Role of tissue resident eosinophils in promoting intestinal immunity

描述（由申请方提供）：嗜酸性粒细胞是健康胃肠道（GI）的常驻免疫细胞。一旦被认为是支持过敏性（Th 2）炎症的唯一炎症细胞，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中的作用。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组成部分。尽管嗜酸性粒细胞在进入组织后被激活，但控制其体内平衡的因素和胃肠道中嗜酸性粒细胞激活的后果仍然是个谜。胃肠道及其相关淋巴组织（GALT）与肠道植物群、食物蛋白质和环境抗原处于并列关系。这些因子作用于GI组织中的多种先天免疫细胞群，包括引发适应性免疫应答的抗原呈递细胞和在组织部位形成这些应答的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主要常驻细胞群体。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导信号的调节：肠道微生物群和饮食代谢产物，尚不清楚。我们的初步数据表明，肠道微生物群和必需的膳食营养素，维生素A，强烈影响嗜酸性粒细胞的激活和生存分别。肠道中固有细胞对饮食和微生物线索的感知是引发和维持分泌IFN-3（Th 1）和/或IL-17（Th 17）的CD 4 + T效应子应答（Teff）的关键。因此，我们使用嗜酸性粒细胞缺陷dblGATA小鼠模型的初步数据表明，嗜酸性粒细胞的缺乏导致在肠道中产生Teff应答的能力受损。本申请的总体目标是1）确定肠道细菌和膳食组分在控制GI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GI道中效应免疫应答的机制。更好地了解胃肠道嗜酸性粒细胞将有助于扩大其在IBD的致病作用的知识。这些研究将阐明嗜酸性粒细胞在胃肠道中促进Teff应答的新途径，并可能提供新的治疗靶点，以预防IBD病理学，同时促进粘膜疫苗背景下的有益免疫。

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.