Dermal Lymphatic Transport and Cutaneous Immune Balance

项目摘要 虽然我们已经建立了大量的知识询问内在白细胞生物学， 广泛的免疫学方法，可以做更多的工作来了解皮肤免疫如何 并将这种理解转化为对抗皮肤免疫反应的疗法， 失衡（自身免疫、慢性炎症、恶性肿瘤）。本提案的目的是阐明 淋巴转运机制，有助于局部炎症和适应性免疫诱导， 为我们如何调节体内免疫反应提供了新的见解。我们已发表的和初步的工作 建立真皮淋巴管系统作为免疫激活（ON）和免疫应答的必要途径。 分辨率（OFF）信号。此外，我们已经证明，真皮淋巴管重塑其间- 内皮连接（称为“拉链”）与病原体传播和免疫功能的后果 诱导这些相同的机制是否在皮肤免疫表型中被激活，以及如何激活 淋巴转运的变化直接影响免疫力仍然是未知的。在本提案中，我们测试了 假设真皮淋巴管表现出积极的，依赖于环境的功能重塑，以协调 皮肤免疫监视这个假设将被测试沿着两个目标：（1）我们将评估串扰 淋巴转运和皮肤间质炎症微环境之间的关系;（2）确定 引流淋巴结中淋巴拉链在适应性免疫激活中的功能意义。到 为了完成这些目标，我们将遗传工具与强大的免疫测定和高分辨率成像结合起来， 解决体内皮肤和引流淋巴结之间的系统级相互作用， 连接淋巴管系统我们认为，淋巴管转运是一个知之甚少，但积极的 皮肤免疫应答决定因素和鉴定特定的分子机制， 调节它们的功能提供了新的治疗机会来调节免疫力。我们的工作不会 这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， 提出了如何管理皮肤免疫反应的新设计原则。这样，我们的工作可以 有助于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靶点 在体内平衡期间和响应于治疗（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).