The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution
Xiaofei Li, … , Veronica De Rosa, George Hajishengallis
Xiaofei Li, … , Veronica De Rosa, George Hajishengallis
Published August 20, 2020
Citation Information: J Clin Invest. 2020;130(12):6261-6277. https://doi.org/10.1172/JCI137530.
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Research Article Autoimmunity Inflammation Article has an altmetric score of 114

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 8

DEL-1 increases FOXP3E2 expression and the suppressive capacity of human iTregs.

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DEL-1 increases FOXP3E2 expression and the suppressive capacity of human...
(A–E) Human Tconv cells were stimulated with anti-CD3/anti-CD28 (0.1 beads/cell) in the presence of DEL-1–Fc or Fc control for 36 hours. (A and C) Representative FACS plots of FOXP3E2+ cells (A) or FOXP3+ cells (C) in CD4+CD25+ cells. (B and D) Percentage (left) and MFI (right) of FOXP3E2+ cells (B) or FOXP3+ cells (D) in CD4+CD25+ cells (n = 17 from 13 [A and B] or 11 [C and D] independent experiments). (E) Relative mRNA expression of RUNX1 (up) (n = 8 from 8 independent experiments) and CBFB (bottom) (n = 7 from 7 independent experiments) measured at 24 hours of Tconv cell stimulation during iTreg generation. (F–I) CFSE-labeled CD4+ T cells were cultured for 72 hours with anti-CD3/anti-CD28 (0.2 beads/cell) alone or in the presence of FACS-isolated DEL-1–Fc–iTregs or Fc control–iTregs (F and G), or long-term-cultured (10 days) DEL-1–Fc–iTregs or Fc control–iTregs (H and I). Representative FACS plots of proliferation of CFSE-labeled CD4+ T cells. Numbers in plots indicate percentage of CFSE dilution in CD4+ T cells cultured alone (top left); numbers above bracketed lines indicate percentage of CFSE dilution in CD4+ T cells cultured with either FACS-isolated DEL-1–Fc–iTregs or Fc control–treated iTregs (F), or long-term-cultured (10 days) DEL-1–Fc–iTregs or Fc control–iTregs (H). Percentage of iTreg suppression in the above conditions (G, n = 29 from 5 independent experiments; I, n = 12 from 4 independent experiments). (J) Methylation of CpG island of FOXP3 CNS2 evaluated in DEL-1–Fc–iTregs or Fc control–iTregs cultured for 10 days in the presence anti-CD3/anti-CD28 (0.1 beads/cell) and IL-2 (50 IU/mL) (n = 6 from 4 independent experiments). (B, D, E, and J) Lines connect paired data for each individual. (G and I) Data are means ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 vs. Fc control (B, D, E, G, I, and J) by 2-tailed, paired Wilcoxon’s test (B, D, E, G, and I) or 2-tailed, paired Student’s t test (J).