A myeloid sentinel that secretes leukotrienes to activate type 2 immunity

项目摘要/摘要 感知是任何免疫反应的必经的第一步，导致激活早期的先天信号， 直接随后的适应性免疫。对细菌、病毒和真菌的感知已有详细的定义， 但我们对寄生蠕虫(蠕虫)和过敏原是如何被检测到从而引发“2型”的理解 仍然缺乏豁免权。第二组先天淋巴样细胞(ILC2s)是最早被激活的免疫细胞之一 一种2型反应，但它们不直接感觉到外来激动剂。相反，主机派生的信号来自 周围组织激活ILC2。其中一个这样的信号是半胱氨酰白三烯(CysLT)，它需要 激活肠道和呼吸道的ILC2s。随着时间的推移，ILC2会被效应器和记忆Th2细胞所取代 获得类似ILC2的转录和表观遗传表型。这些Th2细胞可被IL-33激活 没有抗原，但cysLT在驱动这种与生俱来的功能中的作用尚未得到测试。在肠道中， CysLT必须由上皮绒毛细胞产生，但绒毛细胞对2型呼吸道来说很大程度上是必不可少的 发炎。在这项建议的目标1中，我们试图确定激活呼吸道的CysLTs的细胞来源。 蠕虫感染时的ILC2s。在目标2中，我们测试了CysLT信号在Th2效应和细胞内的内在作用 存储单元。我们的研究承诺揭示组织特异性的启动和维持2型的范例 免疫，从而为治疗干预提供了新的策略。

Project Summary/Abstract Sensing is the obligate first step of any immune response, resulting in activation of early innate signals that direct subsequent adaptive immunity. The sensing of bacteria, viruses, and fungi has been defined in detail, but our understanding of how parasitic worms (helminths) and allergens are detected to initiate “type 2” immunity remains lacking. Group 2 innate lymphoid cells (ILC2s) are among the first immune cells activated in a type 2 response, but they do not directly sense foreign agonists. Instead, host-derived signals from the surrounding tissues activate ILC2s. One such signal is cysteinyl leukotrienes (cysLT), which are required to activate both intestinal and airway ILC2s. Over time, ILC2s are replaced by effector and memory Th2 cells that acquire an ILC2-like transcriptional and epigenetic phenotype. These Th2 cells can be activated by IL-33 in the absence of antigen, but a role for cysLT in driving this innate-like function has not been tested. In the intestine, cysLTs must be produced by epithelial tuft cells, but tuft cells are largely dispensable for airway type 2 inflammation. In Aim 1 of this proposal, we seek to identify the cellular source of cysLTs that activate airway ILC2s during helminth infection. In Aim 2, we test the cell intrinsic role of cysLT signaling in Th2 effector and memory cells. Our studies promise to reveal tissue-specific paradigms for initiation and maintenance of type 2 immunity, thereby suggesting new strategies for therapeutic intervention.