulation; Resistance; Resistance to infection; Role; Severities; Skin; Small Intestines; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Th2 Cells; Therapeutic; Tissues; Work; allergic response; cytokine; design; fatty acid metabolism; fatty acid oxidation; fatty acid-transport protein; genome-wide; helminth infection; human model; insight; lipid metabolism; lipidomics; mesenteric lymph node; metabolomics; mouse model; next generation sequencing; novel; novel therapeutic intervention; oxidation; pathogen; response; restraint; transcription factor; transcriptome

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.

项目摘要 在全世界影响十亿人口，尤其是贫困县的蠕虫感染导致 2型免疫反应的诱导以促进病原体的清除。有趣的是，这种免疫力 响应也响应过敏原而引起，并且与过敏性的发展密切相关 疾病，例如哮喘。因此，2型免疫力可以发挥保护性或致病作用。形成 CD4+ 2型辅助辅助器细胞是自适应2型反应的核心特征，因此了解 控制这些细胞的形成和功能的转录和代谢机制具有潜力 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质代谢发挥了 在Th2细胞中的关键作用，但确切的机制仍然很少了解。为了填补知识的差距，我们 建议评估具有酰基辅酶A合成酶（ACS）的脂肪酸转运蛋白4（FATP4）的作用 促进游离脂肪酸激活脂肪酸氧化和复杂脂质合成的活性。我们的 初步数据表明FATP4是Th2细胞的新调节剂，因为该蛋白在T细胞中的缺失导致了该蛋白 肠系膜脂肪组织和结肠中Th2细胞的基础数量增加。最引人注目的是 T细胞或IL-5分泌细胞中FATP4的删除导致对蠕虫感染的抗性增加 将FATP4建立为Th2细胞的新型调节剂。我们假设未能促进脂肪酸 FATP4缺陷型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，例如PPAR-G，以限制Th2响应。检验我们的假设和 充分了解FATP4在组织居住的Th2细胞中的作用，在AIM 1中，我们将检查表型和 响应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该酶在保护性和致病环境中的作用。在 AIM 2，我们将利用脂质组学和全基因组测序测定法来评估细胞内的变化 脂质含量，转录和染色质可及性。收集到的数据的互动分析将允许 美国定义了FATP4调节Th2细胞的分子机制。总体而言，这项工作的结果 将为我们提供对脂肪酸代谢在Th2细胞中作用的见解，并有可能贡献 开发由2型免疫介导的疾病的新型治疗方法。