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

Xiaofei Li, Alessandra Colamatteo, Lydia Kalafati, Tetsuhiro Kajikawa, Hui Wang, Jong Hyung Lim, Khalil Bdeir, Kyoung Jin Chung, Xiang Yu, Clorinda Fusco, Antonio Porcellini, Salvatore de Simone, Giuseppe Matarese, Triantafyllos Chavakis, Veronica de Rosa, George Hajishengallis

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6261-6277
Number of pages17
JournalJournal of Clinical Investigation
Volume130
Issue number12
DOIs
Publication statusPublished - 2020 Dec 1

Fingerprint

Dive into the research topics of 'The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution'. Together they form a unique fingerprint.

Cite this