Lipid shuttling in memory Th2 cell fate and function in allergic asthma

记忆中的脂质穿梭 过敏性哮喘中 Th2 细胞的命运和功能

• 批准号: 10572303
• 负责人: Rod Amir Rahimi
• 金额: $ 21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572303
• 关键词: Acyl Coenzyme A; Allergens; Allergic Disease; Allergic inflammation; Arachidonic Acids; Asthma; Automobile Driving; Binding; Biology; CD4 Positive T Lymphocytes; Caring; Cell Differentiation process; Cell physiology; Cells; Coenzyme A Ligases; Data; Development; Effector Cell; Eicosanoids; Esterification; Exhibits; Extrinsic asthma; Family member; Genes; Genetic Transcription; Goals; Health Care Costs; Homeostasis; Human; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Journals; Laboratories; Ligands; Lipids; Lung; Maps; Medicine; Memory; Modeling; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Nuclear Receptors; Pathway interactions; Peripheral; Polyunsaturated Fatty Acids; Protein Isoforms; Recurrence; Regulation; Research; Role; Source; Testing; Th2 Cells; Therapeutic; Tissues; Work; allergic airway inflammation; cytokine; environmental allergen; fatty acid metabolism; imprint; in vivo; lipid metabolism; mouse model; new therapeutic target; novel; novel therapeutic intervention; preference; prevent; programs; response; sensor; therapeutic target; transcription factor; transcriptome sequencing

Project Abstract Defining how allergen-specific, memory Th2 cells develop and function has the potential to change our therapeutic approach to allergic asthma, the most common asthma subtype. Th2 cells are a dominant source of type 2 cytokines IL-4, IL-5, and IL-13, which orchestrate inflammation in murine models and humans with allergic asthma. In addition, allergen-specific, memory Th2 cells persist in vivo, driving recurrent allergic inflammation upon allergen re-exposure. We recently showed that tissue-resident memory Th2 cells (Th2 Trm) that durably persist in the lungs are a transcriptionally distinct memory Th2 cell subset that is critical for orchestrating recurrent allergic airway inflammation (Rahimi et al., Journal of Experimental Medicine, 2020). Identifying the mechanisms promoting the development and function of Th2 Trm has the potential to yield new therapeutic targets for allergic asthma. The objective of this proposal is to define the role of the transcription factor PPARg and lipid shuttling in tissue-resident memory Th2 cell development, identity, and function in a murine model of allergic asthma. PPARg is a lipid sensor and nuclear receptor family member, which orchestrates lipid metabolism. Compared to other CD4+ T helper cells, effector Th2 cells exhibit markedly higher expression of PPARg. PPARg activity during initial Th2 differentiation suppresses a Th17 cell program and is required for Th2 cell effector function. A diverse group of polyunsaturated fatty acid (PUFA) ligands, including arachidonic acid and eicosanoids, bind PPARg and promote its transcriptional activity. The central role of PPARg in Th2 cell differentiation and effector function raises important questions regarding the regulation of PPARg activity in Th2 Trm development and function: Does the degree of PPARg activity in effector Th2 cells regulate differentiation into Th2 Trm? Given that PUFA ligands are required for PPARg transcriptional activity, do Th2 Trm depend on PUFA stores that can be used to maintain and upregulate PPARg transcriptional activity during recall responses? In this proposal, we will test the hypothesis that persistent PPARg transcriptional activity promotes Th2 Trm development. We further hypothesize that storage of PUFAs in Th2 cells is required to maintain PPARg activity and promote Th2 Trm development and function. Specifically, we propose to (1) define the role of persistent PPARg activity in Th2 Trm development and identity and (2) define the role of lipid storage and shuttling in Th2 Trm development and function. We propose novel experimental approaches to test our model that persistent PPARg activity, which is maintained by intracellular stores of PUFAs, promotes Th2 Trm development and function. Defining the mechanisms whereby peripheral tissues are imprinted with allergen-specific, Th2 Trm has great potential to identify novel therapeutic targets for allergic diseases including asthma.

项目摘要 确定过敏原特异性记忆性Th 2细胞的发育和功能有可能改变我们的研究。 过敏性哮喘是最常见的哮喘亚型。Th 2细胞是免疫缺陷病毒的主要来源。 2型细胞因子IL-4、IL-5和IL-13，它们在鼠模型和患有过敏性疾病的人中协调炎症。 哮喘此外，过敏原特异性记忆性Th 2细胞在体内持续存在，驱动复发性过敏性炎症 过敏原再次暴露后。我们最近发现，组织驻留记忆Th 2细胞（Th 2 Trm）， 持续存在于肺中的是转录上不同的记忆性Th 2细胞亚群，其对于协调复发性 过敏性气道炎症（Rahimi等，Journal of Experimental Medicine，2020）。确定机制 促进Th 2 Trm的发育和功能有可能产生新的治疗过敏性疾病的靶点。 哮喘该建议的目的是确定转录因子PPARg和脂质穿梭的作用 在变应性哮喘小鼠模型中组织驻留记忆中Th 2细胞发育、身份和功能 PPARg是脂质传感器和核受体家族成员，其协调脂质代谢。相比 其它CD 4 + T辅助细胞、效应Th 2细胞显示出显著更高的PPARg表达。PPARg活性 初始Th 2分化抑制Th 17细胞程序，并且是Th 2细胞效应子功能所必需的。一个多样化 一组多不饱和脂肪酸（PUFA）配体，包括花生四烯酸和类花生酸，结合PPARg， 促进其转录活性。PPARg在Th 2细胞分化和效应子功能中的中心作用 提出了关于Th 2 Trm发育和功能中PPARg活性调节的重要问题： 效应Th 2细胞中PPARg活性的程度是否调节分化为Th 2 Trm？鉴于PUFA 配体是PPARg转录活性所需的，那么Th 2 Trm是否依赖于可用于 维持和上调PPARg转录活性在回忆反应？在本提案中，我们将测试 持续的PPARg转录活性促进Th 2 Trm发育的假说。我们进一步 假设PUFA在Th 2细胞中储存是维持PPARg活性和促进Th 2 Trm所必需的 发展和功能。具体而言，我们建议（1）定义持续PPARg活性在Th 2 Trm中的作用 发展和身份和（2）定义的作用，脂质储存和穿梭在Th 2 Trm的发展， 功能我们提出了新的实验方法来测试我们的模型，持续的PPARg活性，这是 由PUFA的细胞内储存维持，促进Th 2 Trm发育和功能。定义 外周组织被变应原特异性印记的机制，Th 2 Trm具有很大的潜力， 确定包括哮喘在内的过敏性疾病的新治疗靶点。