Goblet Cells in Intestinal Homeostasis

人体最大的免疫细胞集合位于胃肠道(GI)衬里的单层上皮下。 追踪和监测管腔内容物，其中包括数万亿个微生物、它们的产品和来自 节食。健康的肠道免疫系统的基本基调是耐受性的，尽管暴露在数万亿美元的 微生物及其产品。而这种较强的耐受能力有利于宿主避免炎症 在健康状态下，对无害的饮食和共生抗原的反应，无法抑制这一点 在肠道感染的环境中，耐受性可能是有害的，并不适当地抑制这一点 耐受性可能是肠炎性疾病发病机制的基础。我们建议， 肠道具有关闭耐受性反应和产生炎症反应的能力。在取得巨大进步的同时 已经在阐明特定免疫细胞亚群、细胞因子和其他促进因素的作用方面取得了进展 耐受性或免疫力，肠道免疫系统如何从稳态的耐受性反应切换到 需要时的保护性豁免权仍然是我们理解中的一个重大差距。完成研究 这项提案中概述的将通过确定如何抑制主要途径来填补我们理解中的这一空白 运送管腔物质可激活粘膜的细胞和体液免疫反应。 在这个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 形成后，刺激诱导的缝隙处于稳态，乙酰胆碱(ACh)、刺激物和受体调节 间隙形成，包括管腔微生物区系、细胞因子和表皮生长因子受体(EGFR) 配体，以及胃肠道不同区域的空隙的性质。此外，我们还确定了差距的角色， 当生理上存在时，支持对包括饮食和共生在内的腔物质的耐受性 微生物抗原。此外，我们现在已经组装了用于操作的遗传和药理学模型 并准备剖析抑制GAP在促进保护性/炎症性免疫中的作用 没有肠道感染或肠道微生物区系的明显变化。基于我们之前的研究和 初步观察我们假设，当缝隙在稳定状态形成时，它们作用于印记 免疫系统促进耐受，当小肠(SI)间隙被抑制时，它们参与 促进保护性免疫的一连串事件。为了探索这一假设，我们建议(目标1)定义 LP-APC表型，Th17和TFH细胞的来源，以及反应的持久性 当SI间隙被抑制时发生，(目标2)定义引起B细胞反应的驱动因素和特异性 当SI间隙被抑制时，(目标3)确定SI间隙抑制是否改善结果，以及 肠道感染期间的适当反应。

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.