Role of tissue resident eosinophils in promoting intestinal immunity

描述(申请人提供)：嗜酸性粒细胞是健康胃肠道(GI)的常驻免疫细胞。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了作用，曾经被认为是支持过敏性(Th2)炎症的唯一炎性细胞。事实上，嗜酸性粒细胞是炎症性肠病(IBD)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，但控制其稳态的因素以及胃肠道中嗜酸性粒细胞激活的后果仍然是个谜。胃肠道和相关淋巴组织(GALT)与共生菌群、食物蛋白和环境抗原相对应。这些因素作用于胃肠道组织中的多种天然免疫细胞群，包括启动适应性免疫反应的抗原提呈细胞，以及在组织部位塑造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群显著的常驻细胞。然而，这些驻留细胞的功能以及它们如何受到肠道中存在的主导信号：共生微生物区系和饮食代谢物的调节尚不清楚。我们的初步数据表明，共生微生物区系和必需的饮食营养物质维生素A分别强烈影响嗜酸性粒细胞的激活和存活。肠道固有细胞对食物和微生物信号的感知是启动和维持分泌干扰素-3(Th1)和/或IL-17(Th17)的CD4+T效应反应(TEF)的关键。因此，我们使用嗜酸性粒细胞缺乏的dblGATA小鼠模型的初步数据表明，嗜酸性粒细胞的缺乏会导致肠道内安装TJeff反应的能力受损。这项应用的首要目标是1)确定共生细菌和饮食成分在控制胃肠道嗜酸性粒细胞功能和内稳态中的作用，以及2)确定嗜酸性粒细胞调节胃肠道内效应者免疫反应的机制。更好地了解胃肠道嗜酸性粒细胞将有助于扩大对它们在IBD中的致病作用的了解。这些研究将阐明嗜酸性粒细胞在胃肠道中促进TJeff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.