Lamina Propria Antigen Acquisition Pathways and Outcomes

描述(申请人提供)：肠道免疫系统担负着保护大片暴露在环境中的表面免受潜在病原体侵袭的艰巨任务，同时防止对来自食物和共生微生物群的无害外来抗原的炎症反应。未能适当地保护粘膜可能导致危及生命的肠道感染，而未能控制肠道免疫反应会导致慢性衰弱疾病，如炎症性肠病。最近的研究表明，固有层(LP)DC群体主要由二分(CD103+耐受性或CX3CR1+炎症性)DC组成。这一发现表明，耐受性和免疫性之间的平衡取决于哪种LP DC亚型参与免疫反应。然而，一个关键和缺失的部分是体内对哪些LP DC亚型获得抗原的了解，每个LP DC亚型与T细胞和微生物区系相互作用的解剖和细胞背景，以及这些相互作用对细胞免疫反应特征的影响。这项建议中概述的研究将利用两个实验室的互补专业知识来检查引导致病和非致病抗原输送到LP DC的途径，以及与LP DC亚型获得抗原相关的结果。建议的研究广泛利用尖端的双光子成像技术来分析DC和T细胞在活体小鼠肠道中的运输和功能。这一建议的主要假设是，抗原获得途径通过将抗原递送到特定的LP DC亚型来引导免疫反应。AIM 1中的研究将使用补充的体内和体外方法来检查在未感染和感染状态下向LP DC亚型运送抗原的途径。目的2将评估LP DC亚型在有无感染时的特异性反应。目的3将评估LP DC亚型在肠道固有层局部形成预先存在的T细胞介导的免疫反应的能力。这些研究的完成将提出一种新的范式，证明抗原获得途径是一种受控的近端机制，引导免疫反应向耐受或免疫方向发展。 相关性：肠道免疫系统必须保护我们免受一系列潜在病原体的侵袭，同时避免过度兴奋的反应导致慢性肠道炎症。这项研究将探索一种维持免疫和耐受之间平衡的新机制，并将为改进黏膜疫苗治疗和慢性肠炎提供新的途径。

DESCRIPTION (provided by applicant): The intestinal immune system is charged with the difficult task of protecting a large environmentally exposed surface from potential pathogens, while simultaneously preventing inflammatory responses to innocuous foreign antigen from food and commensal microbiota. Failure to appropriately protect the mucosa can result in life-threatening enteric infection, and failure to control intestinal immune responses results in chronic debilitating disorders such as inflammatory bowel disease. Recent studies determined that the lamina propria (LP) DC population is primarily comprised of dichotomous (CD103+ tolerogenic or CX3CR1 + inflammatory) DCs. This discovery suggests that the balance between tolerance and immunity rests upon which LP DC subtype participates in the immune responses. However a key and missing component is in vivo knowledge of which LP DC subtypes acquire antigen, the anatomical and cellular context of the each LP DC subtypes' interactions with T cells and microbiota, and the outcomes of these interactions on the character of the cellular immune response. The studies outlined in this proposal will harness the complementary expertise of two laboratories to examine the pathways guiding the delivery of pathogenic and non-pathogenic antigens to LP DCs and the outcomes associated with antigen acquisition by LP DC subtypes. The proposed studies make extensive use of cutting-edge two-photon imaging technology to analyze the trafficking and function of DCs and T cells in the intestine of living mice. The overarching hypothesis of this proposal is that antigen acquisition pathways guide immune responses by delivering antigen to specific LP DC subtypes. The studies in Aim 1 will use complimentary in vivo and in vitro approaches to examine the pathways delivering antigen to LP DC subtypes in the uninfected and infected state. Aim 2 will evaluate LP DC subtype specific responses in the presence and absence of infection. Aim 3 will evaluate the capacity of the LP DC subtypes to shape pre- existing T cell mediated immune responses locally within the intestinal lamina propria. Completion of these studies will put forth a new paradigm demonstrating that antigen acquisition pathways are a controlled proximal mechanism guiding immune response toward tolerance or immunity. RELEVANCE: The intestinal immune system must protect us from a wide array of potential pathogens and simultaneously avoid over-exuberant responses resulting in chronic intestinal inflammation. This study will investigate a novel mechanism for maintaining the balance between immunity and tolerance and will offer new avenues to pursue for improved mucosal vaccine therapy and chronic intestinal inflammation.