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

项目概要： 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）。在那里，免疫系统必须检测病原体并作出反应，同时 防止自身免疫和促进组织修复。组织中的树突状细胞（DC）是细胞增殖的关键细胞， 平衡自身耐受性（防止我们身体组织的破坏）和病原体监测。 本申请的目的是了解树突状细胞如何独特地发育，并在组织中适应，以执行 平衡这些功能。我们最近发现了一种重要的新机制， 这些靶点决定组织中DC如何以影响其功能的方式分化。这项提案的目的是 为了更深入地了解DC生物学沿着这一调控轴，作为干预的关键第一步， 组织DC恢复健康，当失调。这将推动更好的免疫策略， 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现在测试，第一次 时间，我们的骨髓室是如何构建的，以平衡免疫耐受和病原体监测， 屏障组织部位。 完成本项目后，我们将了解组织中的DC如何局部调节以在部位中表现- 具体方式。我们将了解共享的环境感知模式是如何平衡的 针对单个细胞的身份，并针对特定的致病环境进行定制。我们将了解当地的线索 改变树突状细胞的行为，使我们能够在疾病状态下进行测试。我们还将识别DC行为， 可通过局部线索进行修改，从而能够在疾病发病过程中改善对DC的干预， 成功开发DC以改善过继性细胞治疗的模型。这里的见解是基础性的， 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.