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

doi:10.1016/j.celrep.2022.110727

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 journal › Article › peer-review

23 Scopus citations

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 Foxp3^loCD25^lo 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 CD39^hi 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 language	English (US)
Article number	110727
Journal	Cell reports
Volume	39
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.110727
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.1016/j.celrep.2022.110727

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Saxena, V., Piao, W., Li, L., Paluskievicz, C., Xiong, Y., Simon, T., Lakhan, R., Brinkman, C. C., Walden, S., Hippen, K. L., WillsonShirkey, M., Lee, Y. S., Wagner, C., Blazar, B. R., & Bromberg, J. S. (2022). Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses. Cell reports, 39(3), Article 110727. https://doi.org/10.1016/j.celrep.2022.110727

Saxena, V, Piao, W, Li, L, Paluskievicz, C, Xiong, Y, Simon, T, Lakhan, R, Brinkman, CC, Walden, S, Hippen, KL, WillsonShirkey, M, Lee, YS, Wagner, C, Blazar, BR & Bromberg, JS 2022, 'Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses', Cell reports, vol. 39, no. 3, 110727. https://doi.org/10.1016/j.celrep.2022.110727

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

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.",

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

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

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: {\textcopyright} 2022 The Authors",

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doi = "10.1016/j.celrep.2022.110727",

language = "English (US)",

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T1 - Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses

AU - Saxena, Vikas

AU - Piao, Wenji

AU - Li, Lushen

AU - Paluskievicz, Christina

AU - Xiong, Yanbao

AU - Simon, Thomas

AU - Lakhan, Ram

AU - Brinkman, C. Colin

AU - Walden, Sarah

AU - Hippen, Keli L.

AU - WillsonShirkey, Marina

AU - Lee, Young S.

AU - Wagner, Chelsea

AU - Blazar, Bruce R.

AU - Bromberg, Jonathan S.

N1 - 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

PY - 2022/4/19

Y1 - 2022/4/19

N2 - 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.

AB - 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.

KW - CP: Immunology

KW - Foxp3

KW - IL-6

KW - Treg

KW - adenosine

KW - allograft

KW - exFoxp3

KW - exTreg

KW - immunity

KW - lymphatic endothelial cells

KW - lymphotoxin

KW - migration

KW - regulatory T cells

KW - transplantation

UR - https://www.scopus.com/pages/publications/85128359194

UR - https://www.scopus.com/pages/publications/85128359194#tab=citedBy

U2 - 10.1016/j.celrep.2022.110727

DO - 10.1016/j.celrep.2022.110727

M3 - Article

C2 - 35443187

AN - SCOPUS:85128359194

SN - 2211-1247

VL - 39

JO - Cell reports

JF - Cell reports

IS - 3

M1 - 110727

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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