Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses.
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Author
Saxena, VikasPiao, 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
Date
2022-04-19Journal
Cell ReportsPublisher
ElsevierType
Article
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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: ImmunologyFoxp3
IL-6
Treg
adenosine
allograft
exFoxp3
exTreg
immunity
lymphatic endothelial cells
lymphotoxin
migration
regulatory T cells
transplantation
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http://hdl.handle.net/10713/18679ae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2022.110727
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