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

项目摘要 确定过敏原特异的记忆Th2细胞如何发展和功能可能会改变我们的 过敏性哮喘的治疗方法，最常见的哮喘亚型。Th2细胞是主要的来源 2型细胞因子IL-4、IL-5和IL-13在过敏小鼠和人类模型中协调炎症 哮喘。此外，过敏原特异的记忆性Th2细胞在体内持续存在，推动反复发生的过敏性炎症 当过敏原再次暴露时。我们最近发现，组织驻留的Th2细胞(Th2 Trm)可以持久地 在肺中持续存在的是转录上不同的记忆Th2细胞亚群，这对协调循环至关重要 过敏性呼吸道炎症(Rahimi等人，《实验医学杂志》，2020年)。确定机制 促进Th2Trm的发育和功能有可能产生新的过敏治疗靶点 哮喘。这项建议的目的是确定转录因子PPARg和脂质穿梭的作用 在过敏性哮喘小鼠模型中，组织驻留记忆中Th2细胞的发育、特性和功能。 PPARG是一种脂类感受器和核受体家族成员，负责协调脂类代谢。与.相比 其他CD4+T辅助细胞、效应Th2细胞PPARg表达明显升高。PPARG活动期间 初始的Th2分化抑制Th17细胞程序，并且是Th2细胞效应器功能所必需的。一个多样化的 多不饱和脂肪酸(PUFA)的一组配体，包括花生四烯酸和二十烷酸，结合PPARg和 促进其转录活性。PPARg在Th2细胞分化和效应功能中的中心作用 提出了关于Th2 Trm发育和功能中PPARg活性调节的重要问题： PPARg在效应Th2细胞中的活性程度是否调节向Th2Trm的分化？鉴于PUFA PPARg转录活动需要配体，Th2 Trm依赖于可用于 在回忆反应中维持和上调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的发育。我们进一步 假设在Th2细胞中储存多不饱和脂肪酸是维持PPARg活性和促进Th2 Trm所必需的 发展和功能。具体地说，我们建议(1)定义持续的PPARg活性在Th2 Trm中的作用 定义了脂质储存和穿梭在Th2-Trm发育和识别中的作用 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活动 由细胞内储存的多不饱和脂肪酸维持，促进Th2 Trm的发育和功能。定义 外周组织印记过敏原特异性的机制Th2Trm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目标。

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.