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
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
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Research Article Autoimmunity Inflammation

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

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.

Authors

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

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Figure 6

DEL-1 enhances FOXP3 expression in Tregs in a β3 integrin–dependent manner.

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DEL-1 enhances FOXP3 expression in Tregs in a β3 integrin–dependent mann...
(A) FACS plots of CD51 (αv) and CD61 (β3) expression on mouse naive splenic CD4+ T cells. (B and C) Naive splenic CD4+ cells isolated from WT mice were differentiated, or not, into Tregs in medium containing anti-CD3/anti-CD28, TGF-β1 (5 ng/mL), IL-2 (40 ng/mL), and Fc control or DEL-1–Fc (10 μg/mL) in the presence or not of IgG control or anti-αvβ3 antibody (10 μg/mL; added 15 minutes before DEL-1–Fc treatment). Shown are (B) FACS plots and (C) data analysis of the percentage of FOXP3+ cells in CD4+ T cells from the in vitro culture system on day 4 (n = 6 replicates from 2 separate cell isolations). (D and E) Naive splenic CD4+ cells isolated from WT and ItgalKO mice were differentiated, or not, into Tregs in medium containing anti-CD3/anti-CD28, TGF-β1 (5 ng/mL), IL-2 (40 ng/mL), and Fc control or DEL-1–Fc (10 μg/mL). Shown are (D) FACS plots and (E) data analysis of the percentage of FOXP3+ cells in CD4+ T cells from the in vitro culture system on day 4 (n = 6 replicates from 2 separate cell isolations). Data are means ± SD and are pooled from 2 independent experiments. ****P < 0.0001 between indicated groups by 1-way ANOVA with Dunnett’s post hoc test for comparisons with DEL-1–Fc treatment (C) or by 2-tailed Student’s t test (E). NS, not significant.