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 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-seq 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 TGFβ1. 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 novel therapeutic options for modulating inflammatory/autoimmune disorders.

The DEL-1–β3 integrin axis promotes regulatory T cell responses during inflammation resolution / Li, Xiaofei; Colamatteo, Alessandra; Kalafati, Lydia; Kajikawa, Tetsuhiro; Wang, Hui; Lim, Jong-Hyung; Bdeir, Khalil; Chung, Kyoung-Jin; Yu, Xiang; Fusco, Clorinda; Porcellini, Antonio; De Simone, Salvatore; Matarese, Giuseppe; Chavakis, Triantafyllos; De Rosa, Veronica; Hajishengallis, George. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 130:12(2020), pp. 6261-6277. [10.1172/jci137530]

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

Alessandra Colamatteo
Co-primo
;
Clorinda Fusco;Antonio Porcellini
Data Curation
;
Giuseppe Matarese;
2020

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 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-seq 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 TGFβ1. 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 novel therapeutic options for modulating inflammatory/autoimmune disorders.
2020
The DEL-1–β3 integrin axis promotes regulatory T cell responses during inflammation resolution / Li, Xiaofei; Colamatteo, Alessandra; Kalafati, Lydia; Kajikawa, Tetsuhiro; Wang, Hui; Lim, Jong-Hyung; Bdeir, Khalil; Chung, Kyoung-Jin; Yu, Xiang; Fusco, Clorinda; Porcellini, Antonio; De Simone, Salvatore; Matarese, Giuseppe; Chavakis, Triantafyllos; De Rosa, Veronica; Hajishengallis, George. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 130:12(2020), pp. 6261-6277. [10.1172/jci137530]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/815858
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