TNF family members for lymph angiogenesis and lymph node hypertrophy

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DESCRIPTION (provided by applicant): 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 LT2R 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 LT2R 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-1 production. We will also investigate how LIGHT and TNF-1 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. PUBLIC HEALTH RELEVANCE: Lay summary Understanding the process of LN hypertrophy and defining the parameters regulating leukocyte immune cell migration will help us identify ways to therapeutically manipulate immune responses for better protection against infection, cancer and other immune-mediated diseases. Our study will reveal the cellular and molecular mechanisms underlying LN hypertrophy. This knowledge will be of utmost importance to provide new and novel strategies to more effectively modulate immune responses for the protection against infection and cancer.