Antigen Recognition at Intestinal Epithelial Interphases

描述(申请人提供)：肠道免疫系统与肠道微生物区系共存，这种相互作用的结果由(树突状细胞)树突状细胞的功能特性决定，树突状细胞通过支持抗原采样、病原体识别和天然宿主防御而在免疫反应中发挥关键作用。越来越多的证据表明，肠道微生物区系的抗原识别和处理失调可能是炎症性肠病(IBD)的常见疾病机制，这一相互作用的重要性得到了强调。拟议的研究旨在确定DC亚群的作用，DC亚群在正常和炎症的肠黏膜中负责调节这些关键的宿主防御功能。 我们证明，肠粘膜含有广泛的髓样来源的DC系统，该系统不限于Payer‘s Patches(PP)，而是分布于整个小肠和大肠的固有层。该系统由不同的DC亚群组成，通过Fractalkine(CX3CL1)受体CX3CR1的表达来区分。这些DC代表了一种在肠道中识别抗原的新途径，通过它们能够将过程延伸到肠腔，以便直接采样肠道微生物区系。到目前为止，我们的研究表明，CX3CR1在调节肠道DC的腔抗原采集、病原体摄取和宿主防御方面具有重要的功能意义。 该项目将测试CX3CR1表达调节髓系来源的DC系统的总体假设，该系统构成地填充在固有层中，便于持续监测肠道微生物区系，并充当粘膜防御的第一道线。这一假说将通过旨在综合确定CX3CR1调节粘膜免疫系统中DC亚群的发育和功能的机制的研究来验证。本提案具体目标的协调和互补策略将为肠道DC的反应提供洞察力，以平衡自我反应性和病原体特异性适应性免疫反应的调节与针对微生物感染的即时保护性防御。

DESCRIPTION (provided by applicant): The intestinal immune system coexist in intimate association with the intestinal microbiota and the outcome of this interaction is determined by the functional properties of (dendritic cells) DC, which have a key role for immune responses by enabling antigen sampling, pathogen recognition and innate host defenses. The importance of this interaction is underscored by mounting evidence that dysregulation of antigen recognition and processing of the intestinal microbiota may be a common disease mechanism in Inflammatory Bowel Diseases (IBD). The proposed studies are directed to determine the role of DC subsets, which are responsible in mediating these critical host defense functions in the context of normal and inflamed intestinal mucosa. We demonstrate that the intestinal mucosa contains an extensive myeloid derived DC system, which is not restricted to Payer's patches (PP) but populates the entire lamina propria of the small and large intestine. This system is comprised of distinct DC subsets distinguished by the expression of the fractalkine (CX3CL1) receptor, CX3CR1. These DC represent a novel pathway for antigen recognition in the intestine, through their ability to extent processes into the intestinal lumen for the direct sampling of the intestinal microbiota. Our studies thus far show functional significance of CX3CR1 in the regulation of luminal antigen sampling, pathogen uptake and host defense by intestinal DC. This project will test the overall hypothesis that CX3CR1 expression regulates a myeloid derived DC system, which constitutively populates the lamina propria facilitating constant monitoring of the intestinal microbiota and serving as a 'first line' of mucosal defense. This hypothesis will be tested through studies aimed to determine in aggregate the mechanisms by which CX3CR1 regulates the development and function of DC subsets in the mucosal immune system. The coordinated and complementary strategies of the specific aims of this proposal will provide insights into the responses of intestinal DC required to balance the regulation of self-reactive and pathogen specific adaptive immune responses with an immediate protective defense against microbial infections.