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- Title
The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution.
- Authors
Xiaofei Li; Colamatteo, Alessandra; Kalafati, Lydia; Kajikawa, Tetsuhiro; Hui Wang; Jong-Hyung Lim; Bdeir, Khalil; Kyoung-Jin Chung; Xiang Yu; Fusco, Clorinda; Porcellini, Antonio; De Simone, Salvatore; Matarese, Giuseppe; Chavakis, Triantafyllos; De Rosa, Veronica; Hajishengallis, George; Li, Xiaofei; Wang, Hui; Lim, Jong-Hyung; Chung, Kyoung-Jin
- 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
SUPPRESSOR cells; INTEGRINS; RNA sequencing; T cells; ORAL mucosa; ANIMAL experimentation; ANTIGENS; CALCIUM-binding proteins; CELL adhesion molecules; CELLULAR signal transduction; COMPARATIVE studies; GROWTH factors; INFLAMMATION; RESEARCH methodology; MEDICAL cooperation; MICE; PROTEINS; RESEARCH; EVALUATION research
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 12, p6261
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI137530