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The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution.

Authors :
Li X
Colamatteo A
Kalafati L
Kajikawa T
Wang H
Lim JH
Bdeir K
Chung KJ
Yu X
Fusco C
Porcellini A
De Simone S
Matarese G
Chavakis T
De Rosa V
Hajishengallis G
Source :
The Journal of clinical investigation [J Clin Invest] 2020 Dec 01; Vol. 130 (12), pp. 6261-6277.
Publication Year :
2020

Abstract

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.

Details

Language :
English
ISSN :
1558-8238
Volume :
130
Issue :
12
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
32817592
Full Text :
https://doi.org/10.1172/JCI137530