The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution
FOXP3+CD4+ regulatory T cells (Tregs) are critical for immune homeostasis and respond to local tissue cues, which control their stability and function. We explored here whether developmental endothelial locus-1 (DEL-1), which, like Tregs, increases during resolution of inflammation, promotes Treg responses. DEL-1 enhanced Treg numbers and function at barrier sites (oral and lung mucosa). The underlying mechanism was dissected using mice lacking DEL-1 or expressing a point mutant thereof, or mice with T cell-specific deletion of the transcription factor RUNX1, identified by RNA sequencing analysis of the DEL-1-induced Treg transcriptome. Specifically, through interaction with αvβ3 integrin, DEL-1 promoted induction of RUNX1-dependent FOXP3 expression and conferred stability of FOXP3 expression upon Treg restimulation in the absence of exogenous TGF-β1. Consistently, DEL-1 enhanced the demethylation of the Treg-specific demethylated region (TSDR) in the mouse Foxp3 gene and the suppressive function of sorted induced Tregs. Similarly, DEL-1 increased RUNX1 and FOXP3 expression in human conventional T cells, promoting their conversion into induced Tregs with increased TSDR demethylation, enhanced stability, and suppressive activity. We thus uncovered a DEL-1/αvβ3/RUNX1 axis that promotes Treg responses at barrier sites and offers therapeutic options for modulating inflammatory/autoimmune disorders.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
The Journal of clinical investigation - 130(2020), 12 vom: 01. Dez., Seite 6261-6277 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Xiaofei [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.02.2021 Date Revised 02.03.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI137530 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM313914125 |
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| 100 | 1 | |a Li, Xiaofei |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 16.02.2021 | ||
| 500 | |a Date Revised 02.03.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a FOXP3+CD4+ regulatory T cells (Tregs) are critical for immune homeostasis and respond to local tissue cues, which control their stability and function. We explored here whether developmental endothelial locus-1 (DEL-1), which, like Tregs, increases during resolution of inflammation, promotes Treg responses. DEL-1 enhanced Treg numbers and function at barrier sites (oral and lung mucosa). The underlying mechanism was dissected using mice lacking DEL-1 or expressing a point mutant thereof, or mice with T cell-specific deletion of the transcription factor RUNX1, identified by RNA sequencing analysis of the DEL-1-induced Treg transcriptome. Specifically, through interaction with αvβ3 integrin, DEL-1 promoted induction of RUNX1-dependent FOXP3 expression and conferred stability of FOXP3 expression upon Treg restimulation in the absence of exogenous TGF-β1. Consistently, DEL-1 enhanced the demethylation of the Treg-specific demethylated region (TSDR) in the mouse Foxp3 gene and the suppressive function of sorted induced Tregs. Similarly, DEL-1 increased RUNX1 and FOXP3 expression in human conventional T cells, promoting their conversion into induced Tregs with increased TSDR demethylation, enhanced stability, and suppressive activity. We thus uncovered a DEL-1/αvβ3/RUNX1 axis that promotes Treg responses at barrier sites and offers therapeutic options for modulating inflammatory/autoimmune disorders | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Adaptive immunity | |
| 650 | 4 | |a Autoimmunity | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a T cells | |
| 650 | 7 | |a Calcium-Binding Proteins |2 NLM | |
| 650 | 7 | |a Cell Adhesion Molecules |2 NLM | |
| 650 | 7 | |a Core Binding Factor Alpha 2 Subunit |2 NLM | |
| 650 | 7 | |a EDIL3 protein, human |2 NLM | |
| 650 | 7 | |a Edil3 protein, mouse |2 NLM | |
| 650 | 7 | |a ITGB3 protein, human |2 NLM | |
| 650 | 7 | |a Integrin beta3 |2 NLM | |
| 650 | 7 | |a RUNX1 protein, human |2 NLM | |
| 650 | 7 | |a Runx1 protein, mouse |2 NLM | |
| 650 | 7 | |a TGFB1 protein, human |2 NLM | |
| 650 | 7 | |a Tgfb2 protein, mouse |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta2 |2 NLM | |
| 700 | 1 | |a Colamatteo, Alessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Kalafati, Lydia |e verfasserin |4 aut | |
| 700 | 1 | |a Kajikawa, Tetsuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Jong-Hyung |e verfasserin |4 aut | |
| 700 | 1 | |a Bdeir, Khalil |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Kyoung-Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Fusco, Clorinda |e verfasserin |4 aut | |
| 700 | 1 | |a Porcellini, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a De Simone, Salvatore |e verfasserin |4 aut | |
| 700 | 1 | |a Matarese, Giuseppe |e verfasserin |4 aut | |
| 700 | 1 | |a Chavakis, Triantafyllos |e verfasserin |4 aut | |
| 700 | 1 | |a De Rosa, Veronica |e verfasserin |4 aut | |
| 700 | 1 | |a Hajishengallis, George |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/JCI137530 |3 Volltext |
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