Journal Article

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

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

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Autoimmune diseases / Biomedical research / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - immunology / CD4 antigen / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - immunology / Clonal deletion / Core Binding Factor Alpha 2 Subunit - genetics / Core Binding Factor Alpha 2 Subunit - immunology / Cytokines / Demethylation / Foxp3 protein / Gene expression / Genotype & phenotype / Homeostasis / Humans / Immunology / Immunoregulation / Inflammation / Inflammation - genetics / Inflammation - immunology / Inflammation - pathology / Integrin beta3 - genetics / Integrin beta3 - immunology / Lymphocytes / Lymphocytes T / Mice / Mice, Knockout / Mucosa / Neutrophils / Proteins / Ribonucleic acid / RNA / Runx1 protein / Sequence analysis / Signal Transduction - genetics / Signal Transduction - immunology / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - pathology / Thymus gland / Transcription factors / Transforming Growth Factor beta1 - genetics / Transforming Growth Factor beta1 - immunology / Transforming Growth Factor beta2 - genetics / Transforming Growth Factor beta2 - immunology / Transforming growth factor-b1