TNF family members for lymph angiogenesis and lymph node hypertrophy

外周组织中淋巴管和高内皮微静脉的快速发育 导致炎症/疫苗接种期间引流淋巴结(LN)肥大，但分子 LN肥大的调控机制尚不清楚。淋巴毒素(LT)、肿瘤坏死因子、肥大细胞 树突状细胞在接种后或接种期间都参与了LN肥大的调节。 发炎。出乎意料但有趣的是，我们的初步研究揭示了光 (TNFRSF14)，它与LT共享LT？R受体，也是LN肥大所必需的，因为光 KO小鼠在CFA免疫后未出现LN肥大。在使用小鼠进行的初步研究中 模型，我们还确定朗格汉斯细胞、特化真皮树突状细胞和肥大细胞 对于CFA免疫后的LN肥大是必不可少的。我们假设来自LC的光 与膜LT协同调节LV/HEV的激活和增殖以及 免疫损伤后，白细胞迁移至LN，导致LN肥大。 具体地说，我们将探索朗格汉斯细胞发出的光是否对激活肥大细胞是必不可少的 LT？R信号产生炎症介质，促进LV和HEV的快速发展。我们还将 研究B细胞是否是LN肥大所需的膜LT的来源，以及LT如何 与光配合，放大HEV激活，促进LV/HEV内皮细胞生长。在AIM 1，我们将研究光如何在细胞水平上介导LN肥大，通过确定哪些细胞 在LN肥大过程中需要产生光并对光做出反应。我们将测试朗格汉斯细胞 是LN肥大必不可少的发光细胞。我们还将识别光反应细胞， 根据我们的初步数据，我们推测它是肥大细胞。在目标2中，我们将研究光线如何 在分子水平上介导LN肥大。我们将定义分子机制，通过它 LIGH通过肥大细胞活化和肿瘤坏死因子-β直接和/或间接调节LV/HEV内皮细胞 制作。我们还将研究LIGH和TNF-β是如何在早期协调LV/HEV激活的 疫苗接种阶段。在目标3中，我们将测试B细胞是否是LN肥大LT的主要来源和 确定LN肥大过程中光和LT是否以及如何协同作用。在目标4中，我们将确定 光介导的LN肥大在肿瘤免疫中的作用。我们将定义 光介导的(淋巴)血管生成在抗肿瘤T细胞启动中的作用及探讨其治疗潜力 用Ad-light作为佐剂促进(淋巴)血管生成和DC/T细胞迁移 肿瘤免疫疗法。总之，我们的研究将阐明推动LN的细胞和分子机制 炎症反应中的肥大，以及光介导的DC迁移的作用 在开发功能性抗肿瘤免疫反应和更有效的疫苗方面。 1

Rapid development of lymphatic vessels (LV) and high endothelial venules (HEV) in peripheral tissues leads to hypertrophy of draining lymph nodes (LN) during inflammation/vaccination, but the molecular mechanism regulating LN hypertrophy is poorly understood. Lymphotoxin (LT), TNF, mast cells, and dendritic cells have all been implicated in the regulation of LN hypertrophy after vaccination or during inflammation. Unexpectedly but intriguingly, our preliminary studies have revealed that LIGHT (TNFRSF14), which shares the LT¿R receptor with LT, is also required for LN hypertrophy, since LIGHT KO mice fail to undergo LN hypertrophy after CFA immunization. In preliminary studies using mouse models, we have also determined that Langerhans' cells, specialized dermal DCs, and mast cells are essential for LN hypertrophy after CFA immunization. We hypothesize that LIGHT from LC coordinates with membrane LT to regulate LV/HEV activation and proliferation as well as leukocyte migration into the LN in response to immune insult, leading to LN hypertrophy. Specifically, we will explore whether LIGHT from Langerhans' cells is essential to activate mast cells via LT¿R signaling to produce inflammatory mediators for rapid development of LVs and HEVs. We will also study whether B cells are the source of membrane LT required for LN hypertrophy, and how LT coordinates with LIGHT to amplify the HEV activation and promote LV/HEV endothelial cell growth. In aim 1, we will study how LIGHT mediates LN hypertrophy on a cellular level by determining which cells are required to produce and respond to LIGHT during LN hypertrophy. We will test whether Langerhans' cells are the essential LIGHT-producing cells for LN hypertrophy. We will also identify LIGHT-responding cells, which we hypothesize to be mast cells based on our preliminary data. In aim 2, we will study how LIGHT mediates LN hypertrophy on a molecular level. We will define the molecular mechanisms by which LIGHT regulates LV/HEV endothelial cells directly and/or indirectly through mast cell activation and TNF-¿ production. We will also investigate how LIGHT and TNF-¿ coordinates for LV/HEV activation at the early stage of vaccination. In aim 3, we will test whether B cells are major source of LT for LN hypertrophy and determine whether and how LIGHT and LT cooperate during LN hypertrophy. In aim 4, we will determine the role of LIGHT-mediated LN hypertrophy in tumor immunity. We will define the role of LIGHT-mediated (lymph)angiogenesis in antitumor T cell priming and explore the therapeutic potential of using Ad-LIGHT as an adjuvant to enhance (lymph)angiogenesis and DC/T cell migration for improved tumor immunotherapy. In sum, our study will elucidate cellular and molecular mechanisms that drive LN hypertrophy in response to inflammation, as well as examining the role of LIGHT-mediated DC migration in the development of functional anti-tumor immune responses and more effective vaccines. 1