Role of tissue resident eosinophils in promoting intestinal immunity

描述（由申请人提供）：嗜酸性粒细胞是健康胃肠道的常驻免疫细胞。曾经被认为是唯一支持过敏性（Th2）炎症的炎症细胞，最近的证据表明嗜酸性粒细胞在支持更广泛的炎症反应和维持代谢稳态方面发挥作用。事实上，嗜酸性粒细胞是炎症性肠病（IBD）中活动性和非活动性病变的一个组成部分。虽然嗜酸性粒细胞在进入组织后被激活，但控制其稳态的因素和胃肠道中嗜酸性粒细胞激活的后果仍然是谜。胃肠道及其相关淋巴组织（GALT）与共生菌群、食物蛋白和环境抗原相关联。这些因素作用于胃肠道组织中的多种先天免疫细胞群，包括抗原提呈细胞，它们引发适应性免疫反应，以及在组织部位形成这些反应结果的常驻辅助细胞。嗜酸性粒细胞是小肠和大肠固有层内的一个突出的常驻细胞群。然而，这些常驻细胞的功能以及它们如何受到肠道中存在的主要信号（共生微生物群和膳食代谢物）的调节尚不清楚。我们的初步数据表明，共生菌群和必需的膳食营养素维生素A分别强烈影响嗜酸性粒细胞的活化和存活。肠道内固有细胞对饮食和微生物信号的感知是启动和维持CD4+ T效应反应（Teff）分泌IFN-3 （Th1）和/或IL-17 （Th17）的关键。因此，我们使用嗜酸性粒细胞缺乏的双gata小鼠模型的初步数据表明，缺乏嗜酸性粒细胞会导致肠道中Teff反应的能力受损。本应用程序的总体目标是：1)确定共生菌和膳食成分在控制胃肠道嗜酸性粒细胞功能和稳态中的作用；2)确定嗜酸性粒细胞调节胃肠道效应免疫反应的机制。更好地了解胃肠道嗜酸性粒细胞将有助于扩大对其在IBD中的致病作用的认识。这些研究将阐明嗜酸性粒细胞促进胃肠道Teff反应的新途径，并可能提供新的治疗靶点，既可以预防IBD的病理，也可以在粘膜疫苗的背景下促进有益的免疫。

DESCRIPTION (provided by applicant): Eosinophils are resident immune cells of the healthy gastrointestinal (GI) tract. Once considered exclusively inflammatory cells that support allergic (Th2) inflammation, recent evidence demonstrates a role for eosinophils in supporting a more broad set of inflammatory responses and in the maintenance of metabolic homeostasis. Indeed, eosinophils are a component of both active and inactive lesions in inflammatory bowel disease (IBD). Although eosinophils become activated upon entry into tissues, the factors controlling their homeostasis and the consequences of eosinophil activation in the GI tract remain enigmatic. The GI tract and associated lymphoid tissues (GALT) are in apposition with commensal flora, food protein and environmental antigen. These factors act on multiple innate immune cell populations in the GI tissue including antigen presenting cells, which prime adaptive immune responses, and resident accessory cells which shape the outcome of these responses at tissue sites. Eosinophils are a prominent population of resident cells within lamina propria of the small and large intestine. However, the function of these resident cells and how they are regulated by the dominant signals present in the gut: the commensal microbiota and the dietary metabolites, is unclear. Our preliminary data suggest that commensal microbiota and the essential dietary nutrient, Vitamin A, strongly influence eosinophil activation and survival respectively. Sensing of dietary and microbial cues in the gut by resident innate cells is key to priming and sustaining CD4+ T effector responses (Teff) secreting IFN-3 (Th1) and/or IL-17 (Th17). Accordingly, our preliminary data using the eosinophil deficient dblGATA mouse model, demonstrate that the absence of eosinophils results in impaired ability to mount Teff responses in the gut. The overarching goal of this application is to 1) define the role of commensal bacteria and dietary components in controlling GI eosinophil function and homeostasis and 2) define the mechanisms by which eosinophils are regulating effector immune responses in the GI tract. Better understanding GI eosinophils will help expand knowledge of their pathogenic role in IBD. These studies will elucidate novel pathways of eosinophils in contributing to Teff responses in the GI tract and may provide novel therapeutic targets to both prevent pathology in IBD, but also to promote beneficial immunity in the context of mucosal vaccines.