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 定义过敏原特异性记忆 Th2 细胞如何发育和发挥作用有可能改变我们的 过敏性哮喘（最常见的哮喘亚型）的治疗方法。 Th2细胞是主要来源 2 型细胞因子 IL-4、IL-5 和 IL-13，在小鼠模型和过敏性人类模型中协调炎症 哮喘。此外，过敏原特异性记忆 Th2 细胞在体内持续存在，导致过敏性炎症反复发作 再次接触过敏原后。我们最近证明组织驻留记忆 Th2 细胞 (Th2 Trm) 肺部持续存在的是转录上不同的记忆 Th2 细胞亚群，对于协调复发至关重要 过敏性气道炎症（Rahimi 等人，实验医学杂志，2020）。确定机制 促进 Th2 Trm 的发育和功能有可能为过敏症产生新的治疗靶点 哮喘。该提案的目的是确定转录因子 PPARg 和脂质穿梭的作用 过敏性哮喘小鼠模型中组织驻留记忆 Th2 细胞的发育、身份和功能。 PPARg 是一种脂质传感器和核受体家族成员，负责协调脂质代谢。相比 与其他 CD4+ T 辅助细胞、效应 Th2 细胞相比，PPARg 的表达明显更高。 PPARg 活动期间 初始 Th2 分化抑制 Th17 细胞程序，并且是 Th2 细胞效应功能所必需的。多元化的 一组多不饱和脂肪酸 (PUFA) 配体，包括花生四烯酸和类二十烷酸，可结合 PPARg 并 促进其转录活性。 PPARg 在 Th2 细胞分化和效应功能中的核心作用 提出了有关 Th2 Trm 发育和功能中 PPARg 活性调节的重要问题： 效应 Th2 细胞中 PPARg 活性的程度是否调节向 Th2 Trm 的分化？鉴于 PUFA PPARg 转录活性需要配体，Th2 Trm 是否依赖于可用于 在回忆反应期间维持和上调 PPARg 转录活性？在本提案中，我们将测试 假设持续的 PPARg 转录活性促进 Th2 Trm 发育。我们进一步 假设 Th2 细胞中需要储存 PUFA 来维持 PPARg 活性并促进 Th2 Trm 发育和功能。具体来说，我们建议 (1) 定义持续性 PPARg 活性在 Th2 Trm 中的作用 (2) 定义脂质储存和穿梭在 Th2 Trm 发育和 功能。我们提出了新的实验方法来测试我们的模型，即持久的 PPARg 活性，即 由细胞内 PUFA 储存维持，促进 Th2 Trm 发育和功能。定义 外周组织印有过敏原特异性的机制，Th2 Trm 具有巨大的潜力 确定包括哮喘在内的过敏性疾病的新治疗靶点。