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

Vikas Saxena, Wenji Piao, Lushen Li, Christina Paluskievicz, Yanbao Xiong, Thomas Simon, Ram Lakhan, C. Colin Brinkman, Sarah Walden, Keli L. Hippen, Marina WillsonShirkey, Young S. Lee, Chelsea Wagner, Bruce R. Blazar, Jonathan S. Bromberg

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number110727
JournalCell reports
Volume39
Issue number3
DOIs
StatePublished - Apr 19 2022

Bibliographical note

Funding Information:
This work was supported by NIH grants 1R01AI114496 , 1P01AI153003 , and R37AI062765 (J.S.B.) and the Maryland Living Legacy Foundation (J.S.B. and W.P.). We are thankful to the staff of the Malaria Research Center at University of Maryland School of Medicine for help in pyrosequencing. We are also thankful to University of Maryland Greenebaum Comprehensive Cancer Center Flow Cytometry Shared Service for cell sorting.

Funding Information:
This work was supported by NIH grants 1R01AI114496, 1P01AI153003, and R37AI062765 (J.S.B.) and the Maryland Living Legacy Foundation (J.S.B. and W.P.). We are thankful to the staff of the Malaria Research Center at University of Maryland School of Medicine for help in pyrosequencing. We are also thankful to University of Maryland Greenebaum Comprehensive Cancer Center Flow Cytometry Shared Service for cell sorting. Conceptualization, V.S. and J.S.B.; methodology, V.S. and J.S.B.; investigation, V.S. W.P. L.L. C.P. Y.X. T.S. R.L. C.C.B. S.W. K.L.H. M.W. Y.S.L. C.W. B.R.B. and J.S.B.; writing, V.S. and J.S.B.; funding acquisition, J.S.B.; resources, V.S. and J.S.B.; supervision, J.S.B. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Authors

Keywords

  • CP: Immunology
  • Foxp3
  • IL-6
  • Treg
  • adenosine
  • allograft
  • exFoxp3
  • exTreg
  • immunity
  • lymphatic endothelial cells
  • lymphotoxin
  • migration
  • regulatory T cells
  • transplantation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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