Goblet Cells in Intestinal Homeostasis

人体最大的免疫细胞集合位于胃肠道（GI）的单层上皮细胞之下 跟踪和监测管腔内容物，其中包括数万亿的微生物，它们的产物和物质， 节食健康的肠道免疫系统的基础张力是致耐受性的，尽管暴露于数万亿的抗氧化剂。 微生物及其产物而这种强大的致耐受能力有利于宿主避免炎症反应， 在健康状态下对无害的饮食和唾液抗原的反应，无法抑制这种反应， 致耐受能力在肠道感染的情况下可能是有害的， 致耐受能力可能是肠道炎性疾病发病机制的基础。我们建议 肠道具有关闭致耐受性应答并产生炎症应答的能力。虽然取得了很大进展 已经在阐明特定免疫细胞亚群、细胞因子和其他促进免疫的因素的作用方面取得了进展。 耐受性或免疫性，肠道免疫系统如何从稳态的耐受性应答转换为 在我们的理解中，需要时的保护性免疫仍然是一个重大差距。研究完成 在这个建议中概述的将通过确定如何抑制一个主要途径来填补我们理解中的这一空白 递送管腔物质激活粘膜处的细胞和体液免疫应答。 在该奖项的前几个周期中，我们已经确定了杯状细胞相关抗原通道（GAP）是如何在细胞内表达的。 形成，刺激诱导GAP在稳态，乙酰胆碱（ACh），刺激和受体调节 GAP形成，包括管腔微生物群、细胞因子和表皮生长因子受体（EGFR） 配体，以及胃肠道各个区域中GAP的性质。此外，我们还确定了GAP的作用， 当生理上存在时，支持对管腔物质（包括饮食和药物）的耐受性 微生物抗原此外，我们现在已经组装了基因和药理学模型， 并准备解剖GAP抑制在促进保护性/炎症免疫中的作用， 没有肠道感染或肠道微生物群的明显变化。根据我们之前的研究， 初步观察，我们假设，当差距形成在稳定状态，他们的行为，以印 当小肠（SI）GAP被抑制时，它们参与免疫系统的免疫耐受性， 促进保护性免疫的级联事件。为了探索这一假设，我们建议（目标1）定义 LP-APC的表型、Th17和TFH细胞扩增的起源，以及LP-APC的应答的持久性， 当SI GAP被抑制时发生，（目的2）定义了B细胞应答的驱动因素和特异性 当SI GAP被抑制时，以及（目标3）确定SI GAP抑制是否改善了结果，以及是否需要用于 肠道感染时的适当反应。

The body's largest collection of immune cells underlies the single layer epithelium lining the gastrointestinal (GI) tract and monitors the luminal contents, which includes trillions of microbes, their products, and substances from the diet. The basal tone of the healthy gut immune system is tolerogenic, despite being exposed to trillions of microbes and their products. While this strong tolerogenic capacity is beneficial to the host to avoid inflammatory responses to innocuous dietary and commensal antigens in the healthy state, the inability to dampen this tolerogenic capacity could be detrimental in the setting of enteric infection and inappropriately dampening this tolerogenic capacity could underlie the pathogenesis of intestinal inflammatory diseases. We propose that the gut has a capacity to turn off tolerogenic responses and generate inflammatory responses. While great progress has been made in elucidating the role of specific immune cell subsets, cytokines, and other factors promoting tolerance or immunity, how the gut immune system switches from tolerogenic responses in the steady-state to protective immunity when needed remains a significant gap in our understanding. Completion of the studies outlined in this proposal will fill this void in our understanding by identifying how inhibiting a major pathway delivering luminal substances activates cellular and humoral immune responses at the mucosa. In prior cycles of this award we have identified how goblet cell associated antigen passages (GAPs) are formed, the stimulus inducing GAPs in the steady-state, acetylcholine (ACh), the stimuli and receptors regulating GAP formation, including the luminal microbiota, cytokines, and epidermal growth factor receptor (EGFR) ligands, and the properties of GAPs in various regions of the GI tract. Further we have identified roles for GAPs, when physiologically present, in supporting tolerance to luminal substances including dietary and commensal microbial antigens. Moreover, we have now assembled genetic and pharmacologic models for the manipulation of GAPs and are poised to dissect the role of GAP inhibition in promoting protective/inflammatory immunity in the absence of enteric infection or overt changes in the gut microbiota. Based upon our prior studies and preliminary observations we hypothesize that when GAPs form in the steady state, they act to imprint the immune system to promote tolerance and when small intestine (SI) GAPs are inhibited they participate in a cascade of events promoting protective immunity. To explore this hypothesis we propose to (Aim 1) define the LP-APCs phenotypes, the origins of Th17 and TFH cells that expand, and the durability of the response that occurs when SI GAPs are inhibited, (Aim 2) define the drivers and specificities of the B cell responses arising when SI GAPs are inhibited and (Aim 3) determine if SI GAP inhibition improves outcomes and is required for appropriate responses during enteric infection.