Interrogating unique DC adaptations to tissue to promote barrier immunity and tolerance

项目总结： 免疫系统面对外部世界，并遇到病原体，包括屏障组织中的病毒(例如 皮肤、肺和肠道)。在那里，免疫系统必须检测并对病原体做出反应，同时 预防自身免疫，促进组织修复。组织中的树突状细胞(DC)是 平衡自我耐受(防止破坏我们的身体组织)和病原体监测。 这个应用程序的目标是了解DC如何独特地发育并在组织中适应以执行 并平衡这些功能。我们最近发现了一种重要的新机制和一种新的分子 决定组织中DC如何以影响其功能的方式分化的靶点。这项提议的目标是 为了沿着这个调控轴更深入地了解DC生物学，作为干预的关键第一步 当失调时，组织DC可恢复健康。这将推进更好的免疫策略，如组织 DC是疫苗、病毒和癌症免疫所必需的。这个应用程序使我们能够第一次测试 时间，我们的髓细胞室是如何设计来平衡免疫耐受和病原体监测的 屏障组织部位。 在这个项目完成后，我们将了解组织中的DC是如何在局部条件下在某个部位表现的- 具体的方式。我们将了解共享的环境感知模式是如何平衡的 针对单个细胞身份，并针对特定的致病背景量身定做。我们会了解当地的线索是如何 修改DC的行为，让我们在疾病状态下进行测试。我们还将确定DC行为 可通过局部提示进行修改，从而能够在疾病发病过程中改进对DC的干预，并更好地 成功发展DC的模式，以改进采用细胞治疗。这里的见解是基础性的，填补了 关键的知识差距，代表着促进人类健康所需的基础科学进步。

Project summary: The immune system faces the external world and encounters pathogens, including viruses in barrier tissues (e.g. skin, lung, and gut). There the immune system must detect and respond to pathogens, while simultaneously preventing autoimmunity and promoting tissue repair. Dendritic cells (DC) in tissue are the key cells which balance self-tolerance (preventing destruction of our bodies tissues) with pathogen surveillance. The goal of this application is to understand how DCs develop uniquely and are adapted in the tissue to perform and balance these functions. We have recently identified an important new mechanism, and a new molecular target that dictates how DC in tissues differentiate in ways that impact their function. The goal of this proposal is to gain a deeper understanding of DC biology along this regulatory axis, as a critical first step to intervene upon tissue DC to restore health, when dysregulated. This would advance better immunization strategies as tissue DCs are necessary for vaccine, viral, and cancer immunity. This application enables us to now test, for the first time, how our myeloid compartment is architected to balance immune tolerance and pathogen surveillance in barrier tissue sites. Upon completion of this project we will understand how DCs in tissue are locally conditioned to behave in a site- specific manner. We will gain an appreciation of how shared environmental sensing patterns are balanced against individual cell identities, and tailored to specific pathogenic contexts. We will understand how local cues modify the behavior of DCs, positioning us to test this in disease states. We will also identify DC behaviors that are modifiable by local cues, enabling improved intervention on DC during disease pathogenesis and a better model for successful DC development to improve adoptive cell therapy. The insights here are foundational, fill a critical knowledge gap, and represent basic science advances needed to advance human health.