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    Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses.

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    Author
    Saxena, Vikas
    Piao, Wenji
    Li, Lushen
    Paluskievicz, Christina
    Xiong, Yanbao
    Simon, Thomas
    Lakhan, Ram
    Brinkman, C Colin
    Walden, Sarah
    Hippen, Keli L
    WillsonShirkey, Marina
    Lee, Young S
    Wagner, Chelsea
    Blazar, Bruce R
    Bromberg, Jonathan S
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    Date
    2022-04-19
    Journal
    Cell Reports
    Publisher
    Elsevier
    Type
    Article
    
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    See at
    https://doi.org/10.1016/j.celrep.2022.110727
    Abstract
    Regulatory T cell (Treg) lymphatic migration is required for resolving inflammation and prolonging allograft survival. Focusing on Treg interactions with lymphatic endothelial cells (LECs), we dissect mechanisms and functional consequences of Treg transendothelial migration (TEM). Using three genetic mouse models of pancreatic islet transplantation, we show that Treg lymphotoxin (LT) αβ and LEC LTβ receptor (LTβR) signaling are required for efficient Treg migration and suppressive function to prolong allograft survival. Inhibition of LT signaling increases Treg conversion to Foxp3loCD25lo exTregs. In a transwell-based model of TEM across polarized LECs, non-migrated Tregs become exTregs. Such conversion is regulated by LTβR nuclear factor κB (NF-κB) signaling in LECs, which increases interleukin-6 (IL-6) production and drives exTreg conversion. Migrating Tregs are ectonucleotidase CD39hi and resist exTreg conversion in an adenosine-receptor-2A-dependent fashion. Human Tregs migrating across human LECs behave similarly. These molecular interactions can be targeted for therapeutic manipulation of immunity and suppression.
    Rights/Terms
    Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
    Keyword
    CP: Immunology
    Foxp3
    IL-6
    Treg
    adenosine
    allograft
    exFoxp3
    exTreg
    immunity
    lymphatic endothelial cells
    lymphotoxin
    migration
    regulatory T cells
    transplantation
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    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18679
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.celrep.2022.110727
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