Dermal Lymphatic Transport and Cutaneous Immune Balance

项目总结 虽然我们已经建立了大量的知识来询问内在的白细胞生物学来告知 广泛的免疫治疗方法，可以做更多的工作来了解皮肤免疫 反应是受调节的，并将这种理解转化为对抗皮肤免疫的疗法 失衡(自身免疫、慢性炎症、恶性肿瘤)。这项提议的目的是澄清 淋巴运输促进局部炎症和适应性免疫诱导的机制 为我们如何调整体内的免疫反应提供了新的见解。我们发表的和初步的工作 建立皮肤淋巴管系统作为免疫激活(ON)和免疫的必要途径 分辨率(关)信号。此外，我们还证明了皮肤淋巴管重塑了它们之间的关系。 内皮连接(称为拉链)对病原体传播和免疫有功能影响 归纳法。这些相同的机制是否在皮肤免疫表型中被激活，以及如何被激活 淋巴运输的变化直接影响免疫力仍不清楚。在本提案中，我们测试 皮肤淋巴管呈现活跃的、上下文相关的功能重塑以协调的假说 皮肤免疫监测。这一假设将沿着两个目标进行检验：(1)我们将评估串扰 淋巴运输与皮肤间质炎症微环境之间的关系；(2)确定 淋巴拉链在引流淋巴结适应性免疫激活中的功能意义。至 为了实现这些目标，我们将基因工具与强大的免疫学分析和高分辨率成像相结合，以 在体内解决皮肤和引流淋巴结之间的系统水平的相互作用作为 连接淋巴管系统。我们认为淋巴管运输是一种知之甚少但却很活跃的 皮肤免疫反应决定因素和识别特定的分子机制 调节它们的功能提供了新的治疗机会来调节免疫力的高低。我们的工作不会 只是发展我们对淋巴运输及其对免疫的贡献的生理学理解，而不是进一步 为如何管理皮肤的免疫反应提出新的设计原则。这样，我们的工作就可以 帮助为临床疫苗开发和免疫治疗提供信息，并可能确定维持耐受性的目标 在动态平衡期间和对治疗的反应(例如免疫检查点阻断)。

PROJECT SUMMARY While we have established a tremendous amount of knowledge interrogating intrinsic leukocyte biology to inform a breadth of immunotherapeutic approaches, more can be done to understand how cutaneous immune responses are regulated and to translate that understanding into therapies that combat cutaneous immune imbalance (autoimmunity, chronic inflammation, malignancies). The goal of this proposal is to elucidate mechanisms of lymphatic transport that contribute to local inflammation and adaptive immune induction to provide novel insight into how we may tune immune responses in vivo. Our published and preliminary work establishes the dermal lymphatic vasculature as a necessary route for both immune activation (ON) and immune resolution (OFF) signals. Further, we have demonstrated that dermal lymphatic vessels remodel their inter- endothelial junctions (termed ‘zippering’) with functional consequences for pathogen dissemination and immune induction. Whether these same mechanisms are activated across cutaneous immune phenotypes and how changes in lymphatic transport directly impact immunity remains unknown. In this proposal we test the hypothesis that dermal lymphatic vessels exhibit active, context-dependent functional remodeling to coordinate cutaneous immune surveillance. This hypothesis will be tested along two aims: (1) we will evaluate the crosstalk between lymphatic transport and the interstitial, inflammatory microenvironment in skin; (2) determine the functional significance of lymphatic zippering in adaptive immune activation in draining lymph nodes. To complete these aims, we couple genetic tools with robust immunological assays and high-resolution imaging to resolve the systems-level interactions between skin and draining lymph nodes in vivo as a function of the connecting lymphatic vasculature. We propose that lymphatic vessel transport is a poorly understood but active determinant of cutaneous immune responses and that identification of specific molecular mechanisms that regulate their function provides novel therapeutic opportunities to tune immunity up or down. Our work will not only develop our physiological understanding of lymphatic transport and its contribution to immunity but further suggest novel design principles for how to manage immunological reactions in skin. In this way our work may help to inform clinical vaccine development and immunotherapy and may identify targets to maintain tolerance during homeostasis and in response to therapy (e.g. immune checkpoint blockade).