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The DEL-1–β3 integrin axis promotes regulatory T cell responses during inflammation resolution
- Source :
- J Clin Invest, Journal of Clinical Investigation
- 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.
- Subjects :
- 0301 basic medicine
Regulatory T cell
Adaptive immunity
T cells
Inflammation
chemical and pharmacologic phenomena
Autoimmunity
medicine.disease_cause
T-Lymphocytes, Regulatory
Transcriptome
Transforming Growth Factor beta1
03 medical and health sciences
chemistry.chemical_compound
Mice
Transforming Growth Factor beta2
0302 clinical medicine
medicine
Animals
Humans
Transcription factor
Mice, Knockout
Chemistry
Calcium-Binding Proteins
Integrin beta3
FOXP3
hemic and immune systems
General Medicine
Acquired immune system
Cell biology
030104 developmental biology
medicine.anatomical_structure
RUNX1
030220 oncology & carcinogenesis
Core Binding Factor Alpha 2 Subunit
medicine.symptom
Cell Adhesion Molecules
Signal Transduction
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- J Clin Invest, Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....a44a45d9807d53a39cddc2d14cc31a4b